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<label text="Lysosome"> <bbox w="45.0" h="10.0" x="1160.5" y="1573.5"/> </label> <bbox w="583.0" h="383.0" x="724.0" y="1322.0"/> </glyph> <glyph class="compartment" id="emtc_emtc_c24_emtc_emtc_ca24"> <label text="Endosome"> <bbox w="45.0" h="10.0" x="1326.25" y="1367.5"/> </label> <bbox w="430.5" h="440.0" x="1247.75" y="1039.0"/> </glyph> <glyph class="compartment" id="emtc_emtc_c33_emtc_emtc_ca33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 The C-ter of SARA interacts TGFBR1 and TGFBR2 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:12154066 Small GTPases such as Rab5 catalyse movement of activated receptor complexes to early endosomal compartments Here, the complex encounter SARA: a phospholipid-bound carrier SARA presents Smads to the TGFBR1 PMID:22710166 PMID:11013220 The ligand bound activated receptor complex is internalized via endocytosis PMID:19050695 2 pathways of receptor complex endocytosis: clathrin-mediated or caveolae-mediated Through the clathrin pathway, activated ligan-receptor complex are brought into early endosomes which are enriched with scaffold proteins such as SARA. PMID:12717440 PMID:12724770 Clathrin-dependent internalization into endosome, where the Smad2 anchor SARA is enriched, promotes TGFB signalling. Raft-caveolar internalization pathway contains the Smad7-Smurf2 bound receptor and is required for rapid receptor turnover. Thus, segregation of TGF-b receptors into distinct endocytic compartments regulates Smad activation and receptor turnover PMID:11792802 SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. References_end</body> </html> </notes> <label text="Early Endosome"> <bbox w="75.0" h="10.0" x="5783.0" y="3876.0"/> </label> <bbox w="220.0" h="500.0" x="5797.0" y="3863.5"/> </glyph> <glyph class="compartment" id="emtc_emtc_c40_emtc_emtc_ca40"> <label text="Extracellular space"> <bbox w="100.0" h="10.0" x="381.5" y="92.5"/> </label> <bbox w="6128.0" h="6929.0" x="346.0" y="80.0"/> </glyph> <glyph class="compartment" id="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Cytoplasmic Proteasome"> <bbox w="115.0" h="10.0" x="3538.6978" y="1311.1058"/> </label> <bbox w="320.0" h="160.0" x="3458.0" y="1264.5"/> </glyph> <glyph class="compartment" id="emtc_emtc_c41_emtc_emtc_ca41" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <label text="Nuclear Proteasome"> <bbox w="95.0" h="10.0" x="4236.4688" y="2204.2104"/> </label> <bbox w="163.0" h="100.0" x="4236.0" y="2185.5"/> </glyph> <glyph class="compartment" id="c11_ca11"> <label text="Clathrin coated vesicle"> <bbox w="120.0" h="10.0" x="859.5" y="1216.2499"/> </label> <bbox w="560.5" h="337.0" x="636.75" y="942.0"/> </glyph> <glyph class="compartment" id="c13_ca13"> <label text="Caveolin vesicle"> <bbox w="85.0" h="10.0" x="832.5478" y="866.9768"/> </label> <bbox w="460.0" h="250.0" x="654.0" y="654.0"/> </glyph> <glyph class="compartment" id="c12_ca12"> <label text="Macropinosome"> <bbox w="70.0" h="10.0" x="836.0442" y="554.024"/> </label> <bbox w="450.0" h="230.0" x="662.0" y="361.0"/> </glyph> <glyph class="compartment" id="c14_ca14"> <label text="Neighbouring Cell"> <bbox w="90.0" h="10.0" x="200.5" y="6027.5"/> </label> <bbox w="369.0" h="6026.0" x="166.0" y="38.0"/> </glyph> <glyph class="compartment" id="emtc_emtc_c6_emtc_emtc_ca6" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <label text="Cytosol"> <bbox w="40.0" h="10.0" x="658.5" y="197.5"/> </label> <bbox w="5594.0" h="5883.5" x="608.0" y="182.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s223_emtc_emtc_sa704" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 21 HUGO:MIR21, HGNC:31586, ENTREZ:406991, GENECARDS:GC17P057918 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR21"/> <bbox w="80.0" h="20.0" x="3228.5" y="5021.666"/> <glyph class="unit of information" id="_12b27588-5bb1-4205-b634-0d1f215d2db1"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="5016.666"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1334_emtc_emtc_sa700" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 106b HUGO:MIR106B, HGNC:31495, ENTREZ:406900, GENECARDS:GC07M099695 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth PMID:19726885 PMID:22286770 PMID:21386132 The miR-17 family consists of 3 paralogous polycistronic clusters on different chromosomes: miR-17/92 (miR-17, miR-18a, miR-19a, miR-20a, miR-19b- 1, and miR-92a-1), miR-106b/25 (miR-106b, miR-93, and miR-25) and miR-106a/363 (miR-106a, miR-18b, miR-20b, miR-19b-2, miR-92a-2, and miR-363). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR106B_25*"/> <bbox w="114.0" h="19.0" x="3194.5" y="4471.166"/> <glyph class="unit of information" id="_16633aba-a444-498e-a99b-b178ce837071"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3236.5" y="4466.166"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1337_emtc_emtc_sa705" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 205 HUGO:MIR205, HGNC:31583, ENTREZ:406988, GENECARDS:GC01P209605 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR205"/> <bbox w="80.0" h="20.0" x="3228.5" y="4593.5"/> <glyph class="unit of information" id="_eebe4da1-dc42-4a65-8540-bc1745daffa3"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="4588.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1338_emtc_emtc_sa706" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 192 HUGO:MIR192, HGNC:31562, ENTREZ:406967, GENECARDS:GC11M064676 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR192"/> <bbox w="80.0" h="20.0" x="3228.5" y="4715.834"/> <glyph class="unit of information" id="_31764b9b-3628-49ed-b3d1-b29f6574e3a7"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="4710.834"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1341_emtc_emtc_sa709" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 34b HUGO:MIR34B, HGNC:31636, ENTREZ:407041, GENECARDS:GC11P111383 microRNA 34c HUGO:MIR34C, HGNC:31637, ENTREZ:407042, GENECARDS:GC11P111384 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 PMID:21909380 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34*"/> <bbox w="80.0" h="20.0" x="3228.5" y="5144.0"/> <glyph class="unit of information" id="_812400de-694c-4af0-b389-1ce2407d1eb7"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="5139.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1342_emtc_emtc_sa710" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 microRNA 429 HUGO:MIR429, HGNC:13784, ENTREZ:554210, GENECARDS:GC01P001109 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21336307 PMID:22370643 Regulation of BMI1 and JAG1 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200*"/> <bbox w="81.625" h="20.0" x="3226.875" y="4410.0"/> <glyph class="unit of information" id="_28fcb196-65b7-4e93-af15-7cab87a18cc4"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3252.6875" y="4405.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1343_emtc_emtc_sa712" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 1-1 HUGO:MIR1-1, HGNC:31499, ENTREZ:406904, GENECARDS:GC20P061153 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR1-1"/> <bbox w="80.0" h="20.0" x="3228.5" y="4960.5"/> <glyph class="unit of information" id="_502227ee-f2d9-444a-9681-ff3570a56530"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="4955.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1344_emtc_emtc_sa714" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 31 HUGO:MIR31, HGNC:31630, ENTREZ:407035, GENECARDS:GC09M021507 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR31"/> <bbox w="80.0" h="20.0" x="3228.5" y="4899.334"/> <glyph class="unit of information" id="_c4a44618-cc8e-4ff9-b7ea-f4c7b8e7be9a"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="4894.334"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1347_emtc_emtc_sa717" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 449a HUGO:MIR449A, HGNC:27645, ENTREZ:554213, GENECARDS:GC05M054466 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR449A"/> <bbox w="80.0" h="20.0" x="3228.5" y="4839.166"/> <glyph class="unit of information" id="_bf20aac1-4105-4236-bb4f-e8c834c088ff"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="4834.166"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1351_emtc_emtc_sa721" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 34a HUGO:MIR34A, HGNC:31635, ENTREZ:407040, GENECARDS:GC01M009211 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A"/> <bbox w="80.0" h="20.0" x="3228.5" y="5082.834"/> <glyph class="unit of information" id="_574d2939-3d2d-4c22-aeda-d1161d76c601"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.5" y="5077.834"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1424_emtc_emtc_sa789" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21081489 miR-200b targets Ets-1 and is down-regulated by Hypoxia to induce Angiogenic response of Endothelial cells Overexpression of Est-1 reverses the phenotypic changes caused by miR-200b, supporting that miR-200b inhibits the angiogenic response via silencing of Est-1 PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200B"/> <bbox w="86.0" h="18.0" x="3490.0" y="4472.166"/> <glyph class="unit of information" id="_83d5204d-9002-406c-9192-77fb8b2d43a1"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3518.0" y="4467.166"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3692_emtc_emtc_sa1827" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200A"/> <bbox w="78.0" h="18.0" x="3490.0" y="4411.0"/> <glyph class="unit of information" id="_7616cb75-7e4a-4f51-a46d-d82a13af8d6f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3514.0" y="4406.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3693_emtc_emtc_sa1828" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR141"/> <bbox w="83.0" h="18.0" x="3490.0" y="4594.5"/> <glyph class="unit of information" id="_c11b2e2a-9eaf-460a-b5a2-49a1017a97ea"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3516.5" y="4589.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3694_emtc_emtc_sa1829" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200C"/> <bbox w="84.0" h="17.0" x="3490.0" y="4533.334"/> <glyph class="unit of information" id="_b09a484e-a4a2-4c64-8410-27b63c2387fe"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3517.0" y="4528.334"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3699_emtc_emtc_sa1831" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 429 HUGO:MIR429, HGNC:13784, ENTREZ:554210, GENECARDS:GC01P001109 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR429"/> <bbox w="82.0" h="20.0" x="3491.0" y="4655.666"/> <glyph class="unit of information" id="_530a4b49-3f51-4d6a-865a-1811a886c523"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3517.0" y="4650.666"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3715_emtc_emtc_sa1845" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 183 HUGO:MIR183, HGNC:31554, ENTREZ:406959, GENECARDS:GC07M129416 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR183"/> <bbox w="81.0" h="19.0" x="3227.5" y="4654.666"/> <glyph class="unit of information" id="_3410aef5-977c-4ee4-bf9a-ea11baca0384"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3253.0" y="4649.666"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3743_emtc_emtc_sa1863" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 30E HUGO:MIR30E, HGNC:31629, ENTREZ:407034, GENECARDS:GC01P041220 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="82.0" h="20.0" x="3226.5" y="4777.0"/> <glyph class="unit of information" id="_13a49a7b-4c91-4135-9e0c-79446b2dabbf"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3252.5" y="4772.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3750_emtc_emtc_sa1868" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 93 HUGO:MIR93, HGNC:31645, ENTREZ:407050, GENECARDS:GC07M099720 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22286770 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR93"/> <bbox w="84.0" h="21.0" x="3492.0" y="4778.0"/> <glyph class="unit of information" id="_b7982193-ccd2-4e77-91d4-0e370f84c0f8"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3519.0" y="4773.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3751_emtc_emtc_sa1869" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 106b HUGO:MIR106B, HGNC:31495, ENTREZ:406900, GENECARDS:GC07M099695 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19726885 PMID:22286770 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR106B"/> <bbox w="84.0" h="20.0" x="3493.0" y="4716.834"/> <glyph class="unit of information" id="_e5f73c1d-5178-4ebb-8649-86a1d71a1ea0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3520.0" y="4711.834"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3752_emtc_emtc_sa1870" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 25 HUGO:MIR25, HGNC:31609, ENTREZ:407014, GENECARDS:GC07M099691 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22286770 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR25"/> <bbox w="87.0" h="21.0" x="3501.0" y="4839.166"/> <glyph class="unit of information" id="_7106b7a7-59bb-447f-a382-0aff6744d5df"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3529.5" y="4834.166"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2373_sa2071" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:24335145 β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="miR96"/> <bbox w="90.0" h="25.0" x="3227.0" y="5196.5"/> <glyph class="unit of information" id="_8293058b-b039-4273-9428-f89e9c24d44b"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3257.0" y="5191.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2374_sa2072" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:24335145 β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="miR182"/> <bbox w="90.0" h="25.0" x="3237.0" y="5246.5"/> <glyph class="unit of information" id="_d47dc3a0-8056-4841-b028-9178b96c215f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3267.0" y="5241.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s153_emtc_emtc_csa5" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CRB3:PALS1* Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8365569 PMID:18005931 PMID:11740559 PMID:11740560 CRB3 and PALS1* in the same pathway PALS1* binds to CRB3 via its PDZ domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3/PALS1*"/> <bbox w="80.0" h="54.0" x="6157.0" y="3080.5"/> <glyph class="macromolecule" id="emtc_emtc_s178_emtc_emtc_sa153"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:22881460 CRB3 is the only transmembrane protein among apical polarity regulators PMID:2344615 Link between Drosophila apical membrane Crb and epithelia organization References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: crumbs homolog 3 (Drosophila) HUGO:CRB3, HGNC:20237, ENTREZ:92359, UNIPROT:Q9BUF7, GENECARDS:GC19P006414 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:22881460 CRB3 is the only transmembrane protein among apical polarity regulators PMID:2344615 Link between Drosophila apical membrane Crb and epithelia organization References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3"/> <bbox w="43.0" h="17.0" x="6176.0" y="3081.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s161_emtc_emtc_sa154"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:17486063 References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: membrane protein, palmitoylated 5 (MAGUK p55 subfamily member 5) HUGO:MPP5, HGNC:18669, ENTREZ:64398, UNIPROT:Q8NI35, GENECARDS:GC14P067708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11927608 PALS1 is an adapter linking Crumbs and PATJ* PALS1 contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate kinase domain Interaction PALS1 -LIN7 via the C-terminal L27 domain of PALS1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PALS1*"/> <bbox w="52.0" h="16.0" x="6171.0" y="3099.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s188_emtc_emtc_csa9" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LIN10*:LIN2*:LIN7C Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN2*/LIN7C/LIN10*"/> <bbox w="153.75" h="39.5" x="4951.125" y="3275.75"/> <glyph class="macromolecule" id="emtc_emtc_s189_emtc_emtc_sa177"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: chromosome 16 open reading frame 70 HUGO:C16orf70, HGNC:29564, ENTREZ:80262, UNIPROT:Q9BSU1, GENECARDS:GC16P067143 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN10*"/> <bbox w="51.0" h="16.0" x="4952.875" y="3278.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s191_emtc_emtc_sa175"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: calcium/calmodulin-dependent serine protein kinase (MAGUK family) HUGO:CASK, HGNC:1497, ENTREZ:8573, UNIPROT:O14936, GENECARDS:GC0XM041374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN2*"/> <bbox w="46.0" h="16.0" x="5054.875" y="3277.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s190_emtc_emtc_sa176"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: lin-7 homolog C (C. elegans) HUGO:LIN7C, HGNC:17789, ENTREZ:55327, UNIPROT:Q9NUP9, GENECARDS:GC11M027472 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN7C"/> <bbox w="48.0" h="17.0" x="5004.875" y="3277.25"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s209_emtc_emtc_csa8" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CRB3:LIN7C:PALS1*:PATJ* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10102271 PATJ* is a component of the Crb complex. The L27 domain of PATJ* binds to the L27 domain of PALS1* PMID:18177979 Lin7 is a component of the Crumbs complex in Drosophila epithelia and photoreceptor cells PMID:2288140 Apical recuritment of PATJ* and LIN7 depends on the CRB3/PALS1* complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3/PALS1*/PATJ*/LIN7C"/> <bbox w="156.0" h="71.0" x="6118.0" y="2625.5"/> <glyph class="macromolecule" id="emtc_emtc_s213_emtc_emtc_sa163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:17486063 References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: membrane protein, palmitoylated 5 (MAGUK p55 subfamily member 5) HUGO:MPP5, HGNC:18669, ENTREZ:64398, UNIPROT:Q8NI35, GENECARDS:GC14P067708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11927608 PALS1 is an adapter linking Crumbs and PATJ* PALS1 contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate kinase domain Interaction PALS1 -LIN7 via the C-terminal L27 domain of PALS1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PALS1*"/> <bbox w="55.0" h="16.0" x="6161.5" y="2645.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1651_emtc_emtc_sa164"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:22881460 CRB3 is the only transmembrane protein among apical polarity regulators PMID:2344615 Link between Drosophila apical membrane Crb and epithelia organization References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: crumbs homolog 3 (Drosophila) HUGO:CRB3, HGNC:20237, ENTREZ:92359, UNIPROT:Q9BUF7, GENECARDS:GC19P006414 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:22881460 CRB3 is the only transmembrane protein among apical polarity regulators PMID:2344615 Link between Drosophila apical membrane Crb and epithelia organization References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3"/> <bbox w="53.0" h="16.0" x="6168.0" y="2626.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s215_emtc_emtc_sa189"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 PATJ* is repressed by ZEB1 PMID:10102271 PATJ* is a component of the Crb complex. The L27 domain of PATJ* binds to the L27 domain of PALS1* PMID:22881460 Apical recuritment if PATJ* depends on the CRB3/PALS1* complex PMID:18005931 PATJ contains one L27 domain (interacting with the N-ter L27 of PALS1) and has up to 10 PDZ domains. The 6th PDZ interacts with ZO3 and the 8th interacts with Claudin1. The ZO3 cytoplasmic protein is linked to tight junctions via its association with Occludin. Occludin and Claudin1 are transmembrane proteins PMID:16129888 PATJ expression affects the localization of ZO1, ZO3, Occludin, CRB3 and PALS1 PATJ provides a link between the lateral (Occludin and ZO3) and apical (PALS1 and CRB3) components of tight junctions and stabilizes the CRB3 complex References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: InaD-like (Drosophila) HUGO:INADL, HGNC:28881, ENTREZ:10207, UNIPROT:Q8NI35, GENECARDS:GC01P062208 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 PATJ* is repressed by ZEB1 PMID:10102271 PATJ* is a component of the Crb complex. The L27 domain of PATJ* binds to the L27 domain of PALS1* PMID:22881460 Apical recuritment if PATJ* depends on the CRB3/PALS1* complex PMID:18005931 PATJ contains one L27 domain (interacting with the N-ter L27 of PALS1) and has up to 10 PDZ domains. The 6th PDZ interacts with ZO3 and the 8th interacts with Claudin1. The ZO3 cytoplasmic protein is linked to tight junctions via its association with Occludin. Occludin and Claudin1 are transmembrane proteins PMID:16129888 PATJ expression affects the localization of ZO1, ZO3, Occludin, CRB3 and PALS1 PATJ provides a link between the lateral (Occludin and ZO3) and apical (PALS1 and CRB3) components of tight junctions and stabilizes the CRB3 complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PATJ*"/> <bbox w="45.0" h="16.0" x="6146.0" y="2660.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s216_emtc_emtc_sa190"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lin-7 homolog C (C. elegans) HUGO:LIN7C, HGNC:17789, ENTREZ:55327, UNIPROT:Q9NUP9, GENECARDS:GC11M027472 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN7C"/> <bbox w="47.0" h="16.0" x="6195.0" y="2660.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s236_emtc_emtc_csa11" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:TGFB1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Reference_bigin: PMID:22943793 TGFb binds to homodimer TGFBR2 first TGFBR2 phosphorylates the GS domain of homodimeric TFGBR1 on serine residues This phosphorylation leads to incorporation of TGFBR1 and formation of a large ligand-receptor complex of fimeric TGFB and two pairs of TGFBR1 and TGFBR2 PMID:12809600 PMID:22710166 The active ligand–receptor complex is a heterotetrameric complex This complex consists of an active dimer of TGFB and homodimers of both TGFBRI and TGFBR2. Within the active receptor complex, TGFBR2autophosphorylates itself and catalyzes transphosphorylation of the TGFBR1. Transphosphorylation of the TGFBRI activates its kinase activity. Reference_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1/TGFBR2"/> <bbox w="60.0" h="96.5" x="6169.0" y="4292.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s281_emtc_emtc_sa212"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="52.75" h="46.5" x="6171.625" y="4323.25"/> <glyph class="unit of information" id="_af53433f-c4b4-4d18-9d5e-89a2bd5d8dce"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6188.0" y="4318.25"/> </glyph> <glyph class="state variable" id="_18dcbf63-71fe-4f92-be0c-8e4169b5c9b1"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6159.125" y="4321.0425"/> </glyph> <glyph class="unit of information" id="_870c1daa-1240-4be7-bb11-28c7a217a1b9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6175.5" y="4318.25"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3770_emtc_emtc_sa221"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="50.0" h="26.0" x="6174.25" y="4296.5"/> <glyph class="unit of information" id="_38bf58c7-cb7f-4409-9132-701f15d02c19"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6189.25" y="4291.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s246_emtc_emtc_csa160" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BBC3:BCL2-XL* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. It is via this binding to BBC3 (an apoptic inducer) that BCL2L1 exhibits its anti-apoptic effect. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BBC3/BCL2L1"/> <bbox w="112.0" h="46.0" x="4108.0" y="1095.0"/> <glyph class="macromolecule" id="emtc_emtc_s381_emtc_emtc_sa910"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2 binding component 3 HUGO:BBC3, HGNC:17868, ENTREZ:27113, UNIPROT:Q96PG8, GENECARDS:GC19M047724 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BBC3"/> <bbox w="37.0" h="17.0" x="4113.5" y="1101.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s382_emtc_emtc_sa911"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:12667443 PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:22836101 BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro-survival family members such as BCL2L1 act to inhibit BAX activation PMID:23064052 PMID:11085534 BCL2 and BCL2L1 are known to be overexpressed in several cancers. In particular, BCL2L1 overexpression has been correlated with cancer cells resistance to chemotherapeutic agents References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2-XL*"/> <bbox w="59.0" h="18.0" x="4155.5" y="1101.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s405_emtc_emtc_csa306" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:DTX1:UBE2D1:UBE2D2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="UBE2D1/UBE2D2/DTX1"/> <bbox w="159.0" h="39.0" x="883.0" y="1749.5"/> <glyph class="macromolecule" id="emtc_emtc_s4307_emtc_emtc_sa2098"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ubiquitin-conjugating enzyme E2D1 HUGO:UBE2D1, HGNC:12474, ENTREZ:7321, UNIPROT:P51668, GENECARDS:GC10P060094 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="UBE2D1"/> <bbox w="53.0" h="19.0" x="885.0" y="1750.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4308_emtc_emtc_sa2099"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ubiquitin-conjugating enzyme E2D2 HUGO:UBE2D2, HGNC:12475, ENTREZ:7322, UNIPROT:P62837, GENECARDS:GC05P138920 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="UBE2D2"/> <bbox w="57.0" h="18.0" x="939.5" y="1751.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s409_emtc_emtc_sa2100"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: deltex homolog 1 HUGO:DTX1, HGNC:3060, ENTREZ:1840, UNIPROT:Q86Y01, GENECARDS:GC12P113495 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DTX1"/> <bbox w="45.0" h="17.0" x="997.25" y="1751.667"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s419_emtc_emtc_csa142" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LAP*:SNAI2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR1-1/SNAI2"/> <bbox w="80.0" h="60.0" x="3058.5" y="5531.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s420_emtc_emtc_sa778"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 1-1 HUGO:MIR1-1, HGNC:31499, ENTREZ:406904, GENECARDS:GC20P061153 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAP*"/> <bbox w="75.0" h="20.0" x="3062.5" y="5532.0"/> <glyph class="unit of information" id="_35c474db-a2cb-41e4-a940-f132e6511a0a"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3085.0" y="5527.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3650_emtc_emtc_sa1814"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="60.0" h="20.0" x="3067.385" y="5553.115"/> <glyph class="unit of information" id="_1b9145be-e706-452c-8779-909911effea1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3087.385" y="5548.115"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s422_emtc_emtc_csa141" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR200*:SNAI2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200C/SNAI2"/> <bbox w="80.0" h="60.0" x="2051.5" y="5369.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s424_emtc_emtc_sa775"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 microRNA 429 HUGO:MIR429, HGNC:13784, ENTREZ:554210, GENECARDS:GC01P001109 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21336307 PMID:22370643 Regulation of BMI1 and JAG1 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200*"/> <bbox w="75.0" h="20.0" x="2055.5" y="5370.0"/> <glyph class="unit of information" id="_6263aea2-d239-413a-89ae-c325e11c12a9"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2078.0" y="5365.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3652_emtc_emtc_sa1816"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="60.0" h="20.0" x="2064.334" y="5390.834"/> <glyph class="unit of information" id="_b34a203d-d036-49a6-9918-7e52fffbadf9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2084.334" y="5385.834"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s539_emtc_emtc_csa48" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LTBP1:Latency-associated protein* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAP*/LTBP1"/> <bbox w="176.0" h="62.0" x="898.969" y="6867.5"/> <glyph class="macromolecule multimer" id="emtc_emtc_s2154_emtc_emtc_sa425"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="172.5" h="23.0" x="900.219" y="6888.5"/> <glyph class="unit of information" id="_ef69b746-883e-4d78-b230-2af549b33c52"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="976.469" y="6883.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2155_emtc_emtc_sa423"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1, HGNC:6714, ENTREZ:4052, UNIPROT:Q14766,GENECARDS:GC02P033172, UNIPROT:Q14766 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM There are 4 LTBP proteins (1, 2, 3, 4). Although LTBP1 and 3 bind all three TGFB (1, 2, 3), LTBP4 binds only TGFB1 PMID:9931372 LTBP1 is a member of the fibrillin family An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out PMID:10544215 Extracellular tTgase is located at the basal and apical surfaces of cells and at cell–cell contacts, and that LTBP1 is co-distributed with cell surface tTgase LTPB1 was also found to co-localize with both intracellular and extracellular fibronectin Regulation of tTgase expression is important for controlling matrix storage of latent TGFB1 complexes Fibronectin may be one extracellular component to which LTBP1 is crosslinked when LTBP1 and tTgase interact at the cell surface References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTBP1"/> <bbox w="40.0" h="20.0" x="933.094" y="6868.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s554_emtc_emtc_csa3" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LMO2:ZEB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LMO2/ZEB1"/> <bbox w="71.0" h="64.0" x="3834.0" y="4053.5"/> <glyph class="macromolecule" id="emtc_emtc_s61_emtc_emtc_sa60"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, UNIPROT:P37275, GENECARDS:GC10P031648 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 ZEB1 inhibits MIR200 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1"/> <bbox w="40.0" h="20.0" x="3849.0" y="4079.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s60_emtc_emtc_sa51"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: LIM domain only 2 (rhombotin-like 1) HUGO:LMO2, HGNC:6642, ENTREZ:4005, UNIPROT:P25791, GENECARDS:GC11M033880 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Complex ZEB1-LMO2 PMID:20731704 PMID:22349261 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LMO2"/> <bbox w="40.0" h="20.0" x="3849.0" y="4056.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s562_emtc_emtc_csa50" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD3:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3 homodimer/SMAD4"/> <bbox w="126.0" h="103.25" x="5434.0" y="4232.875"/> <glyph class="macromolecule" id="emtc_emtc_s566_emtc_emtc_sa432"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="5470.0" y="4233.125"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s567_emtc_emtc_sa431"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="118.0" h="55.5" x="5440.0" y="4253.625"/> <glyph class="unit of information" id="_2fb90282-5039-433c-81a8-455edf950c8f"> <label text="N:2"/> <bbox w="20.0" h="10.0" 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multimer" id="emtc_emtc_s570_emtc_emtc_sa433"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="118.0" h="57.0" x="3817.5" y="3432.5"/> <glyph class="unit of information" id="_4e6d58ac-7fdf-485f-85e5-c6c608e4b505"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3866.5" y="3427.5"/> </glyph> <glyph class="state variable" id="_8c4faedf-028f-4a9b-a206-b5b7d125cf14"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="3802.5" y="3460.261"/> </glyph> <glyph class="state variable" id="_46930c4f-c25a-4f3b-9d37-ae0d265c145b"> <state value="" 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value="" variable="T8"/> <bbox w="20.0" h="10.0" x="3865.179" y="3484.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s571_emtc_emtc_sa434"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3871.5" y="3410.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s575_emtc_emtc_csa53" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD3:SMAD4:SNAI1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21041997 Smad3 and Smad4 form a complex with Snail1(SNAI1) that binds to E-box and Smad-binding elements in the promoters of the genes encoding E-Cadherinm Occludinm and the tight junction-associated cell adhesion molecule CAR, consequently repressing their transcription. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAIL1/SMAD3/SMAD4"/> <bbox w="158.0" h="113.0" x="2916.5" y="3403.5"/> <glyph class="macromolecule" id="emtc_emtc_s1393_emtc_emtc_sa437"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: Feedback loops PMID:22514743 PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="40.0" h="20.0" x="2938.5" y="3406.0"/> <glyph class="state variable" id="_6678d66e-831d-4489-b292-0692380a5bb7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2933.5" y="3402.0222"/> </glyph> <glyph class="state variable" id="_469a424b-9eb8-4518-a91d-7bfe3993f607"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2973.5" y="3402.0508"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s670_emtc_emtc_sa438"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="130.0" h="62.0" x="2931.5" y="3429.5"/> <glyph class="unit of information" id="_bc86664a-1d5a-4cd0-8ef1-3e1aec6c21aa"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2986.5" y="3424.5"/> </glyph> <glyph class="state variable" id="_5df90b78-964d-4473-b04d-06bb4def63e7"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="2916.5" y="3460.1348"/> </glyph> <glyph class="state variable" id="_5dec0aaa-9993-4cf9-b86d-221ea95be3fd"> <state value="" variable="S422"/> <bbox w="30.0" h="10.0" x="3046.5" y="3451.4473"/> </glyph> <glyph class="state variable" id="_69061af1-7c33-4f7c-8a94-b954388b6ed5"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="2916.5" y="3480.487"/> </glyph> <glyph class="state variable" id="_6a1d08f2-5552-4183-9221-e40533307c62"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="3044.0" y="3463.8525"/> </glyph> <glyph class="state variable" id="_e6ba73f3-09ff-4568-82c9-85a6fb7584d1"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="3044.0" y="3480.7322"/> </glyph> <glyph class="state variable" id="_3ddfbd90-0744-4b44-aa27-8fdf6640dcd5"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="2916.5" y="3445.8564"/> </glyph> <glyph class="state variable" id="_da4f7ef4-df78-49dd-8a13-f7a45bb76de0"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="2916.5" y="3428.2234"/> </glyph> <glyph class="state variable" id="_36100ce8-b507-4fc7-9b95-cd4adf851248"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="2985.0444" y="3486.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s578_emtc_emtc_sa439"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="2987.5" y="3405.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s600_emtc_emtc_csa55" compartmentRef="emtc_emtc_c33_emtc_emtc_ca33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SARA*:TGFB1:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*/TGFB1/TGFBR1/TGFBR2"/> <bbox w="59.0" h="165.0" x="5980.5" y="3881.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s528_emtc_emtc_sa461"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="54.0" h="46.5" x="5984.0" y="3882.25"/> <glyph class="unit of information" id="_e2821575-0f47-4b9e-9297-85248bd32f6a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6001.0" y="3877.25"/> </glyph> <glyph class="state variable" id="_70c4744d-1da7-4fda-adf6-3b5e0d146ff1"> <state value="P" variable="Ser"/> <bbox w="30.0" h="10.0" x="5969.0" y="3880.0425"/> </glyph> <glyph class="unit of information" id="_0584ba27-3cb7-4924-b5b5-b4760cf0b5ea"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5988.5" y="3877.25"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s529_emtc_emtc_sa462"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="50.0" h="26.0" x="5985.0" y="3930.5"/> <glyph class="unit of information" id="_dfe14127-8139-4d2a-abe5-d4a9730b068a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6000.0" y="3925.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s530_emtc_emtc_sa463"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="50.0" h="44.0" x="5986.5" y="3962.0"/> <glyph class="unit of information" id="_c958ce04-49c9-4eeb-b8c5-e513d5c4be27"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6001.5" y="3957.0"/> </glyph> <glyph class="state variable" id="_c791fe83-cc7b-4cba-94ac-d95fe5fad1d4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6031.5" y="3957.2363"/> </glyph> <glyph class="state variable" id="_8f940b96-eeb7-426d-8672-905531e07504"> <state value="P" variable="Ser"/> <bbox w="30.0" h="10.0" x="5971.5" y="3958.0232"/> </glyph> <glyph class="unit of information" id="_a2402914-82c7-4f65-b408-0a448d9d3faa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5989.0" y="3957.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s610_emtc_emtc_sa464"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger, FYVE domain containing 9 HUGO:ZFYVE9, HGNC:6775, ENTREZ:9372, UNIPROT:O95405, GENECARDS:GC01P052608 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:11792802 -SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. -Several other proteins with possible roles in Smad anchoring: PMID:10678166 Microtubules can anchor inactive Smads in the cytoplasm Activation by a ligand results in dissociation of the Smads from the microtubule network It is possible that microtubules serve as tracks for intracellular Smad movement PMID:11278410 Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*"/> <bbox w="55.0" h="20.0" x="5983.5" y="4008.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s614_emtc_emtc_csa56" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD2:SMAD3:SMAD4:SP1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2/SMAD3/SAMD4/SP1"/> <bbox w="169.0" h="152.0" x="3541.375" y="3361.5"/> <glyph class="macromolecule" id="emtc_emtc_s1402_emtc_emtc_sa468"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3625.375" y="3362.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1403_emtc_emtc_sa469"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="120.0" h="48.0" x="3561.875" y="3441.0"/> <glyph class="state variable" id="_d4f58a3e-b59f-47ab-b789-99c4ba110c02"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="3546.875" y="3463.5881"/> </glyph> <glyph class="state variable" id="_fa8e17b5-b1c5-4f9d-bb52-b4b7f13fe887"> <state value="P" variable="S422"/> <bbox w="35.0" h="10.0" x="3664.375" y="3456.8623"/> </glyph> <glyph class="state variable" id="_1abb07d4-778a-41a3-a785-fc3910f0f1d7"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="3546.875" y="3479.3447"/> </glyph> <glyph class="state variable" id="_f96222ab-f069-40c1-bc5a-237701aeecb0"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="3664.375" y="3466.4666"/> </glyph> <glyph class="state variable" id="_f66b1779-4467-4bd4-abd2-0fb42c1e7cca"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="3664.375" y="3479.5347"/> </glyph> <glyph class="state variable" id="_57d71e0b-ef14-48ec-9d49-18980e078832"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="3546.875" y="3452.534"/> </glyph> <glyph class="state variable" id="_e83aa1f0-97ff-4d13-92f5-6ed590c5f219"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="3546.875" y="3438.8826"/> </glyph> <glyph class="state variable" id="_d6321c4d-0795-4b18-b8c1-2b2b73e34e46"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="3610.5315" y="3484.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s617_emtc_emtc_sa470"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="119.0" h="49.0" x="3557.5" y="3386.0"/> <glyph class="state variable" id="_3f4a35d6-2048-426a-832d-3ce468e6b6b7"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="3659.0" y="3413.1643"/> </glyph> <glyph class="state variable" id="_40c62997-6613-473f-ac36-d9a0494f4eb9"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="3608.0479" y="3430.0"/> </glyph> <glyph class="state variable" id="_f324eb6e-37db-4292-9fb1-87e9a7fc2611"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="3659.0" y="3425.4417"/> </glyph> <glyph class="state variable" id="_73095120-3fd6-427d-80de-30102b8fc4ba"> <state value="P" variable="S464"/> <bbox w="35.0" h="10.0" x="3659.0" y="3403.536"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s620_emtc_emtc_sa473"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Sp1 transcription factor HUGO:SP1, HGNC:11205, ENTREZ:6667, GENECARDS:GC12P053801, UNIPROT:P08047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SP1"/> <bbox w="40.0" h="20.0" x="3567.875" y="3362.5"/> <glyph class="state variable" id="_0dd11a6a-8115-41ef-bed0-7dec2bc22b73"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3562.875" y="3367.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s646_emtc_emtc_csa61" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDK4_6*:CyclinD1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4/Cyclin D1*"/> <bbox w="126.0" h="38.5" x="3142.0" y="1412.25"/> <glyph class="macromolecule" id="emtc_emtc_s1401_emtc_emtc_sa491"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455, UNIPROT:P24385 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Only several CDK–cyclin complexes are directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="63.0" h="19.0" x="3204.5" y="1413.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4282_emtc_emtc_sa2071"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CDK4_6* cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*"/> <bbox w="60.0" h="19.0" x="3146.0" y="1413.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s690_emtc_emtc_csa64" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIZ1*:SMAD2:SMAD3:SMAD4:SP1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:11283614 Miz1: a Myc-interacting Zinc-finger protein that recognizes certain transcriptional initiator elements One of this transcriptional initiator element contains the sequence 5'-CCCACTCTGC corresponding to the p15INK4B transcriptional intiator Physical interaction between Smad proteins and Miz-1: -Immunoprecipitation of endogenous Smad2 and Smad3 followed by anti-Miz western bloting provided evidence for an association -This association was stimulated by addition of TGFB -Interaction was observed between Miz1 and Smad3 and Smad4 but no clear interaction was observed between Miz1 and Smad2 -Smad3 and weakly Smad4 can directly and selectively bind to Miz1 through the MH1 domain -Although Sp1-Smad interactions have been reported, Sp1 does not directly bind to Miz1, even in the presence of TGFB. -The Smad-interaction region of Miz1 does not overlap with the Myc-interaction region. -Myc did not inhibit the Smad-Miz1 interaction -Miz1 can bridge Smad proteins and Myc when these proteins coexist. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIZ1/SMAD2/SMAD3/SAMD4/SP1"/> <bbox w="203.0" h="160.5" x="3291.75" y="3378.25"/> <glyph class="macromolecule" id="emtc_emtc_s686_emtc_emtc_sa517"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3365.25" y="3493.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s687_emtc_emtc_sa518"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="120.0" h="48.0" x="3335.75" y="3440.25"/> <glyph class="state variable" id="_9527efad-1a55-4050-8775-4f3eec9963d1"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="3320.75" y="3462.8381"/> </glyph> <glyph class="state variable" id="_8001f87f-3320-47f0-ac22-f8d4c048f040"> <state value="P" variable="S422"/> <bbox w="35.0" h="10.0" x="3438.25" y="3456.1123"/> </glyph> <glyph class="state variable" id="_920926f0-5a08-4d3f-acc0-14e147035c39"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="3320.75" y="3478.5947"/> </glyph> <glyph class="state variable" id="_a967b340-2296-4129-80ab-25b5233389ff"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="3438.25" y="3465.7166"/> </glyph> <glyph class="state variable" id="_5f554b0e-f7fb-417d-9675-18d8f3f8fc6d"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="3438.25" y="3478.7847"/> </glyph> <glyph class="state variable" id="_c17648f0-ae06-4d2a-b11e-b60d10e35347"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="3320.75" y="3451.784"/> </glyph> <glyph class="state variable" id="_a84841b1-4631-40db-aec5-05e7af682106"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="3320.75" y="3438.1326"/> </glyph> <glyph class="state variable" id="_fda3beee-6f8c-4989-bb9e-058cbc908b9b"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="3384.4065" y="3483.25"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s688_emtc_emtc_sa519"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="119.0" h="49.0" x="3335.25" y="3382.5"/> <glyph class="state variable" id="_a8b2e8bd-33e7-4cb6-ae22-ea0cf5a7e183"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="3436.75" y="3409.6643"/> </glyph> <glyph class="state variable" id="_6bc7eafd-fb8f-4035-80af-ea709d4a6f3c"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="3385.7979" y="3426.5"/> </glyph> <glyph class="state variable" id="_7c3070f0-575e-4259-a37c-b4b82fd5c610"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="3436.75" y="3421.9417"/> </glyph> <glyph class="state variable" id="_cd522c3f-fae7-412c-b47f-df50b1b4cb8f"> <state value="P" variable="S464"/> <bbox w="35.0" h="10.0" x="3436.75" y="3400.036"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1446_emtc_emtc_sa520"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Sp1 transcription factor HUGO:SP1, HGNC:11205, ENTREZ:6667, GENECARDS:GC12P053801, UNIPROT:P08047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SP1"/> <bbox w="40.0" h="20.0" x="3318.25" y="3492.0"/> <glyph class="state variable" id="_46647c1d-001c-42f7-b2f0-e8f8ccf0a477"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3313.25" y="3497.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s684_emtc_emtc_sa521"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger and BTB domain containing 17 HUGO:ZBTB17, HGNC:12936, ENTREZ:7709, GENECARDS:GC01M016268, UNIPROT:Q13105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIZ1*"/> <bbox w="40.0" h="20.0" x="3428.75" y="3494.75"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s756_emtc_emtc_csa310" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:NICD*:p53* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*/TP53"/> <bbox w="107.0" h="53.0" x="3938.0" y="2141.5"/> <glyph class="macromolecule" id="emtc_emtc_s568_emtc_emtc_sa2107"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="45.0" h="24.0" x="3946.5" y="2145.0"/> <glyph class="state variable" id="_5e8d680b-072d-4b33-97c2-4bb8d6ff0de2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3986.5" y="2140.0"/> </glyph> <glyph class="state variable" id="_50736935-0502-4dc3-806a-7f7498bc1fef"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3941.5" y="2140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4339_emtc_emtc_sa2153"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="39.0" h="19.0" x="3996.0" y="2149.0"/> <glyph class="state variable" id="_496edbd4-04c2-4c2e-b5d2-c41f18d5ccbd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4030.0" y="2149.565"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s758_emtc_emtc_csa308" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:DLL1:NOTCH1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DLL1/NOTCH1"/> <bbox w="125.0" h="48.0" x="522.0" y="1854.5"/> <glyph class="macromolecule" id="emtc_emtc_s391_emtc_emtc_sa2103"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: delta-like protein 1 HUGO:DLL1, HGNC:2908, ENTREZ:28514, UNIPROT:O00548, GENECARDS:GC06M170591 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DLL1"/> <bbox w="41.0" h="24.0" x="527.0" y="1856.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s392_emtc_emtc_sa2104"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="60.0" h="29.0" x="582.0" y="1856.5"/> <glyph class="unit of information" id="_14ee7d52-3f94-4fcf-b62b-ad4c886910af"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="589.5" y="1851.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s762_emtc_emtc_csa307" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAG1:NOTCH1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAG1/NOTCH"/> <bbox w="125.0" h="51.0" x="516.0" y="1683.5"/> <glyph class="macromolecule" id="emtc_emtc_s403_emtc_emtc_sa2081"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="62.0" h="30.0" x="573.615" y="1688.808"/> <glyph class="unit of information" id="_f1310562-508c-4638-8ca9-8c75ee21029e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="582.115" y="1683.808"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s403_emtc_emtc_sa2101"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="60.0" h="29.0" x="574.0" y="1685.5"/> <glyph class="unit of information" id="_f4a08ce2-b679-4044-870e-9f54efa33697"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="581.5" y="1680.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4309_emtc_emtc_sa2102"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: jagged 1 HUGO:JAG1, HGNC:6188, ENTREZ:182, UNIPROT:P78504, GENECARDS:GC20M010618 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAG1"/> <bbox w="46.0" h="19.0" x="520.0" y="1686.5"/> <glyph class="state variable" id="_c0b51a61-1b71-4d2b-9bf5-28dd14df84e9"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="556.0" y="1700.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s763_emtc_emtc_csa312" compartmentRef="emtc_emtc_c21_emtc_emtc_ca21"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAG1:NOTCH1:NUMB:_beta_-Catenin* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NUMB/NOTCH/CTNNB1"/> <bbox w="185.0" h="77.0" x="793.0" y="1533.0"/> <glyph class="macromolecule" id="emtc_emtc_s521_emtc_emtc_sa2111"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="57.0" h="22.0" x="824.5" y="1541.5"/> <glyph class="unit of information" id="_8e5fcf35-64de-4d58-9019-937b2c2b3522"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="830.5" y="1536.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s523_emtc_emtc_sa2113"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: protein numb homolog HUGO:NUMB, HGNC:8060, ENTREZ:8650, UNIPROT:P49757, GENECARDS:GC14M073741 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NUMB"/> <bbox w="43.0" h="19.0" x="905.5" y="1570.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4337_emtc_emtc_sa2151"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. 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PMID:22024162 PMID:21909380 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34*"/> <bbox w="75.0" h="20.0" x="2740.562" y="5729.0"/> <glyph class="unit of information" id="_f45b7a2c-607b-4d0a-9ec2-c6c5481de748"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2763.062" y="5724.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s776_emtc_emtc_csa120" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR449A:NOTCH1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR449A/NOTCH1"/> <bbox w="109.0" h="66.0" x="3196.5" y="5534.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s551_emtc_emtc_sa733"> 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 449a HUGO:MIR449A, HGNC:27645, ENTREZ:554213, GENECARDS:GC05M054466 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR449A"/> <bbox w="80.0" h="20.0" x="3217.5" y="5538.5"/> <glyph class="unit of information" id="_14d1809c-9081-437e-912b-5a1b9185b9a4"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3242.5" y="5533.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s777_emtc_emtc_csa117" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR192:ZEB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR192/ZEB2"/> <bbox w="93.0" h="62.0" x="2541.5" y="5539.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1408_emtc_emtc_sa727"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB2"/> <bbox w="60.0" h="20.0" x="2559.5" y="5560.5"/> <glyph class="unit of information" id="_5e11bcf6-689b-4a36-8596-78b51c6110e0"> <label 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<label text="MIR34*"/> <bbox w="75.0" h="20.0" x="2914.137" y="5729.0"/> <glyph class="unit of information" id="_df215f61-eced-4f07-8cbd-a5875a6c4c03"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2936.637" y="5724.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s782_emtc_emtc_csa138" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR34*:WNT3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A/WNT3"/> <bbox w="80.0" h="60.0" x="2995.926" y="5728.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1377_emtc_emtc_sa769"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: wingless-type MMTV integration site family, member 3 HUGO:WNT3, HGNC:12782, ENTREZ:7473, GENECARDS:GC17M044839 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WNT3"/> <bbox w="60.0" h="20.0" x="3014.926" y="5749.0"/> <glyph class="unit of information" id="_6a6f6823-cc47-44aa-8b3f-8e74da9f166f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3034.926" y="5744.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1378_emtc_emtc_sa770"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 34b HUGO:MIR34B, HGNC:31636, ENTREZ:407041, GENECARDS:GC11P111383 microRNA 34c HUGO:MIR34C, HGNC:31637, ENTREZ:407042, GENECARDS:GC11P111384 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 PMID:21909380 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34*"/> <bbox w="75.0" h="20.0" x="2999.926" y="5729.0"/> <glyph class="unit of information" id="_682047b5-4cda-475f-b745-6e56a13074c6"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3022.426" y="5724.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s793_emtc_emtc_csa135" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR34*:MYC Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34/MYC"/> <bbox w="80.0" h="60.0" x="2491.2" y="5728.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s640_emtc_emtc_sa763"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 34b HUGO:MIR34B, HGNC:31636, ENTREZ:407041, GENECARDS:GC11P111383 microRNA 34c HUGO:MIR34C, HGNC:31637, ENTREZ:407042, GENECARDS:GC11P111384 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 PMID:21909380 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34*"/> <bbox w="75.0" h="20.0" x="2495.2" y="5729.0"/> <glyph class="unit of information" id="_8ff6d859-7dfb-4195-947a-addba1e94d6e"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2517.7" y="5724.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s639_emtc_emtc_sa764"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYC"/> <bbox w="60.0" h="20.0" x="2510.2" y="5749.0"/> <glyph class="unit of information" id="_78836a1e-985b-4b3b-a2f7-644bb2244e64"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2530.2" y="5744.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s921_emtc_emtc_csa110" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Occludin*:PARD6A:TGFBR1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*/PAR6*/TGFBR1"/> <bbox w="161.0" h="90.0" x="559.5" y="2187.5"/> <glyph class="macromolecule" id="emtc_emtc_s964_emtc_emtc_sa665"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696, UNIPROT:Q9NPB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="57.0" h="40.0" x="657.5" y="2198.5"/> <glyph class="state variable" id="_0fd7a4be-60a4-4605-aaa6-37dc11afc26e"> <state value="" variable="S345"/> <bbox w="30.0" h="10.0" x="664.94916" y="2193.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s919_emtc_emtc_sa666"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="54.0" h="42.0" x="597.5" y="2193.5"/> <glyph class="unit of information" id="_c65f9fda-f63e-4814-b5af-eafb41f1a91c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="614.5" y="2188.5"/> </glyph> <glyph class="state variable" id="_9e60e521-be83-47f5-a22d-2e2efce9319d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="646.5" y="2188.7256"/> </glyph> <glyph class="state variable" id="_e6906424-39e9-40ec-a619-55189be71a2a"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="585.0" y="2189.4768"/> </glyph> <glyph class="unit of information" id="_bcb32450-5f81-471e-86bf-237c8d61492c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="602.0" y="2188.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s965_emtc_emtc_sa667"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID: PMID: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="60.0" h="20.0" x="591.5" y="2235.5"/> <glyph class="state variable" id="_147cee2e-0a3e-4d83-90ec-844c1c165746"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="646.5" y="2240.5317"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s952_emtc_emtc_csa111" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Occludin*:PARD6A:TGFB1:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*/PAR6*/TGFB/TGFBR1/TGFBR2"/> <bbox w="263.0" h="156.0" x="551.5" y="2018.5"/> <glyph class="macromolecule" id="emtc_emtc_s956_emtc_emtc_sa668"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696, UNIPROT:Q9NPB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="58.0" h="38.0" x="660.5" y="2036.5"/> <glyph class="state variable" id="_32162691-1497-41be-ac25-c1df6a849004"> <state value="" variable="S345"/> <bbox w="30.0" h="10.0" x="668.343" y="2031.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s953_emtc_emtc_sa670"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID: PMID: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="60.0" h="20.0" x="590.5" y="2135.5"/> <glyph class="state variable" id="_ce76b3e2-d8c9-4302-a2ac-900303f4b865"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="645.5" y="2140.5317"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s957_emtc_emtc_sa671"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="58.0" h="46.5" x="590.5" y="2030.25"/> <glyph class="unit of information" id="_32d33dfd-9007-41eb-8527-4e582344d53e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="609.5" y="2025.25"/> </glyph> <glyph class="state variable" id="_d1037315-c13b-48bd-aca2-3b9ac0170700"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="578.0" y="2028.0426"/> </glyph> <glyph class="unit of information" id="_52336bdc-2bda-496e-b898-767b5bfb21fb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="597.0" y="2025.25"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s954_emtc_emtc_sa672"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="50.0" h="26.0" x="658.5" y="2105.5"/> <glyph class="unit of information" id="_340eabec-a117-4016-b1ec-18f21aefc840"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="673.5" y="2100.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s955_emtc_emtc_sa673"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="56.0" h="48.0" x="591.5" y="2085.5"/> <glyph class="unit of information" id="_a043a534-330c-4773-8c6b-f60abd5bc580"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="609.5" y="2080.5"/> </glyph> <glyph class="state variable" id="_efa1354e-8d75-4b26-b3d1-65f3d4012a07"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="642.5" y="2080.7578"/> </glyph> <glyph class="state variable" id="_77c5036a-bff8-40a5-83d2-2f857231af3c"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="579.0" y="2081.6162"/> </glyph> <glyph class="unit of information" id="_56e0abe0-3d67-41ae-a281-ea61d62f860b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="597.0" y="2080.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s958_emtc_emtc_csa112" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Occludin*:PARD6A:TGFB1:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761148 After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. Active TGFBR2 recruited to TIGHT_JUNCTIONS phosphorylates PARD6A on Serine residue S345 and it also phosphorylates TGFBR1 Once phosphorylated by TGFBR2, both TGFBR1 and PARD6A become active References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*/PAR6*/TGFB/TGFBR1/TGFBR2"/> <bbox w="243.0" h="127.0" x="875.5" y="2038.5"/> <glyph class="macromolecule" id="emtc_emtc_s962_emtc_emtc_sa674"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696, UNIPROT:Q9NPB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="63.0" h="38.0" x="883.5" y="2076.5"/> <glyph class="state variable" id="_e3fe690c-90a8-4a19-bcae-9675d22cc949"> <state value="P" variable="S345"/> <bbox w="35.0" h="10.0" x="890.81226" y="2071.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s959_emtc_emtc_sa675"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID: PMID: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. 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In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="50.0" h="26.0" x="1025.5" y="2078.25"/> <glyph class="unit of information" id="_46cc2c25-aa71-46a1-a32f-5b4d925d21b6"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1040.5" y="2073.25"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s961_emtc_emtc_sa678"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD3:SMAD4:SP1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3 homodimer/SMAD4/SP1"/> <bbox w="190.0" h="111.75" x="3090.5" y="3413.125"/> <glyph class="macromolecule multimer" id="emtc_emtc_s692_emtc_emtc_sa522"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="118.0" h="57.0" 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PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3189.75" y="3415.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s689_emtc_emtc_sa524"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Sp1 transcription factor HUGO:SP1, HGNC:11205, ENTREZ:6667, GENECARDS:GC12P053801, UNIPROT:P08047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SP1"/> <bbox w="40.0" h="20.0" x="3146.5" y="3415.0"/> <glyph class="state variable" id="_bba5f86f-c312-45cd-ac90-dfee83aa940d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3141.5" y="3420.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1321_emtc_emtc_csa114" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Integrin A8B1_AVB1_AVB5_AVB6_AVB8*:LTBP1:Latency-associated protein* Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:10025398 Large latent complex binds to aVb6 via the RGD motif present in the LAP of TGFb, then the b6 cytoplasmic domain binds to the actin cytoskeleton, then Cytoskeleton-associated integrin induces release of mature TGFb from the large latent complex PMID:21883891 This is one of the 2 mechanisms for activating TGFb via integrins. In this model, there is no proteolysis of either the LAP or LTBP. PMID:21900405 LAP contains an integrin-binding site called RBD Several RBD-binding integrins are able to activate latent TGFB complex through binding this site. PMID:21909923 The previously mentionned integrins are: a8b1, aVb1, aVb5, aVb6, aVb8. In the complex Ingergin-large latent TGFB complex, I picked aVb6 as example. But a8b1, aVb1, aVb5, and aVb8 can active TGFB with the same mechanism. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Intergrin/LTBP1/LAP*"/> <bbox w="241.0" h="65.5" x="430.0" y="6867.25"/> <glyph class="macromolecule" id="emtc_emtc_s2753_emtc_emtc_sa689"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1, HGNC:6714, ENTREZ:4052, UNIPROT:Q14766,GENECARDS:GC02P033172, UNIPROT:Q14766 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM There are 4 LTBP proteins (1, 2, 3, 4). Although LTBP1 and 3 bind all three TGFB (1, 2, 3), LTBP4 binds only TGFB1 PMID:9931372 LTBP1 is a member of the fibrillin family An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out PMID:10544215 Extracellular tTgase is located at the basal and apical surfaces of cells and at cell–cell contacts, and that LTBP1 is co-distributed with cell surface tTgase LTPB1 was also found to co-localize with both intracellular and extracellular fibronectin Regulation of tTgase expression is important for controlling matrix storage of latent TGFB1 complexes Fibronectin may be one extracellular component to which LTBP1 is crosslinked when LTBP1 and tTgase interact at the cell surface References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTBP1"/> <bbox w="44.070835" h="19.75" x="435.66" y="6870.875"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s2752_emtc_emtc_sa691"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="185.0" h="25.5" x="484.5" y="6868.75"/> <glyph class="unit of information" id="_979c5439-c3cf-4fb7-b8b0-cd314554d5ae"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="567.0" y="6863.75"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3648_emtc_emtc_sa1369"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Integrin A8B1_AVB1_AVB5_AVB6_AVB8* NAME:a8b1* ITGA8/ITGB1 NAME:aVb1* ITGAV/ITGB1 NAME:aVb5* ITGAV/ITGB5 NAME:aVb6* ITGAV/ITGB6 NAME:aVb8* ITGAV/ITGB8 HUGO:ITGA8, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB5, HUGO:ITGAV, HUGO:ITGB6, HUGO:ITGAV, HUGO:ITGB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Integrin A8B1_AVB1_AVB5_AVB6_AVB8*"/> <bbox w="240.0" h="20.0" x="431.0" y="6894.75"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1353_emtc_emtc_csa119" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAG1:MIR200* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200/JAG1"/> <bbox w="80.0" h="60.0" x="1957.5" y="5368.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s616_emtc_emtc_sa731"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: jagged 1 HUGO:JAG1, HGNC:6188, ENTREZ:182, GENECARDS:GC20M010618 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 PMID:20351093 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAG1"/> <bbox w="60.0" h="20.0" x="1976.5" y="5389.0"/> <glyph class="unit of information" id="_add8954e-269b-473b-9d6b-b84550468a55"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1996.5" y="5384.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s615_emtc_emtc_sa732"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 microRNA 429 HUGO:MIR429, HGNC:13784, ENTREZ:554210, GENECARDS:GC01P001109 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21336307 PMID:22370643 Regulation of BMI1 and JAG1 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200*"/> <bbox w="75.0" h="20.0" x="1961.5" y="5369.0"/> <glyph class="unit of information" id="_5559a7af-467e-4edc-ba12-44fce5a78239"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1984.0" y="5364.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1354_emtc_emtc_csa127" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LRP6:MIR34* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34/LRP6"/> <bbox w="80.0" h="60.0" x="3163.5" y="5728.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1369_emtc_emtc_sa747"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: low density lipoprotein receptor-related protein 6 HUGO:LRP6, HGNC:6698, ENTREZ:4040, GENECARDS:GC12M012173 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LRP6"/> <bbox w="60.0" h="20.0" x="3182.5" y="5749.0"/> <glyph class="unit of information" id="_9f9ea6ac-732a-4b9d-8c56-19124bf05980"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3202.5" y="5744.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1387_emtc_emtc_sa748"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 34b HUGO:MIR34B, HGNC:31636, ENTREZ:407041, GENECARDS:GC11P111383 microRNA 34c HUGO:MIR34C, HGNC:31637, ENTREZ:407042, GENECARDS:GC11P111384 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 PMID:21909380 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34*"/> <bbox w="75.0" h="20.0" x="3167.5" y="5729.0"/> <glyph class="unit of information" id="_aac1a53c-f93c-4016-82dc-c2c613d74943"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3190.0" y="5724.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1355_emtc_emtc_csa129" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAG1:MIR34A Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A/JAG1"/> <bbox w="80.0" h="60.0" x="3268.5" y="5727.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s577_emtc_emtc_sa751"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: jagged 1 HUGO:JAG1, HGNC:6188, ENTREZ:182, GENECARDS:GC20M010618 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 PMID:20351093 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAG1"/> <bbox w="60.0" h="20.0" x="3287.5" y="5748.0"/> <glyph class="unit of information" id="_8d4db0b2-8b7a-4a7f-bbed-cc019e18dbde"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3307.5" y="5743.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1416_emtc_emtc_sa752"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 34a HUGO:MIR34A, HGNC:31635, ENTREZ:407040, GENECARDS:GC01M009211 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A"/> <bbox w="75.0" h="20.0" x="3272.5" y="5728.0"/> <glyph class="unit of information" id="_dc702553-e2e9-4f6c-a411-606ee05eef2f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3295.0" y="5723.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1356_emtc_emtc_csa130" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR34A:NOTCH1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A/NOTCH1"/> <bbox w="80.0" h="60.0" x="3268.5" y="5655.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s574_emtc_emtc_sa753"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="78.0" h="20.0" x="3269.5" y="5676.0"/> <glyph class="unit of information" id="_46186841-9a56-4847-93fd-36ded8fe0431"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3298.5" y="5671.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1412_emtc_emtc_sa754"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 34a HUGO:MIR34A, HGNC:31635, ENTREZ:407040, GENECARDS:GC01M009211 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A"/> <bbox w="75.0" h="20.0" x="3272.5" y="5656.0"/> <glyph class="unit of information" id="_a7252e7b-5005-4538-9c67-6a43d79a69af"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3295.0" y="5651.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1361_emtc_emtc_csa146" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BMI1:Cyclin D1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A/BMI1"/> <bbox w="80.0" h="60.0" x="3270.5" y="5795.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1386_emtc_emtc_sa785"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21224848 PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1"/> <bbox w="60.0" h="20.0" x="3289.5" y="5816.0"/> <glyph class="unit of information" id="_6c63ab3e-b8c9-45c9-a502-eb3094f7e85f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3309.5" y="5811.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s645_emtc_emtc_sa786"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 34a HUGO:MIR34A, HGNC:31635, ENTREZ:407040, GENECARDS:GC01M009211 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cyclin D1*"/> <bbox w="75.0" h="20.0" x="3274.5" y="5796.0"/> <glyph class="unit of information" id="_5c75c9ba-e708-496b-abb7-2b0563f16af4"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3297.0" y="5791.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1548_emtc_emtc_csa150" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:RAF1:YWHAB Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD).References_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAF1/YWHAB"/> <bbox w="100.5" h="94.0" x="6067.5" y="1043.0"/> <glyph class="macromolecule" id="emtc_emtc_s1552_emtc_emtc_sa818"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide HUGO:YWHAB, HGNC:12849, ENTREZ:7529, GENECARDS:GC20P043515, UNIPROT:P31946 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: YWHAB is so-called 14-3-3 alpha/beta PMID:9069260 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="YWHAB"/> <bbox w="60.0" h="20.0" x="6091.0" y="1045.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1553_emtc_emtc_sa817"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-raf-1 murine leukemia viral oncogene homolog 1 HUGO:RAF1, HGNC:9829, ENTREZ:5894 , GENECARDS:GC03M012625, UNIPROT:P04049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAF1"/> <bbox w="100.0" h="45.0" x="6068.0" y="1069.5"/> <glyph class="state variable" id="_757c83f5-d677-449e-8c9a-d59802b87fe4"> <state value="closed" variable=""/> <bbox w="40.0" h="10.0" x="6098.0" y="1064.5"/> </glyph> <glyph class="state variable" id="_059383cb-a69d-403a-9c07-ed8a175b4d9e"> <state value="" variable="Y340"/> <bbox w="30.0" h="10.0" x="6152.4595" y="1064.5"/> </glyph> <glyph class="state variable" id="_42f2011d-9d8f-4fab-a711-ba983b37fe4c"> <state value="" variable="Y341"/> <bbox w="30.0" h="10.0" x="6151.9175" y="1109.5"/> </glyph> <glyph class="state variable" id="_22eb5721-967e-48b9-b5c3-a136e29b3835"> <state value="P" variable="S259"/> <bbox w="35.0" h="10.0" x="6050.5" y="1064.6061"/> </glyph> <glyph class="state variable" id="_8e21e7f7-28d5-4fa8-a69b-97d5b2ed4061"> <state value="P" variable="S621"/> <bbox w="35.0" h="10.0" x="6050.5" y="1108.317"/> </glyph> <glyph class="state variable" id="_5be2587b-df89-4aca-8374-27f74d6dacd6"> <state value="" variable="S338"/> <bbox w="30.0" h="10.0" x="6053.0" y="1086.9641"/> </glyph> <glyph class="state variable" id="_0da37b92-172b-4ef0-8912-dd3d3ac8cc93"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="6158.0" y="1087.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1611_emtc_emtc_csa153" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:HIF1B*:HIF_alpha_* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:13130303 Regulation of HIF-1a protein synthesis MNK phosphorylates eIF-4E and stimulates its activity directly. Active eIF-4E increases the rate of HIF1A-mRNA translation into HIF1A protein. PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). http://www.sabiosciences.com/pathway.php?sn=HIF1Alpha_Pathway HIF1 consists of a heterodimer of two basic helix-loop-helix PAS (Per-ARNT-Sim) proteins, HIF-1A, and HIF-1B. HIF-1A accumulates under hypoxic conditions whereas HIF-1B. HIF-1A is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for solid tumor expansion including the angiogenic factor VEGF HIF-1B is the ARNT (Aryl hydrocarbon Receptor Nuclear Translocator), an essential component of the xenobiotic responseReferences_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF1A/HIF1B*"/> <bbox w="88.0" h="45.0" x="3870.0" y="2520.5"/> <glyph class="macromolecule" id="emtc_emtc_s1612_emtc_emtc_sa866"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: aryl hydrocarbon receptor nuclear translocator HUGO:ARNT, HGNC:700, ENTREZ:405, GENECARDS:GC01M150782, UNIPROT:P27540 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: http://www.omicsonline.org/1948-5956/JCST-03-035.php HIF-1 is the Commander of Gateways to Cancer PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF1B*"/> <bbox w="40.0" h="20.0" x="3916.0" y="2524.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1613_emtc_emtc_sa867"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162, UNIPROT:Q16665 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: http://www.omicsonline.org/1948-5956/JCST-03-035.php HIF-1 is the Commander of Gateways to Cancer PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIFα*"/> <bbox w="40.0" h="20.0" x="3874.0" y="2523.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1628_emtc_emtc_csa154" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:VEGFA:VEGFR2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11166270 VEGF stands for the vascular Endothelial Growth Factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults VEGFR2 is highly specific towards VEGFA. VEGFR2 is activated through ligand-stimulated receptor dimerization and transphosphorylation (autophosphorylation) of tyrosine residues in the cytoplasmic kinase domain. A total of four major autophosphorylation sites have been identified in VEGFR2, Y951, Y996, Y1054 and Y1059. Y951 and 996 are in the kinase insert region, and Y1054 and 1059 are in the kinase domain PMID:13678960 Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular functions. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFA/VEGFR2*"/> <bbox w="60.0" h="80.0" x="6161.0" y="4811.5"/> <glyph class="macromolecule" id="emtc_emtc_s1630_emtc_emtc_sa883"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA, HGNC:12680, ENTREZ:7422, GENECARDS:GC06P043737, UNIPROT:P15692 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:15111329 VEGF is a predominant angiogenic factor that mediates ocular neovascularization. VEGF is increased by hypoxia, which is one of the primary stimuli for ocular neovascularization. VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is PKC/ERK pathway-dependent. Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases PMID:11166270 VEGF stands for the vascular Endothelial Growth Factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults PMID:13678960 VEGFs belong to a family of homodimeric glycoproteins that containts five members (VEGF-A, B, C, D, and Placenta growth factor PLGF). VEGFs bind to 3 different VEGF-receptor tyrosine kinases (VEGFR-1, 2, 3). Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular functions. PMID:10022831 PMID:15501236 VEGFA is a homodimer that exists in five different isoforms comprising 121, 145, 165, 189, and 206 amino acids per chain. The isoforms differ in their ability to bind heparan sulfate proteoglycans in the extracellular matrix (ECM). In adult Endothelial cells, VEGFA exhibits high affinity binding to tyrosine kinase receptors, VEGFR1 and VEGFR2. Although ECs express both receptors, recent findings suggest that only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFA"/> <bbox w="40.0" h="20.0" x="6174.0" y="4813.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1629_emtc_emtc_sa884"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: kinase insert domain receptor (a type III receptor tyrosine kinase) HUGO:KDR, HGNC:6307, ENTREZ:3791, GENECARDS:GC04M055944, UNIPROT:P35968 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:11166270 VEGFR2 is highly specific towards VEGFA. PMID:11741095 PMID:13678960 However VEGFR2 also binds to processed forms of VEGF-C, D, E. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. PMID:15501236 PMID:14739162 Although Endothelial cells express both receptors VEGFR1 and VEGFR2, only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR2*"/> <bbox w="60.0" h="40.0" x="6162.0" y="4835.5"/> <glyph class="unit of information" id="_914901ba-d5bb-404c-bd34-3a26aa8305cc"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6182.0" y="4830.5"/> </glyph> <glyph class="state variable" id="_7a4ba0b8-5940-4686-8abc-3a78ccce64c2"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="6154.5" y="4831.045"/> </glyph> <glyph class="unit of information" id="_fcc8831c-532e-4ed3-a97a-ef688a04fca9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6169.5" y="4830.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1634_emtc_emtc_csa155" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:L1CAM:VEGFR2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="L1CAM/VEGFR2*"/> <bbox w="128.0" h="89.0" x="6156.0" y="4684.5"/> <glyph class="macromolecule" id="emtc_emtc_s1632_emtc_emtc_sa886"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: L1 cell adhesion molecule HUGO:L1CAM, HGNC:6470, ENTREZ:3897, GENECARDS:GC0XM153126, UNIPROT:P32004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: ISBN:978-953-51-0410-0 PMID:8893017 PMID:20044598 The adhesion molecule L1CAM (CD171) is a 220 kD transmembrane glyocoprotein and belongs to the immunoglobulin superfamily. The extracellular part of the molecule comprises six Ig-like domains followed by 5 fibronectin type III repeats. The transmembrane domain is followed by a short cytoplasmic tail of 32kD PMID:10413675 L1CAM can be expressed and mediate its effects as a membrane-bound form. L1CAM can also be proteolytically cleaved by different proteases releasing a soluble ectodomain that is likewise functionally active. PMID:16199880 PMID:11706054 The metalloproteases ADAM 10 and 17 as well as plasmin have been described to cleave L1CAM generating a soluble 200 kD and 150 kD form, respectively After ADAM-mediated cleavage, the membrane-bound intracellular C-terminal fragment of L1CAM can be further processed by the presenilin/gamma-secretase complex giving rise of a 28 kD fragment. PMID:19260824 This small intracellular fragment translocates into the nucleus where it is thought to contribute to L1CAM-dependent gene regulation. L1CAM can bind to different substrates/molecules in a cell and context dependent manner. PMID:10469653 LACAM can undergo homophilic binding to itself as a membrane-bound or shedded form. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. PMID:8898967 PMID:8636223 PMID:11553709 PMID:10455125 PMID:16377081 PMID:7613634 PMID:1720120 L1CAM can interact with a plethora of other proteins, e.g. integrins aVb1, aVb3, aVb5, a5b1, neuropilin-1, CD24, neurocan, and axonin-1/TAX-1. PMID:6368220 L1CAM was originally identified in cells of the nervous system PMID:9127006 L1CAM expression has been also found in certain populations of hematopoietic cells. PMID:19273627 Potential role for L1CAM in transendothelial migration and trafficking of murine dendritic cells. PMID:9864376 Furthermore, L1CAM is expressed by renal tubular epithelial cells under physiological conditions being involved in branching of renal tubes in the kidney However, distribution of L1CAM in adults is quite restricted so that its elevated expression in cancerous tissues which is discussed in the next paragraph favours its suitability as therapeutic target in anti-cancer therapy. PMID:19356150 PMID:21195665 L1CAM expression in tumors can be associated with the activation of several signalling pathways that are known to play a pivotal role in tumor progression e.g. the MAPK/ERK and AKT pathway or FAK-mediated signalling PMID:15716380 PMID:17699774 PMID:20501702 L1CAM is a target gene of b-catenin-TCF signaling in colorectal cancer cells. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis The transmembrane localization and shedding of L1CAM by metalloproteases, including ADAM10 could be useful for detection and as target for colon cancer therapy. Expression of L1CAM and ADAM10 in human colon cancer cells induces metastasis. NFkB signaling and ezrin are essential for L1CAM-mediated metastasis of colon cancer cells. PMID:21123622 Gavert and al. showed that L1CAM-mediated colon cancer cell metastasis does not require changes in EMT and cancer stem cell markers. BUT in other context, PMID:19435915 PMID:21109948 Geismann and al. showed that upregulation of L1CAM in pancreatic duct cells is TGFB1- and SNAI2-dependent. Binding of SNAI2 to the L1CAM promoter is essential for TGFB1-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. TGFB1–mediated L1CAM expression is SMAD independent but requires JNK activation. In the context of the human PDAC (pancreatic ductal epithelial cell) line H6c7 which mimics the early steps in PDAC tumorigenesis,TGFB1 induces SNAI2 expression in H6c7 cells through JNK activation. THUS, the impact of L1CAM on EMT might be either tumor specific and/or tumor stage dependent. Further studies are required to elaborate whether upregulation of L1CAM is part of the EMT or even the inducing event. If it is the case, elevated cell migration and apoptosis resistance could be abolished by interfering wih TGFB1 signaling or by supression of SNAI2 or L1CAM. PMID:16506207 PMID:17952127 PMID:21373966 Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated. A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes. Besides its ability to induce Erk1/2 and FAK signalling pathways, L1CAM can also lead to the activation of NF-kB, so that inhibition of NF-kB reduced L1CAM-mediated metastasis of colon cancer cells. PMID:17145883 Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases B-catenin transcriptional activity, thus increases scattering and motility of MCF7 breast carcinoma cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="L1CAM"/> <bbox w="60.0" h="20.0" x="6159.5" y="4685.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1633_emtc_emtc_sa887"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: kinase insert domain receptor (a type III receptor tyrosine kinase) HUGO:KDR, HGNC:6307, ENTREZ:3791, GENECARDS:GC04M055944, UNIPROT:P35968 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:11166270 VEGFR2 is highly specific towards VEGFA. PMID:11741095 PMID:13678960 However VEGFR2 also binds to processed forms of VEGF-C, D, E. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. PMID:15501236 PMID:14739162 Although Endothelial cells express both receptors VEGFR1 and VEGFR2, only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR2*"/> <bbox w="60.0" h="40.0" x="6162.5" y="4707.328"/> <glyph class="unit of information" id="_1e1c54e5-281d-443a-b0c9-a25db5eb147b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6182.5" y="4702.328"/> </glyph> <glyph class="state variable" id="_67ea5510-0c2c-4100-94d4-96c9f0edf721"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="6155.0" y="4702.873"/> </glyph> <glyph class="unit of information" id="_d633eb9d-7427-42ce-b801-b6bcc1947bd9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6170.0" y="4702.328"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1823_emtc_emtc_csa162" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BCL2:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:12667443 Fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1 and BCL2 proteins, resulting in cytochrome c release. PMID:14963330 In other hand, cytosolic localization of endogenous p53 was necessary and sufficient for apoptosis. p53 directly activated the pro-apoptotic BCL2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. Binding of BCL2 or BCL2L1 to TP53 therefore antagonizes the activation of BAX via binding to TP53. Like this BCL2 and BCL2L1 also perform their anti-apoptotic effect. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2/TP53"/> <bbox w="103.0" h="43.0" x="4379.0" y="1095.0"/> <glyph class="macromolecule" id="emtc_emtc_s1818_emtc_emtc_sa914"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="37.0" h="16.0" x="4431.5" y="1100.892"/> <glyph class="state variable" id="_d7c14385-7522-43cf-bc31-873dccd3da43"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4463.5" y="1100.5782"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1819_emtc_emtc_sa915"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="37.0" h="16.0" x="4387.5" y="1099.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1824_emtc_emtc_csa161" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BCL2-XL*:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic protines) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic protines)work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:12667443 p53 induces apoptosis by target gene regulation and transcription-independent signaling. A fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Evidence that p53 translocation to the mitochondria occurs in vivo in irradiatedthymocytes was shown. Further, p53 can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1, resulting in cytochrome c release. p53 binds to BCL2L1 via its DNA binding domain. Tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BCL2L1 and promote cytochrome c release. Fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1 and BCL2 proteins, resulting in cytochrome c release. PMID:14963330 In other hand, cytosolic localization of endogenous p53 was necessary and sufficient for apoptosis. p53 directly activated the pro-apoptotic BCL2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. Binding of BCL2 or BCL2L1 to TP53 therefore antagonizes the activation of BAX via binding to TP53. Like this BCL2 and BCL2L1 also perform their anti-apoptotic effect. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2L1/TP53"/> <bbox w="128.0" h="43.0" x="4522.0" y="1094.0"/> <glyph class="macromolecule" id="emtc_emtc_s1817_emtc_emtc_sa913"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:12667443 PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:22836101 BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro-survival family members such as BCL2L1 act to inhibit BAX activation PMID:23064052 PMID:11085534 BCL2 and BCL2L1 are known to be overexpressed in several cancers. In particular, BCL2L1 overexpression has been correlated with cancer cells resistance to chemotherapeutic agents References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2-XL*"/> <bbox w="56.0" h="19.0" x="4592.5" y="1097.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1834_emtc_emtc_sa912"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="42.0" h="16.0" x="4538.0" y="1100.0"/> <glyph class="state variable" id="_15e9ad8b-cf55-49d7-9ebf-0eff5986328e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4575.0" y="1099.6863"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1825_emtc_emtc_csa158" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAX:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:14963330 Cytosolic localization of endogenous p53 was necessary and sufficient for apoptosis. p53 directly activated the pro-apoptotic BCL2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. It was proposed that when p53 accumulates in the cytosol, it can function analogously to the pro-apoptotic BAX protein to activate Bax and trigger apoptosis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX/TP53"/> <bbox w="66.0" h="64.0" x="3980.0" y="1251.0"/> <glyph class="macromolecule" id="emtc_emtc_s253_emtc_emtc_sa898"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="36.0" h="16.0" x="3992.5" y="1279.608"/> <glyph class="state variable" id="_80f63d03-d31d-47fc-a324-2a454a879973"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4023.5" y="1279.2943"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s252_emtc_emtc_sa899"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-associated X protein HUGO:BAX, HGNC:959, ENTREZ:581, UNIPROT:Q07812, GENECARDS:GC19P049458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. PMID:7644501 The susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner. Multiple BCL2 family members demonstrate selective dimerizations with Bax PMID:21641962 The pro-apoptototic protein Bax plays a central role in the mitochondria- dependent apoptotic pathway. In healthy mammalian cells, Bax is essentially cytosolic and inactive. Following a death signal, the protein is translocated to the outer mitochondrial membrane, where it promotes a permeabilization that favors the release of different apoptogenic factors, such as cytochrome c. PMID:23064052 Inactive Bax can be directly converted into an active conformation following the interaction with activator Bid , Bim (BCL2L11) or Puma (BBC3) The interaction of Bax with BCL2 or BCL2L1 drives the translocation of Bax to the outer mitochondrial membrane Under this condition, active Bax can be liberated from its interaction with BCL2L1 by a derepressor BH3-only protein, such as Bad. Other experiments have shown that Bax can be translocated to the outer mitochondrial membrane and further activated by different proteins such as Myc or p38MapK References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX"/> <bbox w="28.0" h="19.0" x="3997.5" y="1255.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1826_emtc_emtc_csa163" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAX:BCL2-XL* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID9153240 By immunoprecipitation and yeast two-hybrid select studies, it appears that Bax may form homodimers or heterodimers with either Bcl2 or BCL2L1 (so-called BCL-XL) Formation of Bax homodimers has been proposed to promote cell death, and this could be blocked by Bax heterodimerization with BCL2 or BCL2L1. Based on Bax overexpression and dimerization studies, it has been postulated that the relative ratio of Bax homodimers to heterodimers may serve as a key sensory switch that dictates the initiation of apoptosis PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. PMID:7937747 Interactions of the BCL2 protein with itself and other members of the BCL2 family, including BCL2L1 (so-called BCL-XL) and Bax, were explored with a yeast two-hybrid system. This approach gave evidence for BCL2 protein homodimerization. BCL2 also interacted with BCL2L1 with the dominant inhibitors Bax. PMID:11085534 Bax undergoes a concurrent inhibition and priming by BCL2L1 Derepressor (such as Bad or Noxa), is sufficient to trigger apoptosis through interaction with antiapoptotic proteins. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX/BCL2L1"/> <bbox w="110.0" h="42.0" x="4660.0" y="1094.0"/> <glyph class="macromolecule" id="emtc_emtc_s1821_emtc_emtc_sa916"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:12667443 PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:22836101 BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro-survival family members such as BCL2L1 act to inhibit BAX activation PMID:23064052 PMID:11085534 BCL2 and BCL2L1 are known to be overexpressed in several cancers. In particular, BCL2L1 overexpression has been correlated with cancer cells resistance to chemotherapeutic agents References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2-XL*"/> <bbox w="60.0" h="16.0" x="4666.5" y="1098.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2898_emtc_emtc_sa917"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-associated X protein HUGO:BAX, HGNC:959, ENTREZ:581, UNIPROT:Q07812, GENECARDS:GC19P049458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. PMID:7644501 The susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner. Multiple BCL2 family members demonstrate selective dimerizations with Bax PMID:21641962 The pro-apoptototic protein Bax plays a central role in the mitochondria- dependent apoptotic pathway. In healthy mammalian cells, Bax is essentially cytosolic and inactive. Following a death signal, the protein is translocated to the outer mitochondrial membrane, where it promotes a permeabilization that favors the release of different apoptogenic factors, such as cytochrome c. PMID:23064052 Inactive Bax can be directly converted into an active conformation following the interaction with activator Bid , Bim (BCL2L11) or Puma (BBC3) The interaction of Bax with BCL2 or BCL2L1 drives the translocation of Bax to the outer mitochondrial membrane Under this condition, active Bax can be liberated from its interaction with BCL2L1 by a derepressor BH3-only protein, such as Bad. Other experiments have shown that Bax can be translocated to the outer mitochondrial membrane and further activated by different proteins such as Myc or p38MapK References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX"/> <bbox w="31.0" h="16.0" x="4733.5" y="1099.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1827_emtc_emtc_csa164" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAX:BCL2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:9872359 A oncogene-derived protein, Bcl2, confers negative control in the pathway of cellular suicide machinery. A Bcl2-homologous protein, Bax, promotes cell death by competing with Bcl2. While Bax–Bax homodimers act as apoptosis inducers, Bcl2– Bax heterodimer formation evokes a survival signal for the cells. Both Bcl2 and Bax are transcriptional targets for the tumour suppressor protein, p53, which induces cell cycle arrest or apoptosis in response to DNA damage. PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX/BCL2"/> <bbox w="82.0" h="44.0" x="4663.5" y="1339.0"/> <glyph class="macromolecule" id="emtc_emtc_s1831_emtc_emtc_sa919"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="35.0" h="18.0" x="4701.0" y="1343.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1830_emtc_emtc_sa918"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-associated X protein HUGO:BAX, HGNC:959, ENTREZ:581, UNIPROT:Q07812, GENECARDS:GC19P049458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. PMID:7644501 The susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner. Multiple BCL2 family members demonstrate selective dimerizations with Bax PMID:21641962 The pro-apoptototic protein Bax plays a central role in the mitochondria- dependent apoptotic pathway. In healthy mammalian cells, Bax is essentially cytosolic and inactive. Following a death signal, the protein is translocated to the outer mitochondrial membrane, where it promotes a permeabilization that favors the release of different apoptogenic factors, such as cytochrome c. PMID:23064052 Inactive Bax can be directly converted into an active conformation following the interaction with activator Bid , Bim (BCL2L11) or Puma (BBC3) The interaction of Bax with BCL2 or BCL2L1 drives the translocation of Bax to the outer mitochondrial membrane Under this condition, active Bax can be liberated from its interaction with BCL2L1 by a derepressor BH3-only protein, such as Bad. Other experiments have shown that Bax can be translocated to the outer mitochondrial membrane and further activated by different proteins such as Myc or p38MapK References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX"/> <bbox w="32.0" h="16.0" x="4667.0" y="1342.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1835_emtc_emtc_csa167" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BBC3:BCL2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. It is via this binding to BBC3 (an apoptic inducer) that BCL2 and BCL2L1 exhibit their anti-apoptic effect. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BBC3/BCL2"/> <bbox w="87.0" h="43.0" x="4269.0" y="1094.0"/> <glyph class="macromolecule" id="emtc_emtc_s1837_emtc_emtc_sa926"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="37.0" h="19.0" x="4273.5" y="1097.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1839_emtc_emtc_sa927"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2 binding component 3 HUGO:BBC3, HGNC:17868, ENTREZ:27113, UNIPROT:Q96PG8, GENECARDS:GC19M047724 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BBC3"/> <bbox w="37.0" h="17.0" x="4313.5" y="1097.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1842_emtc_emtc_csa166" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAK1:BCL2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1/BCL2"/> <bbox w="83.0" h="48.0" x="4916.0" y="1328.0"/> <glyph class="macromolecule" id="emtc_emtc_s1844_emtc_emtc_sa922"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="33.0" h="17.0" x="4923.5" y="1338.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s240_emtc_emtc_sa923"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-antagonist/killer 1 HUGO:BAK1, HGNC:949, ENTREZ:578, UNIPROT:Q16611, GENECARDS:GC06M033489 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1"/> <bbox w="34.0" h="17.0" x="4958.5" y="1337.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1843_emtc_emtc_csa165" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAK1:BCL2-XL* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1/BCL2L1"/> <bbox w="103.0" h="49.0" x="4774.25" y="1333.0"/> <glyph class="macromolecule" id="emtc_emtc_s2856_emtc_emtc_sa920"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:12667443 PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:22836101 BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro-survival family members such as BCL2L1 act to inhibit BAX activation PMID:23064052 PMID:11085534 BCL2 and BCL2L1 are known to be overexpressed in several cancers. In particular, BCL2L1 overexpression has been correlated with cancer cells resistance to chemotherapeutic agents References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2-XL*"/> <bbox w="61.0" h="22.0" x="4776.75" y="1338.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s380_emtc_emtc_sa921"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-antagonist/killer 1 HUGO:BAK1, HGNC:949, ENTREZ:578, UNIPROT:Q16611, GENECARDS:GC06M033489 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1"/> <bbox w="34.0" h="16.0" x="4839.0" y="1342.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s1846_emtc_emtc_csa168" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAK1:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15077116 p53 has a direct signalling role at mitochondria in the induction of apoptosis p53 interacts with the pro- apoptotic mitochondrial membrane protein Bak. Interaction of p53 with Bak causes oligomerization and thus activation of Bak and release of cytochrome c from mitochondria. Formation of the p53–Bak complex coincides with loss of an interaction between Bak and the anti-apoptotic Bcl2-family member Mcl1. These results are consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1/TP53"/> <bbox w="70.0" h="65.0" x="4097.0" y="1171.5"/> <glyph class="macromolecule" id="emtc_emtc_s1847_emtc_emtc_sa928"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="37.0" h="20.0" x="4107.5" y="1195.5"/> <glyph class="state variable" id="_51cc1bb0-8916-413c-8564-08b31337fdd8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4139.5" y="1196.3579"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1848_emtc_emtc_sa929"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-antagonist/killer 1 HUGO:BAK1, HGNC:949, ENTREZ:578, UNIPROT:Q16611, GENECARDS:GC06M033489 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1"/> <bbox w="39.0" h="19.0" x="4106.5" y="1174.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2355_emtc_emtc_csa173" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin1*:Claudin3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin 1/Claudin 3*"/> <bbox w="118.0" h="35.0" x="512.0" y="2920.5"/> <glyph class="macromolecule" id="emtc_emtc_s2356_emtc_emtc_sa1221"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1*"/> <bbox w="57.0" h="16.0" x="572.4" y="2921.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2357_emtc_emtc_sa1222"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="59.0" h="16.0" x="512.4" y="2921.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2359_emtc_emtc_csa174" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin2*:Claudin3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin 2/Claudin 3*"/> <bbox w="126.0" h="35.0" x="508.0" y="2960.5"/> <glyph class="macromolecule" id="emtc_emtc_s2361_emtc_emtc_sa1223"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="63.0" h="17.0" x="510.0" y="2962.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2362_emtc_emtc_sa1224"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="60.0" h="16.0" x="573.0" y="2962.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2360_emtc_emtc_csa175" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin3*:Claudin5* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin 3/Claudin 5*"/> <bbox w="122.0" h="36.0" x="509.0" y="2999.5"/> <glyph class="macromolecule" id="emtc_emtc_s2365_emtc_emtc_sa1225"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="60.0" h="16.0" x="511.5" y="3000.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2364_emtc_emtc_sa1226"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 5 HUGO:CLDN5, HGNC:2047, ENTREZ:7122, UNIPROT:O00501, GENECARDS:GC22M019510 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin5*"/> <bbox w="61.0" h="16.0" x="568.5" y="3000.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2366_emtc_emtc_csa176" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin1*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin 1/Occludin*"/> <bbox w="123.0" h="35.0" x="508.0" y="2592.5"/> <glyph class="macromolecule" id="emtc_emtc_s2371_emtc_emtc_sa1227"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="568.0" y="2593.5"/> <glyph class="state variable" id="_fda64d18-45fe-4683-ada5-fde7d7fb787f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="622.0" y="2596.5254"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2370_emtc_emtc_sa1228"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1*"/> <bbox w="59.0" h="16.0" x="509.5" y="2593.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2367_emtc_emtc_csa177" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin2*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2/Occludin*"/> <bbox w="123.0" h="34.0" x="509.0" y="2646.5"/> <glyph class="macromolecule" id="emtc_emtc_s2374_emtc_emtc_sa1229"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="571.5" y="2647.5"/> <glyph class="state variable" id="_9faa82dd-a82a-467c-9398-d13c7da09576"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="625.5" y="2650.5254"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2373_emtc_emtc_sa1230"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="61.0" h="16.0" x="509.5" y="2647.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2384_emtc_emtc_csa180" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAM2:JAM3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM2*/JAM3*"/> <bbox w="82.0" h="37.0" x="494.0" y="2477.0"/> <glyph class="macromolecule" id="emtc_emtc_s2386_emtc_emtc_sa1235"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: junctional adhesion molecule 2 HUGO:JAM2, HGNC:14686, ENTREZ:58494, UNIPROT:P57087, GENECARDS:GC21P027011 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM2"/> <bbox w="40.0" h="16.0" x="495.0" y="2478.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2385_emtc_emtc_sa1236"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: junctional adhesion molecule 3 HUGO:JAM3, HGNC:15532, ENTREZ:83700, UNIPROT:Q9BX67, GENECARDS:GC11P133972 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM3"/> <bbox w="41.0" h="16.0" x="535.0" y="2478.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2394_emtc_emtc_csa183" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Cingulin*:JAM1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*/JAM1*"/> <bbox w="109.0" h="41.0" x="995.5" y="2254.5"/> <glyph class="macromolecule" id="emtc_emtc_s2395_emtc_emtc_sa1242"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cingulin HUGO:CGN, HGNC:17429, ENTREZ:57530, UNIPROT:Q9P2M7, GENECARDS:GC01P151483 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*"/> <bbox w="63.0" h="18.0" x="997.5" y="2257.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2396_emtc_emtc_sa1243"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="40.0" h="17.0" x="1061.5" y="2258.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2398_emtc_emtc_csa184" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Afadin*:Cingulin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*/Cingulin*"/> <bbox w="112.5" h="41.0" x="1242.25" y="2253.5"/> <glyph class="macromolecule" id="emtc_emtc_s2401_emtc_emtc_sa1246"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4 HUGO:MLLT4, HGNC:7137, ENTREZ:4301, UNIPROT:P55196, GENECARDS:GC06P168227 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*"/> <bbox w="47.0" h="19.0" x="1306.75" y="2255.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3662_emtc_emtc_sa1248"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cingulin HUGO:CGN, HGNC:17429, ENTREZ:57530, UNIPROT:Q9P2M7, GENECARDS:GC01P151483 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*"/> <bbox w="63.0" h="18.0" x="1244.75" y="2256.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2399_emtc_emtc_csa185" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Cingulin*:MyosinII* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*/Myosin II*"/> <bbox w="135.0" h="41.0" x="1321.0" y="2087.5"/> <glyph class="macromolecule" id="emtc_emtc_s2400_emtc_emtc_sa1245"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cingulin HUGO:CGN, HGNC:17429, ENTREZ:57530, UNIPROT:Q9P2M7, GENECARDS:GC01P151483 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*"/> <bbox w="63.0" h="18.0" x="1322.0" y="2090.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3454_emtc_emtc_sa1659"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: MyosinII* myosin, heavy chain 1, skeletal muscle, adult HUGO:MYH1, HGNC:7567, ENTREZ:4619, GENECARDS:GC17M010395, UNIPROT:P12882 myosin, heavy chain 2, skeletal muscle, adult HUGO:MYH2 HGNC:7572 ENTREZ:4620 UNIPROT:Q9UKX2 myosin, heavy chain 3, skeletal muscle, embryonic HUGO:MYH3 HGNC:7573 ENTREZ:4621 UNIPROT:P11055 myosin, heavy chain 4, skeletal muscle HUGO:MYH4 HGNC:7574 ENTREZ:4622 UNIPROT:Q9Y623 myosin, heavy chain 6, cardiac muscle, alpha "myosin, heavy polypeptide 6, cardiac muscle, alpha (cardiomyopathy, hypertrophic 1)" HUGO:MYH6 HGNC:7576 ENTREZ:4624 UNIPROT:P13533 myosin, heavy chain 7, cardiac muscle, beta CMH1, MPD1, "myopathy, distal 1", "myosin, heavy polypeptide 7, cardiac muscle, beta" HUGO:MYH7 HGNC:7577 ENTREZ:4625 UNIPROT:P12883 myosin, heavy chain 7B, cardiac muscle, beta "myosin, heavy polypeptide 7B, cardiac muscle, beta" HUGO:MYH7B HGNC:15906 ENTREZ:57644 UNIPROT:A7E2Y1 myosin, heavy chain 8, skeletal muscle, perinatal "myosin, heavy polypeptide 8, skeletal muscle, perinatal" HUGO:MYH8 HGNC:7578 ENTREZ:4626 UNIPROT:P13535 myosin, heavy chain 9, non-muscle DFNA17, "myosin, heavy polypeptide 9, non-muscle" HUGO:MYH9 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 myosin, heavy chain 10, non-muscle HUGO:MYH10 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 myosin, heavy chain 11, smooth muscle HUGO:MYH11 HGNC:7569 ENTREZ:4629 UNIPROT:P35749 myosin, heavy chain 13, skeletal muscle HUGO:MYH13 HGNC:7571 ENTREZ:8735 UNIPROT:Q9UKX3 myosin, heavy chain 14, non-muscle HUGO:MYH14 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 myosin, heavy chain 15 HUGO:MYH15 HGNC:31073 ENTREZ:22989 UNIPROT:Q9Y2K3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MyosinII*"/> <bbox w="68.0" h="19.0" x="1384.5" y="2089.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2410_emtc_emtc_csa188" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAM1*:MPDZ Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MPDZ/JAM1*"/> <bbox w="89.0" h="39.0" x="760.0" y="2574.5"/> <glyph class="macromolecule" id="emtc_emtc_s2411_emtc_emtc_sa1254"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: multiple PDZ domain protein HUGO:MPDZ HGNC:7208 ENTREZ:8777 UNIPROT:O75970 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11689568 MPDZ accumulates at the TJ in epithelial cells through its binding to Claudins and JAMs. MPDZ is believed to function as a multivalent scaffold protein that recruits various proteins to TJ References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MPDZ"/> <bbox w="39.0" h="18.0" x="764.5" y="2576.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2412_emtc_emtc_sa1255"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="40.0" h="17.0" x="806.5" y="2576.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2413_emtc_emtc_csa189" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Afadin*:JAM1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*/JAM1*"/> <bbox w="96.0" h="42.0" x="1124.5" y="2253.5"/> <glyph class="macromolecule" id="emtc_emtc_s2414_emtc_emtc_sa1256"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4 HUGO:MLLT4, HGNC:7137, ENTREZ:4301, UNIPROT:P55196, GENECARDS:GC06P168227 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*"/> <bbox w="47.0" h="19.0" x="1127.0" y="2257.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2415_emtc_emtc_sa1257"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="40.0" h="17.0" x="1179.0" y="2258.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2416_emtc_emtc_csa190" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Cingulin*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*/Occludin*"/> <bbox w="126.0" h="37.0" x="854.0" y="2574.5"/> <glyph class="macromolecule" id="emtc_emtc_s2417_emtc_emtc_sa1258"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="917.5" y="2577.5"/> <glyph class="state variable" id="_0ec0386e-95f1-412d-aa68-008dab4cf07f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="971.5" y="2580.5254"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2418_emtc_emtc_sa1259"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cingulin HUGO:CGN, HGNC:17429, ENTREZ:57530, UNIPROT:Q9P2M7, GENECARDS:GC01P151483 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*"/> <bbox w="63.0" h="18.0" x="855.5" y="2576.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2419_emtc_emtc_csa191" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Afadin*:ZO1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afain*/ZO1*"/> <bbox w="99.0" h="44.0" x="1447.5" y="2256.0"/> <glyph class="macromolecule" id="emtc_emtc_s2854_emtc_emtc_sa1260"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4 HUGO:MLLT4, HGNC:7137, ENTREZ:4301, UNIPROT:P55196, GENECARDS:GC06P168227 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*"/> <bbox w="47.0" h="19.0" x="1453.5" y="2259.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2853_emtc_emtc_sa1261"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="1503.5" y="2257.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2427_emtc_emtc_csa193" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Afadin*:Nectin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afain*/Nectin*"/> <bbox w="103.0" h="44.0" x="1706.5" y="2268.5"/> <glyph class="macromolecule" id="emtc_emtc_s2428_emtc_emtc_sa1265"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4 HUGO:MLLT4, HGNC:7137, ENTREZ:4301, UNIPROT:P55196, GENECARDS:GC06P168227 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*"/> <bbox w="47.0" h="19.0" x="1756.0" y="2274.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2429_emtc_emtc_sa1266"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: poliovirus receptor-related 1 (herpesvirus entry mediator C) HUGO:PVRL1, HGNC:9706, ENTREZ:5818, UNIPROT:Q15223, GENECARDS:GC11M119542 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:12354099 Interactions between Nectin, Afadin and Occludin suggest a role of the nectin-afadin system in the organization of TJs in epithelial cells References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Nectin*"/> <bbox w="46.0" h="18.0" x="1709.0" y="2274.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2430_emtc_emtc_csa194" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Nectin*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Nectin*/Occludin*"/> <bbox w="122.0" h="41.0" x="1700.5" y="2463.0"/> <glyph class="macromolecule" id="emtc_emtc_s2431_emtc_emtc_sa1267"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: poliovirus receptor-related 1 (herpesvirus entry mediator C) HUGO:PVRL1, HGNC:9706, ENTREZ:5818, UNIPROT:Q15223, GENECARDS:GC11M119542 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:12354099 Interactions between Nectin, Afadin and Occludin suggest a role of the nectin-afadin system in the organization of TJs in epithelial cells References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Nectin*"/> <bbox w="46.0" h="18.0" x="1702.0" y="2466.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2432_emtc_emtc_sa1268"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="1752.0" y="2466.0"/> <glyph class="state variable" id="_4e98e2cb-67c2-4e9a-8fa0-ce249d062255"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1806.0" y="2469.0254"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2433_emtc_emtc_csa195" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LYRIC*:ZO1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LYRIC*/ZO1*"/> <bbox w="94.0" h="38.0" x="1438.0" y="2739.5"/> <glyph class="macromolecule" id="emtc_emtc_s2435_emtc_emtc_sa1269"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: metadherin HUGO:MTDH, HGNC:29608, ENTREZ:92140, UNIPROT:Q86UE4, GENECARDS:GC08P098658 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15383321 MTDH is so-called LYRIC LYRIC colocalizes with ZO1 and Occludin in polarized epithelial cells. This protein is most likely not involved in the TJ formation as a structural component. However, it is required for the maturation of the TJ complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LYRIC*"/> <bbox w="49.0" h="17.0" x="1439.5" y="2741.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2438_emtc_emtc_sa1272"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="1489.5" y="2743.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2434_emtc_emtc_csa196" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LYRIC*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LYRIC*/Occludin*"/> <bbox w="117.0" h="42.0" x="1438.0" y="2866.5"/> <glyph class="macromolecule" id="emtc_emtc_s2436_emtc_emtc_sa1270"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: metadherin HUGO:MTDH, HGNC:29608, ENTREZ:92140, UNIPROT:Q86UE4, GENECARDS:GC08P098658 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15383321 MTDH is so-called LYRIC LYRIC colocalizes with ZO1 and Occludin in polarized epithelial cells. This protein is most likely not involved in the TJ formation as a structural component. However, it is required for the maturation of the TJ complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LYRIC*"/> <bbox w="50.0" h="17.0" x="1441.5" y="2867.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2437_emtc_emtc_sa1271"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="20.0" x="1490.5" y="2868.5"/> <glyph class="state variable" id="_5f07f6e7-87c8-4d13-aca4-67100c37da92"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1544.5" y="2873.5317"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2439_emtc_emtc_csa197" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin*/Occludin*"/> <bbox w="190.0" h="40.0" x="1729.5" y="1967.5"/> <glyph class="macromolecule" id="emtc_emtc_s2440_emtc_emtc_sa1273"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="115.0" h="19.0" x="1732.5" y="1967.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2441_emtc_emtc_sa1274"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="64.0" h="19.0" x="1850.5" y="1969.5"/> <glyph class="state variable" id="_93828cee-ac56-4800-a145-12c9f63c6b19"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1909.5" y="1974.0303"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2444_emtc_emtc_csa198" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Caveolin1*:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin 1*/Occludin*"/> <bbox w="131.0" h="40.0" x="1438.0" y="2919.5"/> <glyph class="macromolecule" id="emtc_emtc_s2445_emtc_emtc_sa1277"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: caveolin 1, caveolae protein, 22kDa HUGO:CAV1, HGNC:1527, ENTREZ:857, UNIPROT:Q03135, GENECARDS:GC07P116164 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22671595 Caveolin-1 is an endocytic scaffolding protein It binds independently to claudin-2 and occludin (co-immunoprecipitation assays). The finding that caveolin-1 interacts with claudin-2 and occludin, but notwith claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin1*"/> <bbox w="68.0" h="19.0" x="1439.5" y="2921.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2446_emtc_emtc_sa1278"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="1508.5" y="2922.5"/> <glyph class="state variable" id="_b2645271-61ff-45b6-8a17-34c1a8efbf83"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1562.5" y="2925.5254"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2447_emtc_emtc_csa199" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Caveolin1*:Claudin2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin 1*/Claudin 2*"/> <bbox w="139.0" h="44.0" x="1439.0" y="2985.5"/> <glyph class="macromolecule" id="emtc_emtc_s2448_emtc_emtc_sa1279"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: caveolin 1, caveolae protein, 22kDa HUGO:CAV1, HGNC:1527, ENTREZ:857, UNIPROT:Q03135, GENECARDS:GC07P116164 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22671595 Caveolin-1 is an endocytic scaffolding protein It binds independently to claudin-2 and occludin (co-immunoprecipitation assays). The finding that caveolin-1 interacts with claudin-2 and occludin, but notwith claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin1*"/> <bbox w="68.0" h="19.0" x="1441.5" y="2986.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2449_emtc_emtc_sa1280"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="64.0" h="19.0" x="1510.5" y="2987.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2451_emtc_emtc_csa200" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin11*:ITGB1:TSPAN3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin 11*/ITGB1/TSPAN3"/> <bbox w="172.0" h="60.0" x="1151.0" y="3135.5"/> <glyph class="macromolecule" id="emtc_emtc_s2452_emtc_emtc_sa1282"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tetraspanin 3 HUGO:TSPAN3, HGNC:17752, ENTREZ:10099, UNIPROT:O60637, GENECARDS:GC15M077336 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:11309411 PMID:14570575 TSPAN3 is a tetraspanin expressed at high levels in brain. Claudin-11 forms a complex with TSPAN3 and ITGB1. This interaction potentially regulates proliferation and migration of oligodendrocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TSPAN3"/> <bbox w="55.0" h="16.0" x="1249.0" y="3153.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2453_emtc_emtc_sa1283"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: claudin 11 HUGO:CLDN11, HGNC:8514, ENTREZ:5010099, UNIPROT:O75508, GENECARDS:GC03P170136 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:11309411 Claudin-11 forms a complex with TSPAN3 and ITGB1. This interaction potentially regulates proliferation and migration of oligodendrocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin11*"/> <bbox w="70.0" h="17.0" x="1157.0" y="3159.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2454_emtc_emtc_sa1284"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="41.0" h="18.0" x="1179.0" y="3139.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2455_emtc_emtc_csa201" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Caveolin1*:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin 1*/ITGB1"/> <bbox w="114.0" h="40.0" x="1440.0" y="3064.5"/> <glyph class="macromolecule" id="emtc_emtc_s2456_emtc_emtc_sa1285"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: caveolin 1, caveolae protein, 22kDa HUGO:CAV1, HGNC:1527, ENTREZ:857, UNIPROT:Q03135, GENECARDS:GC07P116164 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22671595 Caveolin-1 is an endocytic scaffolding protein It binds independently to claudin-2 and occludin (co-immunoprecipitation assays). The finding that caveolin-1 interacts with claudin-2 and occludin, but notwith claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin1*"/> <bbox w="68.0" h="19.0" x="1440.0" y="3066.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2457_emtc_emtc_sa1286"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="17.0" x="1510.0" y="3068.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2474_emtc_emtc_csa204" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA4 is so-called Connexin 37 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA4/GJA4"/> <bbox w="121.5" h="37.0" x="511.25" y="5324.0"/> <glyph class="macromolecule" id="emtc_emtc_s2475_emtc_emtc_sa1303"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA4 is so-called Connexin 37 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA4"/> <bbox w="37.0" h="16.0" x="594.35" y="5325.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2475_emtc_emtc_sa1304"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA4 is so-called Connexin 37 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA4"/> <bbox w="37.0" h="16.0" x="532.55" y="5325.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2484_emtc_emtc_csa206" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA8 is so-called Connexin 50 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA8/GJA8"/> <bbox w="120.0" h="37.5" x="512.0" y="5523.75"/> <glyph class="macromolecule" id="emtc_emtc_s2486_emtc_emtc_sa1311"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA8 is so-called Connexin 50 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA8"/> <bbox w="35.0" h="16.0" x="531.3" y="5524.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2486_emtc_emtc_sa1312"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA8 is so-called Connexin 50 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA8"/> <bbox w="36.0" h="16.0" x="575.1" y="5524.75"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2508_emtc_emtc_csa209" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJB1:v-SRC* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1/SRC"/> <bbox w="92.0" h="42.0" x="735.0" y="5625.5"/> <glyph class="macromolecule" id="emtc_emtc_s2509_emtc_emtc_sa1335"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="790.6" y="5626.7"/> <glyph class="state variable" id="_096f99ff-ec24-4e48-a7ad-1894485b0712"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="820.6" y="5622.0967"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4538_emtc_emtc_sa1336"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) HUGO:SRC, HGNC:11283, ENTREZ:6714, UNIPROT:P12931, GENECARDS:GC20P035973 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:9278444 Reduction of gap junctional communication in v-src transformed cells is accompanied by tyrosine phosphorylation of the gap junction protein, connexin 43 SH3 and SH2 domains of v-Src bind to proline-rich motifs and a phosphorylated tyrosine residue in the C-terminal tail of Cx43 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="v-SRC*"/> <bbox w="49.0" h="16.0" x="741.6" y="5626.7"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2513_emtc_emtc_csa179" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:JAM1_2_3*:ZO1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1_2_3*/ZO1*"/> <bbox w="107.0" h="56.0" x="954.0" y="2443.5"/> <glyph class="macromolecule" id="emtc_emtc_s2383_emtc_emtc_sa1234"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="981.0" y="2467.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2910_emtc_emtc_sa1343"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: JAM1_2_3* F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 junctional adhesion molecule 2 HUGO:JAM2, HGNC:14686, ENTREZ:58494, UNIPROT:P57087, GENECARDS:GC21P027011 junctional adhesion molecule 3 HUGO:JAM3, HGNC:15532, ENTREZ:83700, UNIPROT:Q9BX67, GENECARDS:GC11P133972 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1_2_3*"/> <bbox w="80.0" h="20.0" x="961.0" y="2445.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2519_emtc_emtc_csa181" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ZO1*:ZO2_3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*/ZO2_3*"/> <bbox w="93.0" h="41.5" x="950.5" y="2656.75"/> <glyph class="macromolecule" id="emtc_emtc_s2388_emtc_emtc_sa1237"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="951.5" y="2660.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2518_emtc_emtc_sa1345"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO2_3* tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO2_3*"/> <bbox w="50.0" h="17.0" x="991.5" y="2659.75"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2527_emtc_emtc_csa187" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin1_5_8*:MPDZ Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1_5_8*/MPDZ"/> <bbox w="158.0" h="43.0" x="896.0" y="2974.5"/> <glyph class="macromolecule" id="emtc_emtc_s2408_emtc_emtc_sa1252"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: multiple PDZ domain protein HUGO:MPDZ HGNC:7208 ENTREZ:8777 UNIPROT:O75970 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11689568 MPDZ accumulates at the TJ in epithelial cells through its binding to Claudins and JAMs. MPDZ is believed to function as a multivalent scaffold protein that recruits various proteins to TJ References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MPDZ"/> <bbox w="39.0" h="18.0" x="1003.5" y="2978.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2528_emtc_emtc_sa1351"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Claudin1_5_8* claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 claudin 5 HUGO:CLDN5, HGNC:2047, ENTREZ:7122, UNIPROT:O00501, GENECARDS:GC22M019510 claudin 8 HUGO:CLDN8, HGNC:2050, ENTREZ:9073, UNIPROT:P56748, GENECARDS:GC21M031586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1_5_8*"/> <bbox w="100.0" h="20.0" x="900.0" y="2977.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2529_emtc_emtc_csa182" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Cingulin*:ZO1_2_3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*/ZO1_2_3*"/> <bbox w="131.0" h="42.5" x="1161.0" y="2732.0"/> <glyph class="macromolecule" id="emtc_emtc_s2392_emtc_emtc_sa1240"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cingulin HUGO:CGN, HGNC:17429, ENTREZ:57530, UNIPROT:Q9P2M7, GENECARDS:GC01P151483 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*"/> <bbox w="63.0" h="18.0" x="1162.5" y="2735.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2530_emtc_emtc_sa1352"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO1_2_3* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2_3*"/> <bbox w="60.0" h="20.0" x="1228.0" y="2734.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2532_emtc_emtc_csa192" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:ZO1_2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin*/ZO1_2*"/> <bbox w="182.25" h="42.0" x="1534.375" y="1964.5"/> <glyph class="macromolecule" id="emtc_emtc_s2423_emtc_emtc_sa1262"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="119.0" h="19.0" x="1538.875" y="1967.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2851_emtc_emtc_sa1386"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO1_2* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2*"/> <bbox w="56.0" h="19.0" x="1658.875" y="1968.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2537_emtc_emtc_csa202" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA1:GJA1_4_GJC1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1/GJA1_4_GJC1*"/> <bbox w="140.0" h="40.0" x="502.0" y="5082.5"/> <glyph class="macromolecule" id="emtc_emtc_s2538_emtc_emtc_sa1297"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1"/> <bbox w="39.0" h="16.0" x="602.5" y="5084.5"/> <glyph class="state variable" id="_069cb8dc-6c3d-49bb-aaa4-87b648ba6cd4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="636.32135" y="5079.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2540_emtc_emtc_sa1358"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: GJA1_4_GJC1* gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1_4_GJC1*"/> <bbox w="100.0" h="20.0" x="504.0" y="5083.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2545_emtc_emtc_csa203" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA1_3_4_8_GJB2*:GJA3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 PMID:8188753 Heterotypic channels composed of Cx46 (GJA3) paired with either Cx43 (GJA1) or Cx50 (GJA8) were also well coupled Cx50 (GJA8) did not form functional channels with Cx43 (GJA1). GJA8 is so-called Connexin 50 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3/GJA1_3_4_8_GJB2*"/> <bbox w="160.0" h="40.0" x="492.0" y="5222.5"/> <glyph class="macromolecule" id="emtc_emtc_s2472_emtc_emtc_sa1301"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3"/> <bbox w="39.0" h="16.0" x="611.6" y="5227.5"/> <glyph class="state variable" id="_df5741e5-ace7-454c-bfb9-56435c42177b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="645.6" y="5223.341"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2544_emtc_emtc_sa1360"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: GJA1_3_4_8_GJB2* gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1_3_4_8_GJB2*"/> <bbox w="120.0" h="20.0" x="492.0" y="5224.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2547_emtc_emtc_csa205" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA1_5_GJC1*:GJA5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA5 is so-called Connexin 40 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA5/GJA1_5_GJC1*"/> <bbox w="140.0" h="40.0" x="502.0" y="5422.5"/> <glyph class="macromolecule" id="emtc_emtc_s2548_emtc_emtc_sa1310"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 5, 40kDa HUGO:GJA5, HGNC:4279, ENTREZ:2702, UNIPROT:P36382, GENECARDS:GC01M147228 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA5 is so-called Connexin 40 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA5"/> <bbox w="35.0" h="16.0" x="604.5" y="5425.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2550_emtc_emtc_sa1362"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: GJA1_5_GJC1* gap junction protein, alpha 5, 40kDa HUGO:GJA5, HGNC:4279, ENTREZ:2702, UNIPROT:P36382, GENECARDS:GC01M147228 gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA5 is so-called Connexin 40 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1_5_GJC1*"/> <bbox w="100.0" h="20.0" x="504.0" y="5423.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2555_emtc_emtc_csa207" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA3_8_GJB1_GJB2*:GJB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1/GJA3_8_GJB1_GJB2*"/> <bbox w="160.0" h="40.0" x="512.0" y="5662.5"/> <glyph class="macromolecule" id="emtc_emtc_s2489_emtc_emtc_sa1315"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="634.5" y="5667.5"/> <glyph class="state variable" id="_658b1a42-850f-4e76-a2a4-85c19885b94a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="664.5" y="5662.8965"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2554_emtc_emtc_sa1364"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: GJA3_8_GJB1_GJB2* gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 gap junction protein, beta 2, 26kDa HUGO:GJB2, HGNC:4284, ENTREZ:2706, UNIPROT:P29033, GENECARDS:GC13M020761 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3_8_GJB1_GJB2*"/> <bbox w="120.0" h="20.0" x="512.0" y="5664.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2565_emtc_emtc_csa178" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Occludin_Claudin1_2_4_5_7_8_16*:ZO1_2_3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin_Claudin1_2_4_5_7_8_16*/ZO1_2_3*"/> <bbox w="278.0" h="43.0" x="803.0" y="2797.5"/> <glyph class="macromolecule" id="emtc_emtc_s2521_emtc_emtc_sa1347"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO1_2_3* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2_3*"/> <bbox w="60.0" h="20.0" x="1017.0" y="2800.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2564_emtc_emtc_sa1349"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Occludin_Claudin1_2_4_5_7_8_16* occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, UNIPROT:O14493, GENECARDS:GC07P073213 claudin 5 HUGO:CLDN5, HGNC:2047, ENTREZ:7122, UNIPROT:O00501, GENECARDS:GC22M019510 Claudin 7 HUGO:CLDN7, HGNC:2049, ENTREZ:1366, UNIPROT:O95471, GENECARDS:GC17M007163 Claudin 8 HUGO:CLDN8, HGNC:2050, ENTREZ:9073, UNIPROT:P56748, GENECARDS:GC21M031586 Claudin 16 HUGO:CLDN16, HGNC:2037, ENTREZ:10686, UNIPROT:Q9Y5I7, GENECARDS:GC03P190040 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin_Claudin1_2_4_5_7_8_16*"/> <bbox w="207.0" h="18.0" x="806.0" y="2799.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2567_emtc_emtc_csa210" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA3_8*:ZO1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:12808044 Cx46 (GJA3) and Cx50 (GJA8) interact with ZO-1 PMID:21965293 Cx50 requires an intact PDZ-binding motif and ZO-1 for the formation of functional intercellular channels. PMID:19439604 ZO-1 formed a clear margin around the large Cx50 plaques instead of being colocalized with the connexin staining. This finding suggests the involvement of ZO-1 in the composition of tight or adherens junctions around gap-junctional plaques instead of interacting with connexins directly References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3_8*/ZO1"/> <bbox w="105.0" h="39.0" x="1059.5" y="5263.0"/> <glyph class="macromolecule" id="emtc_emtc_s2568_emtc_emtc_sa1373"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: GJA3_8* gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:12808044 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3_8*"/> <bbox w="60.0" h="20.0" x="1061.5" y="5265.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2569_emtc_emtc_sa1374"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="1122.5" y="5265.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2833_emtc_emtc_csa211" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJB1:Occludin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:10581193 Induction of tight junctions in human connexin 32-transfected mouse hepatocytes: connexin 32 interacts with occludin. PMID:17568974 Connexins induce and maintain tight junctions in epithelial cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1/Occludin*"/> <bbox w="85.0" h="50.0" x="869.5" y="5617.5"/> <glyph class="macromolecule" id="emtc_emtc_s2834_emtc_emtc_sa1375"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="892.0" y="5617.5"/> <glyph class="state variable" id="_e47d45c3-288e-4c01-a067-493a0a854b01"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="922.0" y="5612.8965"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2836_emtc_emtc_sa1377"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="880.0" y="5634.5"/> <glyph class="state variable" id="_4db0ccfd-2f57-45e6-9bfe-08e187fdc30c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="934.0" y="5637.5254"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2839_emtc_emtc_csa212" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJB1:ZO1_2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1/ZO1_2*"/> <bbox w="100.0" h="40.0" x="982.0" y="5622.5"/> <glyph class="macromolecule" id="emtc_emtc_s2840_emtc_emtc_sa1379"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO1_2* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2*"/> <bbox w="60.0" h="20.0" x="983.0" y="5624.078"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2841_emtc_emtc_sa1380"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="1041.5" y="5624.078"/> <glyph class="state variable" id="_cd9cbfed-24c6-4a83-b4bb-faefa2f389c0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1071.5" y="5619.4746"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2842_emtc_emtc_csa208" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA1:ZO1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:15980428 PMID:19284610 The associations between Cx43 and ZO-1 and ZO-2 proteins were shown to be under cell-cycle stage-specific control. Connexin 43 interacts preferentially with ZO-1 during G0 stage, whereas the interaction with ZO-2 is approximately the same during the various stages References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1/ZO1*"/> <bbox w="100.0" h="40.0" x="942.0" y="5002.5"/> <glyph class="macromolecule" id="emtc_emtc_s2494_emtc_emtc_sa1319"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1"/> <bbox w="39.0" h="16.0" x="950.5" y="5005.166"/> <glyph class="state variable" id="_b94bdc64-8223-4351-b120-74e6648831d7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="984.32135" y="5000.166"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2843_emtc_emtc_sa1381"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="995.0" y="5005.166"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2844_emtc_emtc_csa213" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJA1:ZO2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:15980428 PMID:19284610 The associations between Cx43 and ZO-1 and ZO-2 proteins were shown to be under cell-cycle stage-specific control. Connexin 43 interacts preferentially with ZO-1 during G0 stage, whereas the interaction with ZO-2 is approximately the same during the various stages References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1/ZO2*"/> <bbox w="100.0" h="40.0" x="1082.0" y="5002.5"/> <glyph class="macromolecule" id="emtc_emtc_s2845_emtc_emtc_sa1382"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1"/> <bbox w="39.0" h="16.0" x="1085.5" y="5003.5"/> <glyph class="state variable" id="_39379952-fce3-42d1-ba4d-637cd7a5f486"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1119.3213" y="4998.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2847_emtc_emtc_sa1383"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO2*"/> <bbox w="40.0" h="20.0" x="1137.0" y="5003.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2852_emtc_emtc_csa186" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:Afadin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin*/Afadin*"/> <bbox w="165.5" h="41.0" x="1351.25" y="1966.5"/> <glyph class="macromolecule" id="emtc_emtc_s3661_emtc_emtc_sa1249"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="105.0" h="20.0" x="1408.25" y="1967.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2406_emtc_emtc_sa1250"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4 HUGO:MLLT4, HGNC:7137, ENTREZ:4301, UNIPROT:P55196, GENECARDS:GC06P168227 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*"/> <bbox w="47.0" h="19.0" x="1358.25" y="1967.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2859_emtc_emtc_csa214" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJC1:ZO1_3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11557048 GJC1 interacts with the PDZ domains of ZO-1 and ZO-3 but not ZO-2 PMID:11313345 Connexin45 (GJC1) interacts with ZO-1 and connexin43 (GJA1) in osteoblastic cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1/ZO1_3*"/> <bbox w="105.0" h="40.0" x="1107.5" y="5624.5"/> <glyph class="macromolecule" id="emtc_emtc_s2861_emtc_emtc_sa1388"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO1_3* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:Identifiers_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_3*"/> <bbox w="60.0" h="20.0" x="1144.5" y="5624.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2858_emtc_emtc_sa1389"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11557048 GJC1 interacts with the PDZ domains of ZO-1 and ZO-3 but not ZO-2 PMID:11313345 Connexin45 (GJC1) interacts with ZO-1 and connexin43 (GJA1) in osteoblastic cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1"/> <bbox w="35.0" h="16.0" x="1108.0" y="5626.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2865_emtc_emtc_csa216" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJD2:ZO1_2_3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:19418635 GJD2 is widely expressed in neurons and was previously shown to interact with the PDZ domain-containing protein ZO-1. Direct association of connexin36 (GJD2) with ZO-2 and ZO-3 was also demonstrated. PMID:15558297 Association of connexin36 with ZO-1 in HeLa cells, betaTC-3 cells, pancreas, and adrenal gland. The functional significance of Cx36/ZO-1 interaction remains to be established Interestingly, ZO-1 was not associated with Cx36 intracellularly, suggesting that functions of its interaction with at least Cx36 may be restricted to intact gap junctions at plasma membranes. PMID:16650609 Association of connexin36 and ZO-1 with ZO-2 and the transcription factor ZO-1-associated nucleic acid-binding protein at neuronal gap junctions in rodent retina. PMID:17681699 In the outer plexiform layer of mouse retina, ZO-1 interacts with connexin36 but not with Cx57, and there is an absence of connexin57/connexin36 heterotypic gap junctional coupling in mouse retina References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2/ZO1_2_3*"/> <bbox w="100.0" h="40.0" x="1270.0" y="5624.5"/> <glyph class="macromolecule" id="emtc_emtc_s2305_emtc_emtc_sa1392"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, delta 2, 36kDa HUGO:GJD2, HGNC:19154, ENTREZ:57369, UNIPROT:Q9UKL4, GENECARDS:GC15M035043 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJD2 is so-called Connexin 36 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2"/> <bbox w="34.0" h="16.0" x="1273.0" y="5626.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2867_emtc_emtc_sa1393"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZO1_2_3* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2_3*"/> <bbox w="60.0" h="20.0" x="1308.0" y="5626.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2868_emtc_emtc_csa217" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJD2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJD2 is so-called Connexin 36 PMID:19418635 GJD2 is widely expressed in neurons and was previously shown to interact with the PDZ domain-containing protein ZO-1. Direct association of connexin36 (GJD2) with ZO-2 and ZO-3 was also demonstrated. PMID:15558297 Association of connexin36 with ZO-1 in HeLa cells, betaTC-3 cells, pancreas, and adrenal gland. PMID:16650609 Association of connexin36 and ZO-1 with ZO-2 and the transcription factor ZO-1-associated nucleic acid-binding protein at neuronal gap junctions in rodent retina. PMID:17681699 In the outer plexiform layer of mouse retina, ZO-1 interacts with connexin36 but not with Cx57, and there is an absence of connexin57/connexin36 heterotypic gap junctional coupling in mouse retina PMID:18815262 Cx36 and Cx45 coexpressed in HeLacells. However, Cx36 and Cx45 expressed separately did not form immunofluorescent puncta containing both connexins, supporting lack of heterotypic coupling competence. Cx45 is almost always accompanied by Cx36, forming bihomotypic gap junctions, with Cx45 structurally coupling to Cx45 and Cx36 coupling to Cx36. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2/GJD2"/> <bbox w="120.0" h="40.0" x="512.0" y="5982.5"/> <glyph class="macromolecule" id="emtc_emtc_s2871_emtc_emtc_sa1394"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, delta 2, 36kDa HUGO:GJD2, HGNC:19154, ENTREZ:57369, UNIPROT:Q9UKL4, GENECARDS:GC15M035043 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJD2 is so-called Connexin 36 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2"/> <bbox w="34.0" h="16.0" x="531.0" y="5985.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2871_emtc_emtc_sa1395"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, delta 2, 36kDa HUGO:GJD2, HGNC:19154, ENTREZ:57369, UNIPROT:Q9UKL4, GENECARDS:GC15M035043 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJD2 is so-called Connexin 36 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2"/> <bbox w="34.0" h="16.0" x="569.0" y="5985.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2873_emtc_emtc_csa218" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GJC1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJC1is so-called Connexin 45 PMID:18815262 Cx36 and Cx45 coexpressed in HeLacells. However, Cx36 and Cx45 expressed separately did not form immunofluorescent puncta containing both connexins, supporting lack of heterotypic coupling competence. Cx45 is almost always accompanied by Cx36, forming bihomotypic gap junctions, with Cx45 structurally coupling to Cx45 and Cx36 coupling to Cx36. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1/GJC1"/> <bbox w="120.0" h="40.0" x="512.0" y="5882.5"/> <glyph class="macromolecule" id="emtc_emtc_s2875_emtc_emtc_sa1396"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11557048 GJC1 interacts with the PDZ domains of ZO-1 and ZO-3 but not ZO-2 PMID:11313345 Connexin45 (GJC1) interacts with ZO-1 and connexin43 (GJA1) in osteoblastic cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1"/> <bbox w="35.0" h="16.0" x="574.5" y="5885.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2875_emtc_emtc_sa1397"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11557048 GJC1 interacts with the PDZ domains of ZO-1 and ZO-3 but not ZO-2 PMID:11313345 Connexin45 (GJC1) interacts with ZO-1 and connexin43 (GJA1) in osteoblastic cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1"/> <bbox w="35.0" h="16.0" x="534.5" y="5885.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2905_emtc_emtc_csa219" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:RHOA Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_GTP"/> <bbox w="66.0" h="57.0" x="4839.5" y="2154.0"/> <glyph class="simple chemical" id="emtc_emtc_s2904_emtc_emtc_sa1412"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="4852.5" y="2177.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2906_emtc_emtc_sa1413"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOA"/> <bbox w="52.0" h="20.0" x="4848.5" y="2159.857"/> <glyph class="state variable" id="_09fc7d15-1817-49c6-92f9-8514bf6b05bb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4843.5" y="2164.841"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2907_emtc_emtc_csa220" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GDP:RHOA Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_GDP"/> <bbox w="67.0" h="59.0" x="4838.5" y="1913.0"/> <glyph class="macromolecule" id="emtc_emtc_s970_emtc_emtc_sa684"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOA"/> <bbox w="52.0" h="20.0" x="4851.5" y="1914.0"/> <glyph class="state variable" id="_b9ddd2da-40b3-4ddc-9bee-7f0081063f97"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4846.5" y="1918.9841"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2908_emtc_emtc_sa1414"> <label text="GDP"/> <bbox w="35.0" h="17.0" x="4857.5" y="1935.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2917_emtc_emtc_csa221" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:RHOA:ROCK* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12778124 In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop. Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_GTP/ROCK*"/> <bbox w="101.0" h="63.0" x="4865.0" y="2309.5"/> <glyph class="macromolecule" id="emtc_emtc_s2914_emtc_emtc_sa1417"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOA"/> <bbox w="52.0" h="20.0" x="4871.5" y="2314.5"/> <glyph class="state variable" id="_4ccdfb43-ef1c-493e-a9f8-e4f15eed5d7f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4866.5" y="2319.4841"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2915_emtc_emtc_sa1418"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="4870.5" y="2332.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2916_emtc_emtc_sa1419"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ROCK Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 Rho-associated, coiled-coil containing protein kinase 2 HUGO:ROCK2, HGNC:10252, ENTREZ:9475, UNIPROT:O75116, GENECARDS:GC02M011272 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:12778124 In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop. Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK*"/> <bbox w="40.0" h="26.0" x="4921.5" y="2318.5"/> <glyph class="state variable" id="_96451998-4825-47eb-99d8-0e6773b4771a"> <state value="open" variable=""/> <bbox w="30.0" h="10.0" x="4926.5" y="2313.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2920_emtc_emtc_csa222" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:DIA*:GTP:RHOA Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_GTP/DIA*"/> <bbox w="101.0" h="62.0" x="4995.0" y="2310.5"/> <glyph class="macromolecule" id="emtc_emtc_s2921_emtc_emtc_sa1421"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOA"/> <bbox w="52.0" h="20.0" x="5001.5" y="2312.5"/> <glyph class="state variable" id="_aa15b0f4-e6ce-4a06-8c6a-b054d1f05aaa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4996.5" y="2317.4841"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2922_emtc_emtc_sa1422"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5000.5" y="2330.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2923_emtc_emtc_sa1423"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: DIA* diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 diaphanous homolog 3 (Drosophila) HUGO:DIAPH3, HGNC:15480, ENTREZ:81624, GENECARDS:GC13M060239, UNIPROT:Q9NSV4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DIA*"/> <bbox w="44.0" h="29.0" x="5046.0" y="2317.5"/> <glyph class="state variable" id="_c05e1fd9-3b10-4e13-b0e3-8d44a7fa898c"> <state value="open" variable=""/> <bbox w="30.0" h="10.0" x="5053.0" y="2312.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2942_emtc_emtc_csa223" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:RHOB Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB_GTP"/> <bbox w="70.0" h="60.0" x="5458.0" y="2008.5"/> <glyph class="macromolecule" id="emtc_emtc_s2241_emtc_emtc_sa1106"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member B HUGO:RHOB, HGNC:668, ENTREZ:388, GENECARDS:GC02P020568, UNIPROT:P62745 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOB"/> <bbox w="41.0" h="18.0" x="5477.5" y="2013.5"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2940_emtc_emtc_sa1445"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5473.0" y="2028.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2943_emtc_emtc_csa224" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GDP:RHOB Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB_GDP"/> <bbox w="70.0" h="60.0" x="5458.0" y="1868.5"/> <glyph class="macromolecule" id="emtc_emtc_s2944_emtc_emtc_sa1446"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member B HUGO:RHOB, HGNC:668, ENTREZ:388, GENECARDS:GC02P020568, UNIPROT:P62745 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOB"/> <bbox w="41.0" h="18.0" x="5467.5" y="1873.5"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2946_emtc_emtc_sa1448"> <label text="GDP"/> <bbox w="35.0" h="17.0" x="5470.5" y="1894.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2957_emtc_emtc_csa226" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:RHOB:RhoB_cytoskeletal_effectors* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: Once activated, the GTPases bind to a spectrum of effectors to stimulate downstream signaling pathways. RhoB binding to DIAPH1, DIAPH2 and RHPN2 leads to actin polymerization and cytoskeleton rearrangements, and also regulates endosomal trafficking. PRK1 and RTKN are also RhoB downstream effectors. RhoB can directly bind to PLCE1 and stimulate its enzymatic activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB/RhoB_cytoskeletal_effectors*"/> <bbox w="200.0" h="60.0" x="5312.0" y="2612.5"/> <glyph class="macromolecule" id="emtc_emtc_s2959_emtc_emtc_sa1460"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: RhoB_cytoskeletal_effectors* diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 diaphanous homolog 3 (Drosophila) HUGO:DIAPH3, HGNC:15480, ENTREZ:81624, GENECARDS:GC13M060239, UNIPROT:Q9NSV4 rhophilin, Rho GTPase binding protein 2 HUGO:RHPN2, HGNC:19974, ENTREZ:85415, GENECARDS:GC19M033469, UNIPROT:Q8IUC4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB_cytoskeletal_effectors*"/> <bbox w="160.0" h="20.0" x="5332.0" y="2632.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2960_emtc_emtc_sa1461"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member B HUGO:RHOB, HGNC:668, ENTREZ:388, GENECARDS:GC02P020568, UNIPROT:P62745 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOB"/> <bbox w="41.0" h="18.0" x="5351.5" y="2615.5"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2961_emtc_emtc_sa1462"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5392.0" y="2614.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2958_emtc_emtc_csa225" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:RHOA:RhoA_cytoskeletal_effectors* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: Once activated, the GTPases bind to a spectrum of effectors to stimulate downstream signaling pathways. Binding of RhoA to TOCK, DIAPH1, THPN1 leads to actin polymerization and cytoskeleton rearrangements. PRK1 is a RhoA effector involved in endosomal trafficking RhoA can directly bind and activate PLD1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA/RhoA_cytoskeletal_effectors*"/> <bbox w="210.0" h="60.0" x="4987.0" y="2612.5"/> <glyph class="macromolecule" id="emtc_emtc_s2954_emtc_emtc_sa1457"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: RhoA_cytoskeletal_effectors* diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 rhophilin, Rho GTPase binding protein 1 HUGO:RHPN1, HGNC:19973, ENTREZ:114822, GENECARDS:GC08P144451, UNIPROT:114822 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_cytoskeletal_effectors*"/> <bbox w="160.0" h="20.0" x="5010.0" y="2633.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2955_emtc_emtc_sa1458"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOA"/> <bbox w="52.0" h="20.0" x="5031.0" y="2615.5"/> <glyph class="state variable" id="_25ada3ea-f6e5-4b08-850d-2ab9a5fa8454"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5026.0" y="2620.4841"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2956_emtc_emtc_sa1459"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5077.0" y="2614.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2963_emtc_emtc_csa227" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PKN1:RhoA_B* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8571126 PKN1 and RHPN1 as targets of small GTPase Rho. PMID:8662891 RTKN is a new putative target for Rho bearing homology to PKN1, and RHPN proteins in the rho-binding domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_B*/PKN1"/> <bbox w="119.0" h="48.0" x="5287.0" y="2419.5"/> <glyph class="macromolecule" id="emtc_emtc_s2965_emtc_emtc_sa1465"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: RhoA_B* ras homolog family member B HUGO:RHOB, HGNC:668, ENTREZ:388, GENECARDS:GC02P020568, UNIPROT:P62745 ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_B*"/> <bbox w="60.0" h="20.0" x="5296.0" y="2425.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2966_emtc_emtc_sa1466"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: protein kinase N1 HUGO:PKN1, HGNC:9405, ENTREZ:5585, GENECARDS:GC19P014544, UNIPROT:Q16512 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8571126 PKN1 and RHPN1 as targets of small GTPase Rho. PMID:8662891 RTKN is a new putative target for Rho bearing homology to PKN1, and RHPN proteins in the rho-binding domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PKN1"/> <bbox w="40.0" h="17.0" x="5362.0" y="2434.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2968_emtc_emtc_csa228" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GDP:RAC1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12480336 PMID:16212495 Rac1 is a member of the Ras superfamily of small GTPases. It plays essential role in control of the cell polarity, actin cytoskeleton rearrangements, protein trafficking and directed motility in a wide variety of mammalian cells References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1_GDP"/> <bbox w="70.0" h="60.0" x="5758.0" y="1885.5"/> <glyph class="macromolecule" id="emtc_emtc_s2166_emtc_emtc_sa1031"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="42.0" h="18.0" x="5772.0" y="1886.5"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2967_emtc_emtc_sa1467"> <label text="GDP"/> <bbox w="35.0" h="17.0" x="5773.5" y="1907.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2969_emtc_emtc_csa229" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:RAC1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12480336 PMID:16212495 Rac1 is a member of the Ras superfamily of small GTPases. It plays essential role in control of the cell polarity, actin cytoskeleton rearrangements, protein trafficking and directed motility in a wide variety of mammalian cells PMID:11152757 Rac1 belongs to the Rho supgroup of small GTPases protein family. This subgroup is involved in cytoskeletal control, regulation of stress fibers formation, focal adhesions, cell growth, membrane trafficking, development. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1_GTP"/> <bbox w="70.0" h="66.0" x="5758.0" y="2042.5"/> <glyph class="macromolecule" id="emtc_emtc_s2970_emtc_emtc_sa1468"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="42.0" h="18.0" x="5771.0" y="2046.5"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s2971_emtc_emtc_sa1469"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end</body> </html> </notes> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5773.0" y="2069.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2991_emtc_emtc_csa230" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARP2_3*:Actin cytoskeletal* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15094799 ARP2_3 complex nucleates new actin filaments from the sides of preexisting filaments. PMID:15866889 The ARP2_3 complex and Cofilin are involved in protrusion at the leading edge: the actin-severing activity of cofilin and the actin-branching activity of Arp2_3 act in synergy to drive the extension of lamellipodia. Cofilin is also required for the maintenance of a polarized cytoskeleton and thus for directional cell migration. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin/ARP2_3*"/> <bbox w="122.0" h="74.0" x="5531.0" y="2727.5"/> <glyph class="macromolecule" id="emtc_emtc_s2994_emtc_emtc_sa1498"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5537.0" y="2732.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3055_emtc_emtc_sa1558"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ARP2/3* ARP2 actin-related protein 2 homolog (yeast) "ARP2 (actin-related protein 2, yeast) homolog" HUGO:ACTR2 HGNC:169 ENTREZ:10097 UNIPROT:P61160 ARP3 actin-related protein 3 homolog (yeast) "ARP3 (actin-related protein 3, yeast) homolog" HUGO:ACTR3 HGNC:170 ENTREZ:10096 UNIPROT:P61158 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARP2_3*"/> <bbox w="60.0" h="20.0" x="5560.5" y="2755.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2995_emtc_emtc_csa231" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:WASF2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin/WASF2"/> <bbox w="126.0" h="77.0" x="5826.0" y="2946.5"/> <glyph class="macromolecule" id="emtc_emtc_s2996_emtc_emtc_sa1499"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5833.0" y="2951.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2997_emtc_emtc_sa1500"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: WAS protein family, member 2 HUGO:WASF2 HGNC:12733 ENTREZ:10163 UNIPROT:Q9Y6W5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASF2"/> <bbox w="47.0" h="21.0" x="5864.5" y="2979.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s2998_emtc_emtc_csa232" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:NCK1:NCKAP1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCK1/NCKAP1"/> <bbox w="90.0" h="60.0" x="5966.0" y="2286.5"/> <glyph class="macromolecule" id="emtc_emtc_s3000_emtc_emtc_sa1503"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NCK adaptor protein 1 HUGO:NCK1 HGNC:7664 ENTREZ:4690 UNIPROT:P16333 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCK1"/> <bbox w="37.0" h="18.0" x="5997.5" y="2288.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2999_emtc_emtc_sa1504"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NCK-associated protein 1 HUGO:NCKAP1 HGNC:7666 ENTREZ:10787 UNIPROT:Q9Y2A7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCKAP1"/> <bbox w="52.0" h="18.0" x="5990.0" y="2310.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3001_emtc_emtc_csa233" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:NCK1:RAC1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12181570 Rac1 binds to NCKAP1 and CYFIP2 and also promotes NCK1 binding to NCKAP1. This binding inhibits NCKAP1 and CYFIP2 binding to WASF1 and promotes release of the complex of WASF1 and BRK1, thus activating WASF1. Activated WASF1 then stimulates ARP2/3 that mediates actin cytoskeletal polymerizatioin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCK1/RAC1"/> <bbox w="85.0" h="73.0" x="5942.0" y="2210.5"/> <glyph class="macromolecule" id="emtc_emtc_s3002_emtc_emtc_sa1505"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="42.0" h="18.0" x="5972.0" y="2231.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3003_emtc_emtc_sa1506"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NCK adaptor protein 1 HUGO:NCK1 HGNC:7664 ENTREZ:4690 UNIPROT:P16333 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCK1"/> <bbox w="37.0" h="18.0" x="5974.5" y="2247.5"/> </glyph> <glyph class="simple chemical" id="s2509_sa2175"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end</body> </html> </notes> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5949.2" y="2213.6"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3009_emtc_emtc_csa148" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:HRAS Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS_GTP"/> <bbox w="68.5" h="67.0" x="5951.0" y="917.5"/> <glyph class="macromolecule" id="emtc_emtc_s1539_emtc_emtc_sa809"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-Ha-ras Harvey rat sarcoma viral oncogene homolog HUGO:HRAS, HGNC:5173, ENTREZ:3265, GENECARDS:GC11M000522, UNIPROT:P01112 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS"/> <bbox w="40.0" h="18.0" x="5962.0" y="925.5"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s1540_emtc_emtc_sa810"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5962.0" y="947.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3011_emtc_emtc_csa234" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDC42:GTP Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42_GTP"/> <bbox w="75.0" h="68.0" x="6014.0" y="2137.5"/> <glyph class="simple chemical" id="emtc_emtc_s3013_emtc_emtc_sa1521"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="6031.0" y="2167.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3014_emtc_emtc_sa1522"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cell division cycle 42 HUGO:CDC42, HGNC:1736, ENTREZ:998, UNIPROT:P60953, GENECARDS:GC01P022379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 is a member of the RAS superfamily of small GTPases and plays an essential role in control of cell polarity, actin cytoskeleton rearrangements, protein traffickinf and directed cell movements. PMID:10934474 PMID:11248548 PMID:11340065 PMID:15003621 CDC42 and cell polarity: PMID:15020669 CDC42 functions in vivo: PMID:18719708 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42"/> <bbox w="45.0" h="19.0" x="6029.0" y="2143.5"/> <glyph class="state variable" id="_70a95b16-ae15-46a4-b04d-83c193420952"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6069.0" y="2138.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3012_emtc_emtc_csa235" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDC42:GDP Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42_GDP"/> <bbox w="76.0" h="62.0" x="6013.0" y="2009.5"/> <glyph class="macromolecule" id="emtc_emtc_s1852_emtc_emtc_sa931"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cell division cycle 42 HUGO:CDC42, HGNC:1736, ENTREZ:998, UNIPROT:P60953, GENECARDS:GC01P022379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 is a member of the RAS superfamily of small GTPases and plays an essential role in control of cell polarity, actin cytoskeleton rearrangements, protein traffickinf and directed cell movements. PMID:10934474 PMID:11248548 PMID:11340065 PMID:15003621 CDC42 and cell polarity: PMID:15020669 CDC42 functions in vivo: PMID:18719708 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42"/> <bbox w="45.0" h="19.0" x="6032.5" y="2017.0"/> <glyph class="state variable" id="_a8d0bb56-5ec5-417d-96da-6dc433959a70"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6072.5" y="2012.0"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s3015_emtc_emtc_sa1523"> <label text="GDP"/> <bbox w="35.0" h="17.0" x="6032.0" y="2036.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3022_emtc_emtc_csa236" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:DSTN Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin/Destrin*"/> <bbox w="122.0" h="67.0" x="5063.0" y="2939.5"/> <glyph class="macromolecule" id="emtc_emtc_s3024_emtc_emtc_sa1531"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5069.0" y="2944.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3023_emtc_emtc_sa1530"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: destrin (actin depolymerizing factor) HUGO:DSTN HGNC:15750 ENTREZ:11034 UNIPROT:P60981 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DSTN"/> <bbox w="38.0" h="18.0" x="5105.0" y="2969.5"/> <glyph class="state variable" id="_b1d088e4-09d0-4af2-b644-e6356e60b53b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5100.234" y="2964.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3027_emtc_emtc_csa149" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:HRAS:RAF1:YWHAB Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS_GTP/RAF1"/> <bbox w="137.25" h="130.0" x="5933.375" y="725.5"/> <glyph class="simple chemical" id="emtc_emtc_s1544_emtc_emtc_sa812"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="6010.625" y="728.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1545_emtc_emtc_sa813"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-Ha-ras Harvey rat sarcoma viral oncogene homolog HUGO:HRAS, HGNC:5173, ENTREZ:3265, GENECARDS:GC11M000522, UNIPROT:P01112 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS"/> <bbox w="40.0" h="18.0" x="5945.625" y="734.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1546_emtc_emtc_sa814"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-raf-1 murine leukemia viral oncogene homolog 1 HUGO:RAF1, HGNC:9829, ENTREZ:5894 , GENECARDS:GC03M012625, UNIPROT:P04049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). 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Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS_GTP/RAF1/YWHAB"/> <bbox w="129.0" h="114.0" x="5758.0" y="784.5"/> <glyph class="simple chemical" id="emtc_emtc_s1560_emtc_emtc_sa820"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="5826.0" y="787.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1562_emtc_emtc_sa821"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-raf-1 murine leukemia viral oncogene homolog 1 HUGO:RAF1, HGNC:9829, ENTREZ:5894 , GENECARDS:GC03M012625, UNIPROT:P04049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAF1"/> <bbox w="99.0" h="43.0" x="5778.0" y="816.5"/> <glyph class="state variable" id="_03f5953f-dde5-4e16-813a-fe2e2a3f99c0"> <state value="open" variable=""/> <bbox w="30.0" h="10.0" x="5812.5" y="811.5"/> </glyph> <glyph class="state variable" id="_82f8c00e-a3d5-4612-bb11-db26304ba2a8"> <state value="" variable="Y340"/> <bbox w="30.0" h="10.0" x="5861.465" y="811.5"/> </glyph> <glyph class="state variable" id="_00b4e62c-3885-4062-861c-0b5fdbebb1fb"> <state value="" variable="Y341"/> <bbox w="30.0" h="10.0" x="5860.928" y="854.5"/> </glyph> <glyph class="state variable" id="_f767117d-60fe-426c-bb14-65d5c70eb31a"> <state value="P" variable="S259"/> <bbox w="35.0" h="10.0" x="5760.5" y="811.6013"/> </glyph> <glyph class="state variable" id="_ca2c35d7-e905-438d-9b6c-33f0f5ae305b"> <state value="P" variable="S621"/> <bbox w="35.0" h="10.0" x="5760.5" y="853.3696"/> </glyph> <glyph class="state variable" id="_a6402b93-2ec6-4867-a389-c257982513c3"> <state value="" variable="S338"/> <bbox w="30.0" h="10.0" x="5763.0" y="832.96576"/> </glyph> <glyph class="state variable" id="_b66afd42-a11b-4ed8-a99f-29e77d686f53"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="5867.0" y="833.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1563_emtc_emtc_sa822"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide HUGO:YWHAB, HGNC:12849, ENTREZ:7529, GENECARDS:GC20P043515, UNIPROT:P31946 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: YWHAB is so-called 14-3-3 alpha/beta PMID:9069260 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="YWHAB"/> <bbox w="60.0" h="20.0" x="5795.0" y="861.5"/> </glyph> <glyph class="macromolecule" id="s2499_sa2174"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-Ha-ras Harvey rat sarcoma viral oncogene homolog HUGO:HRAS, HGNC:5173, ENTREZ:3265, GENECARDS:GC11M000522, UNIPROT:P01112 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS"/> <bbox w="40.0" h="18.0" x="5768.3335" y="789.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3035_emtc_emtc_csa237" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDC42:GTP:PAR6* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10873802 PARD6 contains a PDZ domain and a Cdc42/Rac interactive binding (CRIB) motif PARD6 interacts with Rac1 and Cdc42 in a GTP-dependent manner PMID:10934475 PARD6 binds to Cdc42/Rac1 GTPases PMID:10954424 PARD6 is a binding partner for the Rho GTPases Cdc42 and Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42_GTP/PARD6*"/> <bbox w="122.0" h="64.0" x="6067.0" y="2474.5"/> <glyph class="simple chemical" id="emtc_emtc_s3032_emtc_emtc_sa1538"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="6130.5" y="2477.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3033_emtc_emtc_sa1539"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cell division cycle 42 HUGO:CDC42, HGNC:1736, ENTREZ:998, UNIPROT:P60953, GENECARDS:GC01P022379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 is a member of the RAS superfamily of small GTPases and plays an essential role in control of cell polarity, actin cytoskeleton rearrangements, protein traffickinf and directed cell movements. PMID:10934474 PMID:11248548 PMID:11340065 PMID:15003621 CDC42 and cell polarity: PMID:15020669 CDC42 functions in vivo: PMID:18719708 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42"/> <bbox w="45.0" h="19.0" x="6087.5" y="2478.5"/> <glyph class="state variable" id="_5edc9c32-5d7b-429e-92a4-f28c63ce0636"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6127.5" y="2473.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3034_emtc_emtc_sa1540"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog alpha" HUGO:PARD6A HGNC:15943 ENTREZ:50855 UNIPROT:Q9NPB6 par-6 partitioning defective 6 homolog beta (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog beta" HUGO:PARD6B HGNC:16245 ENTREZ:84612 UNIPROT:Q9BYG5 par-6 partitioning defective 6 homolog gamma (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog gamma" HUGO:PARD6G HGNC:16076 ENTREZ:84552 UNIPROT:Q9BYG4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR6*"/> <bbox w="60.0" h="20.0" x="6102.5" y="2498.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3038_emtc_emtc_csa238" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDC42:CDC42EP*:GTP Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 promotes cytoskeleton remodeling by binding to CDC42EPs (CDC42EP2 and CDC42EP3) PMID:10490598 PMID:11035016 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42/CDC42EP*"/> <bbox w="116.0" h="66.0" x="6066.0" y="2344.5"/> <glyph class="macromolecule" id="emtc_emtc_s3039_emtc_emtc_sa1546"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CDC42EP* CDC42 effector protein (Rho GTPase binding) 2 HUGO:CDC42EP2 HGNC:16263 ENTREZ:10435 UNIPROT:O14613 CDC42 effector protein (Rho GTPase binding) 3 HUGO:CDC42EP3 HGNC:16943 ENTREZ:10602 UNIPROT:Q9UKI2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 promotes cytoskeleton remodeling by binding to CDC42EPs (CDC42EP2 and CDC42EP3) PMID:10490598 PMID:11035016 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42EP*"/> <bbox w="73.0" h="21.0" x="6081.5" y="2369.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1851_emtc_emtc_sa930"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cell division cycle 42 HUGO:CDC42, HGNC:1736, ENTREZ:998, UNIPROT:P60953, GENECARDS:GC01P022379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 is a member of the RAS superfamily of small GTPases and plays an essential role in control of cell polarity, actin cytoskeleton rearrangements, protein traffickinf and directed cell movements. PMID:10934474 PMID:11248548 PMID:11340065 PMID:15003621 CDC42 and cell polarity: PMID:15020669 CDC42 functions in vivo: PMID:18719708 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42"/> <bbox w="50.0" h="20.0" x="6081.0" y="2349.5"/> <glyph class="state variable" id="_307bd121-7dcb-404d-8dbb-55b334c5cc08"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6126.0" y="2344.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s2510_sa2176"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="6140.2" y="2355.6"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3047_emtc_emtc_csa240" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARHGAP5:RASA1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP5/RASA1"/> <bbox w="111.0" h="38.0" x="5256.0" y="1736.5"/> <glyph class="macromolecule" id="emtc_emtc_s3048_emtc_emtc_sa1555"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: RAS p21 protein activator (GTPase activating protein) 1 RASA HUGO:RASA1 HGNC:9871 ENTREZ:5921 UNIPROT:P20936 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RASA1"/> <bbox w="42.0" h="16.0" x="5323.5" y="1741.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3049_emtc_emtc_sa1556"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Rho GTPase activating protein 5 GFI2, "growth factor independent 2" HUGO:ARHGAP5 HGNC:675 ENTREZ:394 UNIPROT:Q13017 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 ARHGAP5 as a GAP of CDC42 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP5"/> <bbox w="66.0" h="16.0" x="5258.5" y="1740.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3050_emtc_emtc_csa239" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARHGAP1:BNIP2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP1/BNIP2"/> <bbox w="111.0" h="42.0" x="5951.0" y="2482.5"/> <glyph class="macromolecule" id="emtc_emtc_s3044_emtc_emtc_sa1552"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2/adenovirus E1B 19kDa interacting protein 2 "BCL2/adenovirus E1B 19kD-interacting protein 2" HUGO:BNIP2 HGNC:1083 ENTREZ:663 UNIPROT:Q12982 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10551883 FGFR1 regulates activity of CDC42 by binding and phosphorylating thus inactivating BCL2. Phosphorylated BCL2 binds to another CDC42_GAP, ARHGAP1 and neutralize the GAP activity of ARHGAP1 as well. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BNIP2"/> <bbox w="39.0" h="17.0" x="5955.5" y="2486.5"/> <glyph class="state variable" id="_13748697-502e-42fc-bb7a-ef10123cfb7e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5948.0" y="2481.8953"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3045_emtc_emtc_sa1553"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Rho GTPase activating protein 1 HUGO:ARHGAP1, HGNC:673, ENTREZ:392, GENECARDS:GC11M046698, UNIPROT:Q07960 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9548756 RhoGAP1 (so-called ARHGAP1 or p50RhoGAP) is an RhoGTPase activiating protein. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP1"/> <bbox w="64.0" h="19.0" x="5997.5" y="2486.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3056_emtc_emtc_csa241" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:CFL1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10436159 ROCK phosphorylates LIMK1,2 which phosphorylates Cofilin (CFL1) Cofilin exhibits actin depolymerizing activity followed by reorganization of the Actin cytoskeleton. PMID:15866889 The ARP2_3 complex and Cofilin are involved in protrusion at the leading edge: the actin-severing activity of cofilin and the actin-branching activity of Arp2_3 act in synergy to drive the extension of lamellipodia. Cofilin is also required for the maintenance of a polarized cytoskeleton and thus for directional cell migration. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin/Cofilin*"/> <bbox w="122.0" h="62.0" x="5062.0" y="2818.5"/> <glyph class="macromolecule" id="emtc_emtc_s3057_emtc_emtc_sa1559"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5065.5" y="2820.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3058_emtc_emtc_sa1560"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cofilin 1 HUGO:CFL1, HGNC:1874, ENTREZ:1072, UNIPROT:P23528, GENECARDS:GC11M065622 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15866889 Cofilin is required for the maintenance of a polarized cytoskeleton and thus for directional cell miogration. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CFL1"/> <bbox w="36.0" h="19.0" x="5100.5" y="2839.5"/> <glyph class="state variable" id="_eeac5a22-9158-4f8f-8391-3be253a12004"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5095.5" y="2834.942"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3067_emtc_emtc_csa76" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA1:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a1b1*"/> <bbox w="40.0" h="60.0" x="3546.5" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3084_emtc_emtc_sa555"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3546.5" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3085_emtc_emtc_sa557"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA1"/> <bbox w="40.0" h="20.0" x="3546.5" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3071_emtc_emtc_csa74" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA2:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrin a2b1 predominantly binds to fibrillar collagen Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*"/> <bbox w="40.0" h="60.0" x="3595.773" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3076_emtc_emtc_sa551"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3595.773" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3077_emtc_emtc_sa552"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2"/> <bbox w="40.0" h="20.0" x="3595.773" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3072_emtc_emtc_csa97" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA2B:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2bb3*"/> <bbox w="40.0" h="60.0" x="3645.047" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3073_emtc_emtc_sa617"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="3645.047" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3074_emtc_emtc_sa618"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2B"/> <bbox w="40.0" h="20.0" x="3645.047" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3086_emtc_emtc_csa66" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA3:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22203675 EMT and pulmonary fibrogenesis require epithelial integrin a3b1-mediated crosstalk betweenTGFB1 and Wntsignaling pathways PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a3b1*"/> <bbox w="40.0" h="60.0" x="3697.32" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3087_emtc_emtc_sa529"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA3"/> <bbox w="40.0" h="20.0" x="3697.32" y="5565.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3088_emtc_emtc_sa530"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3697.32" y="5585.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3089_emtc_emtc_csa87" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA4:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a4b1*"/> <bbox w="40.0" h="60.0" x="3746.592" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3090_emtc_emtc_sa591"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3746.592" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3091_emtc_emtc_sa593"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="40.0" h="20.0" x="3746.592" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3092_emtc_emtc_csa95" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA4:ITGB7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a4b7*"/> <bbox w="40.0" h="60.0" x="3795.865" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3093_emtc_emtc_sa612"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="40.0" h="20.0" x="3795.865" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3094_emtc_emtc_sa613"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="40.0" h="20.0" x="3795.865" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3095_emtc_emtc_csa89" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA5:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a5b1*"/> <bbox w="40.0" h="60.0" x="3845.139" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3096_emtc_emtc_sa596"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3845.139" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3097_emtc_emtc_sa598"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="40.0" h="20.0" x="3845.139" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3098_emtc_emtc_csa68" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA6:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b1*"/> <bbox w="40.0" h="60.0" x="3894.412" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3099_emtc_emtc_sa533"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3894.412" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3100_emtc_emtc_sa535"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="40.0" h="20.0" x="3894.412" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3101_emtc_emtc_csa70" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA6:ITGB4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b4*"/> <bbox w="40.0" h="60.0" x="3943.686" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3102_emtc_emtc_sa539"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="40.0" h="20.0" x="3943.729" y="5566.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3103_emtc_emtc_sa540"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB4"/> <bbox w="38.0" h="18.0" x="3944.729" y="5587.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3104_emtc_emtc_csa72" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA7:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a7b1*"/> <bbox w="40.0" h="60.0" x="3992.959" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3105_emtc_emtc_sa543"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3992.959" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3106_emtc_emtc_sa547"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 7 HUGO:ITGA7 HGNC:6143 ENTREZ:3679 UNIPROT:Q13683 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA7"/> <bbox w="40.0" h="20.0" x="3992.959" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3107_emtc_emtc_csa84" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA8:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for a8b1: Latent TGFb, tenascin, fibronectin, osteoponitin, vitronectin, nephronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a8b1*"/> <bbox w="40.0" h="59.78846" x="4042.232" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3108_emtc_emtc_sa577"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4042.232" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3109_emtc_emtc_sa579"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 8 HUGO:ITGA8 HGNC:6144 ENTREZ:8516 UNIPROT:P53708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA8"/> <bbox w="40.0" h="20.0" x="4042.232" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3110_emtc_emtc_csa80" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA10:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a10b1*"/> <bbox w="40.0" h="60.0" x="4140.777" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3112_emtc_emtc_sa566"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4140.777" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3111_emtc_emtc_sa568"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA10"/> <bbox w="40.0" h="20.0" x="4140.777" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3113_emtc_emtc_csa91" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA9:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a9b1*"/> <bbox w="40.0" h="59.576923" x="4091.504" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s2825_emtc_emtc_sa601"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4091.504" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3216_emtc_emtc_sa603"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 9 HUGO:ITGA9 HGNC:6145 ENTREZ:3680 UNIPROT:Q13797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA9"/> <bbox w="40.0" h="20.0" x="4091.504" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3114_emtc_emtc_csa78" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA11:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a11b1*"/> <bbox w="40.0" h="60.0" x="4193.05" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3764_emtc_emtc_sa561"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4193.05" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3765_emtc_emtc_sa563"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 11 HUGO:ITGA11 HGNC:6136 ENTREZ:22801 UNIPROT:Q9UKX5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA11"/> <bbox w="40.0" h="20.0" x="4193.05" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3117_emtc_emtc_csa99" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAD:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aDb2*"/> <bbox w="40.0" h="60.0" x="4245.324" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3118_emtc_emtc_sa626"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha D HUGO:ITGAD HGNC:6146 ENTREZ:3681 UNIPROT:Q13349 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAD"/> <bbox w="40.0" h="20.0" x="4245.324" y="5565.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3119_emtc_emtc_sa627"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4245.324" y="5585.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3120_emtc_emtc_csa82" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAE:ITGB7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:17325197 Integrin aEb7 binds to E-Cadherin This interaction promotes antitumor "killer T cell" activity by triggering lytic granule polarization and exocytosis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aEb7*"/> <bbox w="40.0" h="60.0" x="4294.598" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3122_emtc_emtc_sa573"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha E (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide) HUGO:ITGAE HGNC:6147 ENTREZ:3682 UNIPROT:P38570 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAE"/> <bbox w="40.0" h="20.0" x="4294.598" y="5565.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3121_emtc_emtc_sa574"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="40.0" h="20.0" x="4294.598" y="5585.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3123_emtc_emtc_csa103" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAM:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aMb2*"/> <bbox w="40.0" h="60.0" x="4343.871" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3125_emtc_emtc_sa635"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4343.871" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3124_emtc_emtc_sa636"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha M (complement component 3 receptor 3 subunit) CD11B, CR3A, "integrin, alpha M (complement component receptor 3, alpha; also known as CD11b (p170), macrophage antigen alpha polypeptide)" HUGO:ITGAM HGNC:6149 ENTREZ:3684 UNIPROT:P11215 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAM"/> <bbox w="40.0" h="20.0" x="4343.871" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3126_emtc_emtc_csa105" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAL:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21270398 The aLb2 integrin (so-called LFA-1) is important for the adhesion of T cells and NK (natural killer) cells to target cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aLb2*"/> <bbox w="43.0" h="57.0" x="4393.145" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3766_emtc_emtc_sa643"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4396.361" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3767_emtc_emtc_sa645"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide) CD11A HUGO:ITGAL HGNC:6148 ENTREZ:3683 UNIPROT:P20701 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAL"/> <bbox w="40.0" h="20.0" x="4396.361" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3129_emtc_emtc_csa107" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAX:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aXb2*"/> <bbox w="40.0" h="60.0" x="4445.701" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3130_emtc_emtc_sa648"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4445.701" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3131_emtc_emtc_sa650"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha X (complement component 3 receptor 4 subunit) CD11C, "integrin, alpha X (antigen CD11C (p150), alpha polypeptide)" HUGO:ITGAX HGNC:6152 ENTREZ:3687 UNIPROT:P20702 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAX"/> <bbox w="40.0" h="20.0" x="4445.701" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3132_emtc_emtc_csa23" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb1: Latent TGFB, fibronectin, osteopontin, vitronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb1*"/> <bbox w="40.0" h="60.0" x="4494.975" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3134_emtc_emtc_sa350"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4494.975" y="5565.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3133_emtc_emtc_sa348"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4494.975" y="5585.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3135_emtc_emtc_csa93" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:8636223 Integrin aVb3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. aVb3 can also interact with the neural cell adhesion molecule L1CAM; a member of the immunoglobulin superfamily (IgSF). In other words, aVb3 undergoes heterophilic binding with L1CAM M21 cells display some aVb3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and aVb3 was also observed to promote significant haptotactic cell migration. Significant aVb3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. aVb3 may recognize L1 in a cell-cell or cell-substrate interaction. PMID:11553709 Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin aVb3 has been associated with the metastatic potential of tumor cells. In the context of in vitro monolayer of human lung microvascular, L1CAM was shown to serve as a potential ligand for aVb3 during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and aVb3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin aVb3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells. PMID:10022831 Interaction between integrin avb3 and extracellular matrix,as the most important survival system for nascent vessels, is crucial for endothelial cells sprouting from capillaries and for angiogenesis. Tyrosine-phosphorylated VEGFR2 co-immunoprecipitated with b3 integrin subunit, but not with b1 or b5, from cells stimulated with VEGFA (165 amino acid isoform) VEGFR2 phosphorylation and mitogenicity induced by VEGFA were enhanced in cells plated on the avb3 ligand, vitronectin, compared with cells plated on the a5b1 ligand, fibronectin or the a2b1 ligand, collagen. A new role for avb3 integrin in the activation of an in vitro angiogenic program in endothelial cells. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, avb3 integrin participates in the full activation of VEGFR2 triggered by VEGFA. PMID:7512751 PMID:8755653 Integrin avb3 is expressed in high quantities on angiogenic endothelial cells where it suppresses the activity of p53 and the p53-inducible cell-cycle inhibitor p21WAF1/CIP1 and increases the BCL2:Bax ratio, with a consequent antiapoptotic effect References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb3*"/> <bbox w="40.0" h="60.0" x="4544.248" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3137_emtc_emtc_sa637"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4544.248" y="5565.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3136_emtc_emtc_sa639"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="4544.248" y="5585.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3138_emtc_emtc_csa22" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb5: Latent TGFB, Osteopontin, vitronectin, References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb5*"/> <bbox w="40.0" h="60.0" x="4593.521" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3140_emtc_emtc_sa327"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB5"/> <bbox w="40.0" h="20.0" x="4593.521" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3139_emtc_emtc_sa352"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4593.521" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3141_emtc_emtc_csa20" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb6: Latent TGFB, fibronectin, osteopontin, ADAM References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb6*"/> <bbox w="40.0" h="60.0" x="4642.793" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3143_emtc_emtc_sa322"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 6 HUGO:ITGB6 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB6"/> <bbox w="40.0" h="20.0" x="4642.793" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3142_emtc_emtc_sa351"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4642.793" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3144_emtc_emtc_csa21" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb8: Latent TGFB, vitronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb8*"/> <bbox w="40.0" h="60.0" x="4692.066" y="5562.125"/> <glyph class="macromolecule" id="emtc_emtc_s3146_emtc_emtc_sa326"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 8 HUGO:ITGB8 HGNC:6163 ENTREZ:3696 UNIPROT:P26012 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB8"/> <bbox w="40.0" h="20.0" x="4692.066" y="5585.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3145_emtc_emtc_sa353"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4692.066" y="5565.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3289_emtc_emtc_csa244" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA1:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a1b1*"/> <bbox w="40.0" h="60.0" x="3546.5" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3301_emtc_emtc_sa1565"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3546.5" y="6055.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3302_emtc_emtc_sa1566"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA1"/> <bbox w="40.0" h="20.0" x="3546.5" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3290_emtc_emtc_csa98" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA2B:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2bb3*"/> <bbox w="40.0" h="60.0" x="3645.316" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3314_emtc_emtc_sa620"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="3645.316" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3315_emtc_emtc_sa619"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2B"/> <bbox w="40.0" h="20.0" x="3645.316" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3291_emtc_emtc_csa242" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA2:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrin a2b1 predominantly binds to fibrillar collagen Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*"/> <bbox w="40.0" h="60.0" x="3595.908" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3312_emtc_emtc_sa1561"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3595.908" y="6057.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3313_emtc_emtc_sa1562"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2"/> <bbox w="40.0" h="20.0" x="3595.908" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3292_emtc_emtc_csa88" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA4:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a4b1*"/> <bbox w="40.0" h="60.0" x="3747.133" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3318_emtc_emtc_sa595"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3747.133" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3319_emtc_emtc_sa594"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="40.0" h="20.0" x="3747.133" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3293_emtc_emtc_csa67" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA3:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22203675 EMT and pulmonary fibrogenesis require epithelial integrin a3b1-mediated crosstalk betweenTGFB1 and Wntsignaling pathways PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a3b1*"/> <bbox w="40.0" h="60.0" x="3697.725" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3316_emtc_emtc_sa532"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3697.725" y="6059.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3317_emtc_emtc_sa531"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA3"/> <bbox w="40.0" h="20.0" x="3697.725" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3294_emtc_emtc_csa96" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA4:ITGB7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a4b7*"/> <bbox w="40.0" h="60.0" x="3796.543" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3310_emtc_emtc_sa615"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="40.0" h="20.0" x="3796.543" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3311_emtc_emtc_sa614"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="40.0" h="20.0" x="3796.543" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3295_emtc_emtc_csa90" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA5:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a5b1*"/> <bbox w="40.0" h="60.0" x="3845.951" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3412_emtc_emtc_sa600"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3845.951" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3413_emtc_emtc_sa599"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="40.0" h="20.0" x="3845.951" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3296_emtc_emtc_csa71" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA6:ITGB4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b4*"/> <bbox w="40.0" h="60.0" x="3944.768" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3306_emtc_emtc_sa542"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB4"/> <bbox w="40.0" h="20.0" x="3944.768" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3307_emtc_emtc_sa541"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="40.0" h="20.0" x="3944.768" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3297_emtc_emtc_csa69" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA6:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b1*"/> <bbox w="40.0" h="60.057693" x="3895.36" y="6035.066"/> <glyph class="macromolecule" id="emtc_emtc_s3320_emtc_emtc_sa537"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="40.0" h="20.0" x="3895.36" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3321_emtc_emtc_sa536"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3895.36" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3298_emtc_emtc_csa85" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA8:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for a8b1: Latent TGFb, tenascin, fibronectin, osteoponitin, vitronectin, nephronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a8b1*"/> <bbox w="40.0" h="59.75" x="4043.584" y="6035.375"/> <glyph class="macromolecule" id="emtc_emtc_s3299_emtc_emtc_sa581"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 8 HUGO:ITGA8 HGNC:6144 ENTREZ:8516 UNIPROT:P53708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA8"/> <bbox w="40.0" h="20.0" x="4043.584" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3300_emtc_emtc_sa580"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4043.584" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3303_emtc_emtc_csa73" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA7:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a7b1*"/> <bbox w="40.0" h="60.0" x="3994.176" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3304_emtc_emtc_sa560"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 7 HUGO:ITGA7 HGNC:6143 ENTREZ:3679 UNIPROT:Q13683 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA7"/> <bbox w="40.0" h="20.0" x="3994.176" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3305_emtc_emtc_sa545"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="3994.176" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3322_emtc_emtc_csa92" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA9:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a9b1*"/> <bbox w="40.0" h="59.576923" x="4092.992" y="6035.547"/> <glyph class="macromolecule" id="emtc_emtc_s3323_emtc_emtc_sa605"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4092.992" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3324_emtc_emtc_sa604"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 9 HUGO:ITGA9 HGNC:6145 ENTREZ:3680 UNIPROT:Q13797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA9"/> <bbox w="36.0" h="20.0" x="4094.992" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3325_emtc_emtc_csa79" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA11:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a11b1*"/> <bbox w="40.0" h="60.0" x="4194.809" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3326_emtc_emtc_sa565"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 11 HUGO:ITGA11 HGNC:6136 ENTREZ:22801 UNIPROT:Q9UKX5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA11"/> <bbox w="40.0" h="20.0" x="4194.809" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3327_emtc_emtc_sa564"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4194.809" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3328_emtc_emtc_csa81" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA10:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a10b1*"/> <bbox w="40.0" h="60.0" x="4142.4" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3329_emtc_emtc_sa570"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA10"/> <bbox w="40.0" h="20.0" x="4142.4" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3330_emtc_emtc_sa569"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4142.4" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3331_emtc_emtc_csa100" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAD:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aDb2*"/> <bbox w="40.0" h="60.0" x="4247.219" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3332_emtc_emtc_sa629"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha D HUGO:ITGAD HGNC:6146 ENTREZ:3681 UNIPROT:Q13349 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAD"/> <bbox w="40.0" h="20.0" x="4247.219" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3333_emtc_emtc_sa628"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4247.219" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3334_emtc_emtc_csa104" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAM:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aMb2*"/> <bbox w="40.0" h="60.0" x="4346.035" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3335_emtc_emtc_sa642"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha M (complement component 3 receptor 3 subunit) CD11B, CR3A, "integrin, alpha M (complement component receptor 3, alpha; also known as CD11b (p170), macrophage antigen alpha polypeptide)" HUGO:ITGAM HGNC:6149 ENTREZ:3684 UNIPROT:P11215 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAM"/> <bbox w="40.0" h="20.0" x="4346.035" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3336_emtc_emtc_sa641"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4346.035" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3337_emtc_emtc_csa83" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAE:ITGB7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:17325197 Integrin aEb7 binds to E-Cadherin This interaction promotes antitumor "killer T cell" activity by triggering lytic granule polarization and exocytosis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aEb7*"/> <bbox w="40.0" h="60.0" x="4296.627" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3338_emtc_emtc_sa576"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="40.0" h="20.0" x="4296.627" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3339_emtc_emtc_sa575"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha E (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide) HUGO:ITGAE HGNC:6147 ENTREZ:3682 UNIPROT:P38570 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAE"/> <bbox w="40.0" h="20.0" x="4296.627" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3340_emtc_emtc_csa108" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAX:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aXb2*"/> <bbox w="40.0" h="60.0" x="4445.025" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3341_emtc_emtc_sa652"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4445.025" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3342_emtc_emtc_sa651"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha X (complement component 3 receptor 4 subunit) CD11C, "integrin, alpha X (antigen CD11C (p150), alpha polypeptide)" HUGO:ITGAX HGNC:6152 ENTREZ:3687 UNIPROT:P20702 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAX"/> <bbox w="40.0" h="20.0" x="4445.025" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3343_emtc_emtc_csa106" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAL:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21270398 The aLb2 integrin (so-called LFA-1) is important for the adhesion of T cells and NK (natural killer) cells to target cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aLb2*"/> <bbox w="40.173912" h="60.0" x="4395.443" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3344_emtc_emtc_sa647"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4395.617" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3345_emtc_emtc_sa646"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide) CD11A HUGO:ITGAL HGNC:6148 ENTREZ:3683 UNIPROT:P20701 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAL"/> <bbox w="40.0" h="20.0" x="4395.53" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3346_emtc_emtc_csa24" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb1: Latent TGFB, fibronectin, osteopontin, vitronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb1*"/> <bbox w="40.0" h="60.0" x="4494.434" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3347_emtc_emtc_sa349"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4494.434" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3348_emtc_emtc_sa549"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4494.434" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3349_emtc_emtc_csa156" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:8636223 Integrin aVb3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. aVb3 can also interact with the neural cell adhesion molecule L1CAM; a member of the immunoglobulin superfamily (IgSF). In other words, aVb3 undergoes heterophilic binding with L1CAM M21 cells display some aVb3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and aVb3 was also observed to promote significant haptotactic cell migration. Significant aVb3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. aVb3 may recognize L1 in a cell-cell or cell-substrate interaction. PMID:11553709 Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin aVb3 has been associated with the metastatic potential of tumor cells. In the context of in vitro monolayer of human lung microvascular, L1CAM was shown to serve as a potential ligand for aVb3 during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and aVb3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin aVb3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells. PMID:10022831 Interaction between integrin avb3 and extracellular matrix,as the most important survival system for nascent vessels, is crucial for endothelial cells sprouting from capillaries and for angiogenesis. Tyrosine-phosphorylated VEGFR2 co-immunoprecipitated with b3 integrin subunit, but not with b1 or b5, from cells stimulated with VEGFA (165 amino acid isoform) VEGFR2 phosphorylation and mitogenicity induced by VEGFA were enhanced in cells plated on the avb3 ligand, vitronectin, compared with cells plated on the a5b1 ligand, fibronectin or the a2b1 ligand, collagen. A new role for avb3 integrin in the activation of an in vitro angiogenic program in endothelial cells. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, avb3 integrin participates in the full activation of VEGFR2 triggered by VEGFA. PMID:7512751 PMID:8755653 Integrin avb3 is expressed in high quantities on angiogenic endothelial cells where it suppresses the activity of p53 and the p53-inducible cell-cycle inhibitor p21WAF1/CIP1 and increases the BCL2/Bax ratio, with a consequent antiapoptotic effect References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb3*"/> <bbox w="40.0" h="60.0" x="4543.842" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3415_emtc_emtc_sa890"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="4543.842" y="6058.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3416_emtc_emtc_sa889"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4543.842" y="6038.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3352_emtc_emtc_csa25" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb5: Latent TGFB, Osteopontin, vitronectin, References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb5*"/> <bbox w="40.0" h="60.0" x="4593.25" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3353_emtc_emtc_sa354"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4593.25" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3354_emtc_emtc_sa332"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB5"/> <bbox w="40.0" h="20.0" x="4593.25" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3355_emtc_emtc_csa26" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb6: Latent TGFB, fibronectin, osteopontin, ADAM References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb6*"/> <bbox w="40.0" h="60.0" x="4642.658" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3356_emtc_emtc_sa355"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4642.658" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3357_emtc_emtc_sa334"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 6 HUGO:ITGB6 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB6"/> <bbox w="40.0" h="20.0" x="4642.658" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3358_emtc_emtc_csa28" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:21909923 Ligands for aVb8: Latent TGFB, vitronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb8*"/> <bbox w="40.0" h="60.0" x="4692.066" y="6035.125"/> <glyph class="macromolecule" id="emtc_emtc_s3359_emtc_emtc_sa356"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4692.066" y="6038.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3360_emtc_emtc_sa337"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 8 HUGO:ITGB8 HGNC:6163 ENTREZ:3696 UNIPROT:P26012 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB8"/> <bbox w="40.0" h="20.0" x="4692.066" y="6058.125"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3362_emtc_emtc_csa245" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:COL4A1:a2b1*_a3b1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*_a3b1*/COL4A1"/> <bbox w="137.0" h="41.0" x="4045.0" y="6475.0"/> <glyph class="macromolecule" id="emtc_emtc_s3369_emtc_emtc_sa1572"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: a2b1*_a3b1* NAME:a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:a3b1* ITGA3/ITGB1 integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrin a2b1 predominantly binds to fibrillar collagen Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*_a3b1*"/> <bbox w="83.0" h="19.0" x="4047.5" y="6476.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3370_emtc_emtc_sa1573"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: collagen, type IV, alpha 1 HUGO:COL4A1 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL4A1"/> <bbox w="49.0" h="19.0" x="4129.5" y="6476.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3364_emtc_emtc_csa246" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Collagen1*:a1b1*_a2b1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a1b1*_a2b1*/Collagen 1*"/> <bbox w="166.0" h="42.0" x="3871.0" y="6473.0"/> <glyph class="macromolecule" id="emtc_emtc_s3365_emtc_emtc_sa1569"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: a1b1*_a2b1* NAME:a1b1* ITGA1/ITGB1 integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME: a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a1b1*_a2b1*"/> <bbox w="88.0" h="19.0" x="3872.5" y="6476.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3367_emtc_emtc_sa1570"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Collagen 1* collagen, type I, alpha 1 HUGO:COL1A1 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023, UNIPROT:P08123 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen1*"/> <bbox w="74.0" h="19.0" x="3962.5" y="6476.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3371_emtc_emtc_csa247" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Fibronectin*:a5b1*_aVb3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. PMID:15866889 Fibronectin binds to alphaV/beta3 integrins supports persistent migration( directional cell migration) Fibronectin binds to alpha5/beta1 integrins supports random migration. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*_a3b1*/Fibronectin*"/> <bbox w="160.0" h="41.0" x="4342.0" y="6476.0"/> <glyph class="macromolecule" id="emtc_emtc_s3375_emtc_emtc_sa1576"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:2409071 Fibronectin is located on the apical and basal cell surfaces. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="72.0" h="20.0" x="4427.5" y="6477.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3379_emtc_emtc_sa1579"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: a5b1*_aVb3* NAME:a5b1* ITGA5/ITGB1 integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a5b1*_aVb3*"/> <bbox w="82.0" h="19.0" x="4344.5" y="6477.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3381_emtc_emtc_csa249" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Vitronectin*:aVb3*_aVb5* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aEb3*_aVb5*/VTN"/> <bbox w="149.0" h="40.0" x="4506.0" y="6477.0"/> <glyph class="macromolecule" id="emtc_emtc_s3383_emtc_emtc_sa1582"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: aVb3*_aVb5* NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 NAME:aVb5* ITGAV/ITGB5 integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb3*_aVb5*"/> <bbox w="83.0" h="19.0" x="4510.5" y="6480.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3384_emtc_emtc_sa1583"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: vitronectin "vitronectin (serum spreading factor, somatomedin B, complement S-protein)" HUGO:VTN HGNC:12724 ENTREZ:7448 UNIPROT:P04004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vitronectin*"/> <bbox w="62.0" h="18.0" x="4591.5" y="6480.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3398_emtc_emtc_csa251" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Laminin8*:a6b1*_a6b4* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin Laminin-8 interacts with integrins. PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b1*_a6b4*/Laminin 8*"/> <bbox w="153.0" h="38.0" x="4660.0" y="6479.0"/> <glyph class="macromolecule" id="emtc_emtc_s3401_emtc_emtc_sa1597"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: a6b1*_a6b4* NAME:a6b1* ITGA6/ITGB1 integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:a6b4* ITGA6/ITGB4 integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b1*_a6b4*"/> <bbox w="79.0" h="20.0" x="4661.0" y="6480.666"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3402_emtc_emtc_sa1598"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Laminin 8* laminin, alpha 4 HUGO:LAMA4 HGNC:6484 ENTREZ:3910 UNIPROT:Q16363 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:10809728 Laminin-8 contains LAMA4, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin8*"/> <bbox w="72.0" h="20.0" x="4739.666" y="6480.666"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3399_emtc_emtc_csa248" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Laminin1*:a2b1*_a3b1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*_a3b1*/Laminin 1*"/> <bbox w="151.0" h="40.0" x="4187.0" y="6476.0"/> <glyph class="macromolecule" id="emtc_emtc_s3374_emtc_emtc_sa1575"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: a2b1*_a3b1* NAME:a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:a3b1* ITGA3/ITGB1 integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrin a2b1 predominantly binds to fibrillar collagen Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*_a3b1*"/> <bbox w="84.0" h="19.0" x="4187.5" y="6477.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3400_emtc_emtc_sa1596"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:114518 Laminin-1: LAMA1, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin1*"/> <bbox w="74.0" h="18.0" x="4261.666" y="6478.666"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3411_emtc_emtc_csa252" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA5:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a5b1*"/> <bbox w="40.0" h="60.0" x="4606.5" y="6612.0"/> <glyph class="macromolecule" id="emtc_emtc_s3308_emtc_emtc_sa1607"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4605.5" y="6633.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3309_emtc_emtc_sa1608"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="40.0" h="20.0" x="4606.5" y="6615.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3414_emtc_emtc_csa253" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:8636223 Integrin aVb3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. aVb3 can also interact with the neural cell adhesion molecule L1CAM; a member of the immunoglobulin superfamily (IgSF). In other words, aVb3 undergoes heterophilic binding with L1CAM M21 cells display some aVb3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and aVb3 was also observed to promote significant haptotactic cell migration. Significant aVb3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. aVb3 may recognize L1 in a cell-cell or cell-substrate interaction. PMID:11553709 Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin aVb3 has been associated with the metastatic potential of tumor cells. In the context of in vitro monolayer of human lung microvascular, L1CAM was shown to serve as a potential ligand for aVb3 during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and aVb3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin aVb3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells. PMID:10022831 Interaction between integrin avb3 and extracellular matrix,as the most important survival system for nascent vessels, is crucial for endothelial cells sprouting from capillaries and for angiogenesis. Tyrosine-phosphorylated VEGFR2 co-immunoprecipitated with b3 integrin subunit, but not with b1 or b5, from cells stimulated with VEGFA (165 amino acid isoform) VEGFR2 phosphorylation and mitogenicity induced by VEGFA were enhanced in cells plated on the avb3 ligand, vitronectin, compared with cells plated on the a5b1 ligand, fibronectin or the a2b1 ligand, collagen. A new role for avb3 integrin in the activation of an in vitro angiogenic program in endothelial cells. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, avb3 integrin participates in the full activation of VEGFR2 triggered by VEGFA. PMID:7512751 PMID:8755653 Integrin avb3 is expressed in high quantities on angiogenic endothelial cells where it suppresses the activity of p53 and the p53-inducible cell-cycle inhibitor p21WAF1/CIP1 and increases the BCL2/Bax ratio, with a consequent antiapoptotic effect References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb3*"/> <bbox w="40.0" h="60.0" x="4663.5" y="6613.0"/> <glyph class="macromolecule" id="emtc_emtc_s3350_emtc_emtc_sa1609"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="4662.5" y="6635.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3351_emtc_emtc_sa1610"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4663.5" y="6616.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3418_emtc_emtc_csa254" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GDP:HRAS Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS_GDP"/> <bbox w="67.0" h="60.0" x="6104.875" y="924.25"/> <glyph class="macromolecule" id="emtc_emtc_s1537_emtc_emtc_sa808"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-Ha-ras Harvey rat sarcoma viral oncogene homolog HUGO:HRAS, HGNC:5173, ENTREZ:3265, GENECARDS:GC11M000522, UNIPROT:P01112 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS"/> <bbox w="40.0" h="20.0" x="6119.875" y="930.25"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s3419_emtc_emtc_sa1612"> <label text="GDP"/> <bbox w="35.0" h="17.0" x="6123.75" y="948.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3421_emtc_emtc_csa255" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARHGAP35:RASA1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by PTK6.. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP35/RASA1"/> <bbox w="116.0" h="38.0" x="5534.0" y="1738.5"/> <glyph class="macromolecule" id="emtc_emtc_s3422_emtc_emtc_sa1614"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RAS p21 protein activator (GTPase activating protein) 1 RASA HUGO:RASA1 HGNC:9871 ENTREZ:5921 UNIPROT:P20936 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RASA1"/> <bbox w="42.0" h="16.0" x="5605.0" y="1742.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3423_emtc_emtc_sa1616"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Rho GTPase activating protein 35 HUGO:ARHGAP35 HGNC:4591 ENTREZ:2909 UNIPROT:Q9NRY4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9819392 The GAP activity of ARHGAP35 (p190RhoGAP) is specific for RhoA inhibition. PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by PTK6.. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP35"/> <bbox w="62.0" h="19.0" x="5536.0" y="1741.5"/> <glyph class="state variable" id="_7a2a933e-5646-4223-80bb-6fe1ed09064b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5590.5" y="1746.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3457_emtc_emtc_csa256" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGA5:NISCH Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5/NISCH"/> <bbox w="97.0" h="47.0" x="4883.0" y="3549.5"/> <glyph class="macromolecule" id="emtc_emtc_s3458_emtc_emtc_sa1662"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="40.0" h="20.0" x="4884.5" y="3554.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3459_emtc_emtc_sa1663"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Nischarin HUGO:NISCH HGNC:18006 ENTREZ:11188 UNIPROT:Q9Y2I1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NISCH"/> <bbox w="49.0" h="16.0" x="4928.5" y="3557.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3460_emtc_emtc_csa257" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:NISCH:PAK1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NISCH/PAK1"/> <bbox w="98.0" h="49.0" x="4991.0" y="3547.5"/> <glyph class="macromolecule" id="emtc_emtc_s3461_emtc_emtc_sa1664"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Nischarin HUGO:NISCH HGNC:18006 ENTREZ:11188 UNIPROT:Q9Y2I1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NISCH"/> <bbox w="49.0" h="16.0" x="4994.5" y="3555.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3462_emtc_emtc_sa1665"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 1 "p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)", "p21/Cdc42/Rac1-activated kinase 1 (yeast Ste20-related)" HUGO:PAK1 HGNC:8590 ENTREZ:5058 UNIPROT:Q13153 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK1"/> <bbox w="35.0" h="20.0" x="5048.5" y="3553.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3477_emtc_emtc_csa258" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:FAK1*:c-SRC* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: Autophosphorylation of PTK2: PMID:7529872 PMID:19339212 PMID:7657702 PMID:16919435 Autophosphorylation of PTK2 at Y397 creates binding site for CSK, a member of Scr family kinases. In response to integrin engagement with the ECM, FAK is autophosphorylated predominantly on Y397 This Y397 is the consensus binding site for the SH2 domain of c-Src (CSK) PMID:11114741 Interaction of CSK with FAK leads to phosphorylation of FAK on other tyrosine residues including Y407, 576, 577, 861, 925/ These phosphorylation events promote PTK2 to its maximal catalytic activity. Upon autophosphorylation of FAK, a signaling complex of FAK, CSK binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CSK/PTK2"/> <bbox w="123.0" h="55.0" x="5295.0" y="5587.5"/> <glyph class="macromolecule" id="emtc_emtc_s3478_emtc_emtc_sa1680"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: protein tyrosine kinase 2 "PTK2 protein tyrosine kinase 2" HUGO:PTK2 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAK1*"/> <bbox w="64.0" h="21.0" x="5349.65" y="5598.5"/> <glyph class="state variable" id="_f382c647-98ee-4e50-ade8-25d3f05b4c23"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5339.65" y="5593.9883"/> </glyph> <glyph class="state variable" id="_4cfcd884-42ce-4952-83b2-647163082d0f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5403.4155" y="5593.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3479_emtc_emtc_sa1681"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:18829532 PMID:9819392 PTK6 and CSK both can phosphorylate ARHGAP35 (p190) at Y1105 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-SRC*"/> <bbox w="50.0" h="18.0" x="5296.4" y="5595.5"/> <glyph class="state variable" id="_d236b394-d0df-48ef-8698-12dd17e1437a"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5338.9" y="5591.282"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3533_emtc_emtc_csa263" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:Actinin*:BCAR1:FAK1*:PXN:Talin*:Vinculin*:ZYX:c-SRC* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:15688067 Zyxin is an alpha-actinin- and stress-fibre- binding protein that is present in mature contacts References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Mature focal adhesion complex)"/> <bbox w="227.0" h="100.0" x="5627.0" y="5937.5"/> <glyph class="macromolecule" id="emtc_emtc_s3523_emtc_emtc_sa1711"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5736.074" y="5940.48"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3526_emtc_emtc_sa1712"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vinculin HUGO:VCL HGNC:12665 ENTREZ:7414 UNIPROT:P18206 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vinculin*"/> <bbox w="46.0" h="16.0" x="5628.502" y="5941.246"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3524_emtc_emtc_sa1713"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actinin* actinin, alpha 1 HUGO:ACTN1 HGNC:163 ENTREZ:87 UNIPROT:P12814 actinin, alpha 2 HUGO:ACTN2 HGNC:164 ENTREZ:88 UNIPROT:P35609 actinin, alpha 4 "focal segmental glomerulosclerosis 1", FSGS1 HUGO:ACTN4 HGNC:166 ENTREZ:81 UNIPROT:O43707 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:15688067 Alpha-actinin is a cytoskeletal protein that binds to viculin (VCL). Via this binding, Alpha-actinin crosslinks actin (in actomyosin stress fibres) and tether them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 (PTK2) reduces the crossliking of stress fibres and prevents the maturation of focal contacts. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actinin*"/> <bbox w="62.0" h="18.0" x="5675.252" y="5941.246"/> <glyph class="state variable" id="_d529499c-f1af-49f4-9670-463232d68d6e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5731.968" y="5936.246"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3527_emtc_emtc_sa1714"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: paxillin HUGO:PXN HGNC:9718 ENTREZ:5829 UNIPROT:P49023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PXN"/> <bbox w="35.0" h="29.0" x="5631.502" y="5958.496"/> <glyph class="state variable" id="_546eb3d1-bedf-416f-b644-a14753f5f054"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5625.5483" y="5953.496"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3528_emtc_emtc_sa1715"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Talin* talin 1 HUGO:TLN1 HGNC:11845 ENTREZ:7094 UNIPROT:Q9Y490 talin 2 HUGO:TLN2 HGNC:15447 ENTREZ:83660 UNIPROT:Q9Y4G6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: Identifiers_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Talin*"/> <bbox w="39.0" h="16.0" x="5667.502" y="5966.246"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3529_emtc_emtc_sa1716"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine kinase 2 "PTK2 protein tyrosine kinase 2" HUGO:PTK2 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAK1*"/> <bbox w="64.0" h="21.0" x="5636.152" y="5992.246"/> <glyph class="state variable" id="_7de1f226-35e5-4db7-822e-b69ce467711c"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5626.152" y="5987.7344"/> </glyph> <glyph class="state variable" id="_58b18940-0e74-450f-9020-b243580c04a1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5689.9175" y="5987.246"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3525_emtc_emtc_sa1717"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:18829532 PMID:9819392 PTK6 and CSK both can phosphorylate ARHGAP35 (p190) at Y1105 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. 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Phosphorylation of alpha-actinin by FAK1 (PTK2) redues this ability of linking actin to vinculin, thus prevents the maturation of focal contacts. 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Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PXN"/> <bbox w="35.0" h="29.0" x="5471.25" y="5831.75"/> <glyph class="state variable" id="_2923d071-1159-4afb-b78c-d2d465aaf7be"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5465.2964" y="5826.75"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3514_emtc_emtc_sa1706"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Talin* talin 1 HUGO:TLN1 HGNC:11845 ENTREZ:7094 UNIPROT:Q9Y490 talin 2 HUGO:TLN2 HGNC:15447 ENTREZ:83660 UNIPROT:Q9Y4G6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: Identifiers_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Talin*"/> <bbox w="39.0" h="16.0" x="5507.25" y="5839.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3517_emtc_emtc_sa1707"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine kinase 2 "PTK2 protein tyrosine kinase 2" HUGO:PTK2 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAK1*"/> <bbox w="64.0" h="21.0" x="5475.9" y="5865.5"/> <glyph class="state variable" id="_88ff32bd-573c-4d21-a921-50ff36c28730"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5465.9" y="5860.9883"/> </glyph> <glyph class="state variable" id="_0f38fd05-ac0a-40a1-b8d2-527b06f2c897"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5529.6655" y="5860.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3515_emtc_emtc_sa1708"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:18829532 PMID:9819392 PTK6 and CSK both can phosphorylate ARHGAP35 (p190) at Y1105 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-SRC*"/> <bbox w="49.0" h="19.0" x="5547.65" y="5855.5"/> <glyph class="state variable" id="_4a236b75-c3dc-4b7a-9763-2b44a8590619"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5589.15" y="5851.3257"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3518_emtc_emtc_sa1709"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: breast cancer anti-estrogen resistance 1 HUGO:BCAR1 HGNC:971 ENTREZ:9564 UNIPROT:P56945 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCAR1"/> <bbox w="50.0" h="19.0" x="5547.25" y="5876.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3520_emtc_emtc_sa1710"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5600.824" y="5824.734"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3536_emtc_emtc_csa46" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Latency-associated protein*:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. Each TGFB gene encodes a preproprotein sequence consisting of a signal peptide, a propeptide (LAP) and the mature TGFB After translocation into the endoplamic reticulum, TGFB proprotein monomers form homomdimers liked by disulfide bonds, forming pro-TGFB In the Golgi, the prodomains undergo glycosylation. Also in the Golgi, FURIN hydolyzes the leavage site from LAP, creating TGFB and LAP-derived homodimers The 2 homodimers remain noncovalently associated and are secreted. The LAP-derived homodimer prevents TGFB from binding TGFB receptors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Pre-TGFB1 complex)"/> <bbox w="176.0" h="61.0" x="441.0" y="6174.0"/> <glyph class="macromolecule" id="emtc_emtc_s519_emtc_emtc_sa417"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="170.0" h="19.0" x="444.5" y="6175.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s520_emtc_emtc_sa418"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="40.0" h="20.0" x="506.0" y="6194.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3537_emtc_emtc_csa86" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Latency-associated protein*:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. Each TGFB gene encodes a preproprotein sequence consisting of a signal peptide, a propeptide (LAP) and the mature TGFB After translocation into the endoplamic reticulum, TGFB proprotein monomers form homomdimers liked by disulfide bonds, forming pro-TGFB In the Golgi, the prodomains undergo glycosylation. Also in the Golgi, FURIN hydolyzes the leavage site from LAP, creating TGFB and LAP-derived homodimers The 2 homodimers remain noncovalently associated and are secreted. The LAP-derived homodimer prevents TGFB from binding TGFB receptors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Pro-TGFB1 complex)"/> <bbox w="181.0" h="66.0" x="439.0" y="6283.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s783_emtc_emtc_sa585"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="180.0" h="20.0" x="442.25" y="6287.75"/> <glyph class="unit of information" id="_1585719b-840b-475f-9e24-9d00df7c3734"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="522.25" y="6282.75"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s784_emtc_emtc_sa586"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="46.0" h="26.0" x="512.25" y="6305.75"/> <glyph class="unit of information" id="_a08a9396-2568-44eb-8fc5-7c405bf61aa3"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="525.25" y="6300.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3538_emtc_emtc_csa15" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Latency-associated protein*:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. Each TGFB gene encodes a preproprotein sequence consisting of a signal peptide, a propeptide (LAP) and the mature TGFB After translocation into the endoplamic reticulum, TGFB proprotein monomers form homomdimers liked by disulfide bonds, forming pro-TGFB In the Golgi, the prodomains undergo glycosylation. Also in the Golgi, FURIN hydolyzes the leavage site from LAP, creating TGFB and LAP-derived homodimers The 2 homodimers remain noncovalently associated and are secreted. The LAP-derived homodimer prevents TGFB from binding TGFB receptors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Small latent Complex)"/> <bbox w="199.0" h="65.0" x="699.0" y="6386.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s1243_emtc_emtc_sa219"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="46.25" h="24.5" x="770.3125" y="6409.438"/> <glyph class="unit of information" id="_d15f35e2-8784-4bc8-bcd8-18c08bd7d50a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="783.4375" y="6404.438"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1245_emtc_emtc_sa343"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="196.25" h="19.2875" x="699.9375" y="6390.713"/> <glyph class="unit of information" id="_209f5555-d92e-4184-bc8a-db9fc5cde1e6"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="788.0625" y="6385.713"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3539_emtc_emtc_csa14" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LTBP1:Latency-associated protein*:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:15611103 PMID:21900405 TGFB is released from cells in a latent complex formed by 3 proteins: (i) TGFB, (ii) the processed TGFB propeptide (LAP) and (iii) a member of the latent TGFB binding protein (LTBP) family LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Large Latent complex)"/> <bbox w="168.9375" h="68.0" x="714.031" y="6531.0"/> <glyph class="macromolecule" id="emtc_emtc_s418_emtc_emtc_sa225"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1, HGNC:6714, ENTREZ:4052, UNIPROT:Q14766,GENECARDS:GC02P033172, UNIPROT:Q14766 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM There are 4 LTBP proteins (1, 2, 3, 4). Although LTBP1 and 3 bind all three TGFB (1, 2, 3), LTBP4 binds only TGFB1 PMID:9931372 LTBP1 is a member of the fibrillin family An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out PMID:10544215 Extracellular tTgase is located at the basal and apical surfaces of cells and at cell–cell contacts, and that LTBP1 is co-distributed with cell surface tTgase LTPB1 was also found to co-localize with both intracellular and extracellular fibronectin Regulation of tTgase expression is important for controlling matrix storage of latent TGFB1 complexes Fibronectin may be one extracellular component to which LTBP1 is crosslinked when LTBP1 and tTgase interact at the cell surface References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTBP1"/> <bbox w="40.0" h="20.0" x="810.156" y="6558.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1391_emtc_emtc_sa238"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="46.25" h="24.5" x="756.594" y="6558.5"/> <glyph class="unit of information" id="_548ae4d6-fd2d-4189-a0e1-e33a87237817"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="769.719" y="6553.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1392_emtc_emtc_sa344"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="167.5" h="24.0" x="714.281" y="6532.0"/> <glyph class="unit of information" id="_79f1f64d-b660-4dd3-83ab-287c398d7738"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="788.031" y="6527.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3541_emtc_emtc_csa35" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:Integrin A8B1_AVB1_AVB5_AVB6_AVB8*:LTBP1:Latency-associated protein*:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:10025398 Large latent complex binds to aVb6 via the RGD motif present in the LAP of TGFb, then the b6 cytoplasmic domain binds to the actin cytoskeleton, then Cytoskeleton-associated integrin induces release of mature TGFb from the large latent complex PMID:21883891 This is one of the 2 mechanisms for activating TGFb via integrins. In this model, there is no proteolysis of either the LAP or LTBP. PMID:21900405 LAP contains an integrin-binding site called RBD Several RBD-binding integrins are able to activate latent TGFB complex through binding this site. PMID:21909923 The previously mentionned integrins are: a8b1, aVb1, aVb5, aVb6, aVb8. In the complex Ingergin-large latent TGFB complex, I picked aVb6 as example. But a8b1, aVb1, aVb5, and aVb8 can active TGFB with the same mechanism. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Actin*/Integrin*/Large Latent Complex)"/> <bbox w="337.0" h="66.5" x="405.0" y="6633.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s1390_emtc_emtc_sa363"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="46.25" h="24.5" x="659.0" y="6656.5"/> <glyph class="unit of information" id="_64e8a9ad-7c63-4057-99b1-44b5922404a6"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="672.125" y="6651.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s549_emtc_emtc_sa362"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="176.0" h="21.75" x="529.0" y="6634.75"/> <glyph class="unit of information" id="_a2ca62cf-891e-4bfd-8522-408af897551a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="607.0" y="6629.75"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s449_emtc_emtc_sa361"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1, HGNC:6714, ENTREZ:4052, UNIPROT:Q14766,GENECARDS:GC02P033172, UNIPROT:Q14766 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM There are 4 LTBP proteins (1, 2, 3, 4). Although LTBP1 and 3 bind all three TGFB (1, 2, 3), LTBP4 binds only TGFB1 PMID:9931372 LTBP1 is a member of the fibrillin family An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out PMID:10544215 Extracellular tTgase is located at the basal and apical surfaces of cells and at cell–cell contacts, and that LTBP1 is co-distributed with cell surface tTgase LTPB1 was also found to co-localize with both intracellular and extracellular fibronectin Regulation of tTgase expression is important for controlling matrix storage of latent TGFB1 complexes Fibronectin may be one extracellular component to which LTBP1 is crosslinked when LTBP1 and tTgase interact at the cell surface References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTBP1"/> <bbox w="40.0" h="20.0" x="697.5" y="6635.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2560_emtc_emtc_sa1368"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Integrin A8B1_AVB1_AVB5_AVB6_AVB8* NAME:a8b1* ITGA8/ITGB1 NAME:aVb1* ITGAV/ITGB1 NAME:aVb5* ITGAV/ITGB5 NAME:aVb6* ITGAV/ITGB6 NAME:aVb8* ITGAV/ITGB8 HUGO:ITGA8, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB5, HUGO:ITGAV, HUGO:ITGB6, HUGO:ITGAV, HUGO:ITGB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Integrin A8B1_AVB1_AVB5_AVB6_AVB8*"/> <bbox w="240.0" h="20.0" x="412.0" y="6657.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2562_emtc_emtc_sa1370"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="117.0" h="19.0" x="410.0" y="6634.75"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3542_emtc_emtc_csa29" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Integrin A8B1_AVB1_AVB5_AVB6_AVB8*:LTBP1:Latency-associated protein*:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:10025398 Large latent complex binds to aVb6 via the RGD motif present in the LAP of TGFb, then the b6 cytoplasmic domain binds to the actin cytoskeleton, then Cytoskeleton-associated integrin induces release of mature TGFb from the large latent complex PMID:21883891 This is one of the 2 mechanisms for activating TGFb via integrins. In this model, there is no proteolysis of either the LAP or LTBP. PMID:21900405 LAP contains an integrin-binding site called RBD Several RBD-binding integrins are able to activate latent TGFB complex through binding this site. PMID:21909923 The previously mentionned integrins are: a8b1, aVb1, aVb5, aVb6, aVb8. In the complex Ingergin-large latent TGFB complex, I picked aVb6 as example. But a8b1, aVb1, aVb5, and aVb8 can active TGFB with the same mechanism. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Integrin/Large Latent Complex)"/> <bbox w="280.0" h="71.5" x="1049.0" y="6635.75"/> <glyph class="macromolecule" id="emtc_emtc_s279_emtc_emtc_sa345"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1, HGNC:6714, ENTREZ:4052, UNIPROT:Q14766,GENECARDS:GC02P033172, UNIPROT:Q14766 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM There are 4 LTBP proteins (1, 2, 3, 4). Although LTBP1 and 3 bind all three TGFB (1, 2, 3), LTBP4 binds only TGFB1 PMID:9931372 LTBP1 is a member of the fibrillin family An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out PMID:10544215 Extracellular tTgase is located at the basal and apical surfaces of cells and at cell–cell contacts, and that LTBP1 is co-distributed with cell surface tTgase LTPB1 was also found to co-localize with both intracellular and extracellular fibronectin Regulation of tTgase expression is important for controlling matrix storage of latent TGFB1 complexes Fibronectin may be one extracellular component to which LTBP1 is crosslinked when LTBP1 and tTgase interact at the cell surface References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTBP1"/> <bbox w="43.070835" h="24.75" x="1274.465" y="6637.375"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s546_emtc_emtc_sa346"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="46.25" h="24.5" x="1281.429" y="6663.5"/> <glyph class="unit of information" id="_5640feca-fb5b-4a1b-b96b-ef4512428acf"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1294.554" y="6658.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s545_emtc_emtc_sa347"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="183.0" h="22.5" x="1091.304" y="6636.75"/> <glyph class="unit of information" id="_33870b78-963c-47da-8ef1-f587157dee8b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1172.804" y="6631.75"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2559_emtc_emtc_sa1367"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Integrin A8B1_AVB1_AVB5_AVB6_AVB8* NAME:a8b1* ITGA8/ITGB1 NAME:aVb1* ITGAV/ITGB1 NAME:aVb5* ITGAV/ITGB5 NAME:aVb6* ITGAV/ITGB6 NAME:aVb8* ITGAV/ITGB8 HUGO:ITGA8, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB5, HUGO:ITGAV, HUGO:ITGB6, HUGO:ITGAV, HUGO:ITGB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Integrin A8B1_AVB1_AVB5_AVB6_AVB8*"/> <bbox w="231.0" h="22.0" x="1052.0" y="6662.25"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3544_emtc_emtc_csa264" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARP2_3*:Actin cytoskeletal*:Actinin*:BCAR1:FAK1*:PXN:Talin*:Vinculin*:c-SRC* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:12473693 PMID:14749719 PMID:15094799 Vinculin recruits Arp2_3 complex to new sites of focal adhesions to nucleate new actin filaments, promoting actin polymerization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Focal adhesion complex/Actinin*/Actin*/ARP2_3*)"/> <bbox w="305.0" h="133.0" x="5638.0" y="5628.5"/> <glyph class="macromolecule" id="emtc_emtc_s3543_emtc_emtc_sa1721"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ARP2/3* ARP2 actin-related protein 2 homolog (yeast) "ARP2 (actin-related protein 2, yeast) homolog" HUGO:ACTR2 HGNC:169 ENTREZ:10097 UNIPROT:P61160 ARP3 actin-related protein 3 homolog (yeast) "ARP3 (actin-related protein 3, yeast) homolog" HUGO:ACTR3 HGNC:170 ENTREZ:10096 UNIPROT:P61158 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARP2_3*"/> <bbox w="60.0" h="20.0" x="5714.455" y="5636.863"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3556_emtc_emtc_sa1731"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine kinase 2 "PTK2 protein tyrosine kinase 2" HUGO:PTK2 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAK1*"/> <bbox w="64.0" h="21.0" x="5744.97" y="5715.064"/> <glyph class="state variable" id="_bdb26628-cc63-44d8-8583-c9750b7d6dc4"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5734.97" y="5710.5522"/> </glyph> <glyph class="state variable" id="_6bfce880-1cf0-4cfa-811a-044e3ad77d5d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5798.736" y="5710.064"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3552_emtc_emtc_sa1732"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: paxillin HUGO:PXN HGNC:9718 ENTREZ:5829 UNIPROT:P49023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PXN"/> <bbox w="35.0" h="29.0" x="5740.32" y="5681.314"/> <glyph class="state variable" id="_8272922a-d626-4377-9523-bd242655507d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5734.366" y="5676.314"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3553_emtc_emtc_sa1733"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vinculin HUGO:VCL HGNC:12665 ENTREZ:7414 UNIPROT:P18206 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vinculin*"/> <bbox w="59.0" h="16.0" x="5724.32" y="5664.064"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3549_emtc_emtc_sa1734"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actinin* actinin, alpha 1 HUGO:ACTN1 HGNC:163 ENTREZ:87 UNIPROT:P12814 actinin, alpha 2 HUGO:ACTN2 HGNC:164 ENTREZ:88 UNIPROT:P35609 actinin, alpha 4 "focal segmental glomerulosclerosis 1", FSGS1 HUGO:ACTN4 HGNC:166 ENTREZ:81 UNIPROT:O43707 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:15688067 Alpha-actinin is a cytoskeletal protein that binds to viculin (VCL). Via this binding, Alpha-actinin crosslinks actin (in actomyosin stress fibres) and tether them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 (PTK2) reduces the crossliking of stress fibres and prevents the maturation of focal contacts. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actinin*"/> <bbox w="62.0" h="18.0" x="5784.07" y="5664.064"/> <glyph class="state variable" id="_d9758ed3-c7c7-42d5-a2f3-0532a9f07d17"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5840.7856" y="5659.064"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3550_emtc_emtc_sa1735"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="5787.895" y="5639.299"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3554_emtc_emtc_sa1736"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Talin* talin 1 HUGO:TLN1 HGNC:11845 ENTREZ:7094 UNIPROT:Q9Y490 talin 2 HUGO:TLN2 HGNC:15447 ENTREZ:83660 UNIPROT:Q9Y4G6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: Identifiers_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Talin*"/> <bbox w="39.0" h="16.0" x="5782.32" y="5688.064"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3551_emtc_emtc_sa1737"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:18829532 PMID:9819392 PTK6 and CSK both can phosphorylate ARHGAP35 (p190) at Y1105 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-SRC*"/> <bbox w="46.0" h="18.0" x="5816.72" y="5705.064"/> <glyph class="state variable" id="_a506b6ba-25ad-4814-b0be-fdc4ad879e41"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5855.22" y="5700.846"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3555_emtc_emtc_sa1738"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: breast cancer anti-estrogen resistance 1 HUGO:BCAR1 HGNC:971 ENTREZ:9564 UNIPROT:P56945 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCAR1"/> <bbox w="50.0" h="19.0" x="5816.32" y="5726.064"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3582_emtc_emtc_csa269" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:APC:AXIN1:_beta_-Catenin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:16288291Maps_Modules_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC/AXIN1/CTNNB1"/> <bbox w="127.0625" h="80.0" x="1382.734" y="3585.5"/> <glyph class="macromolecule" id="emtc_emtc_s3581_emtc_emtc_sa1762"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="74.0" h="28.0" x="1401.5" y="3589.5"/> <glyph class="state variable" id="_62faba8d-7c6d-44aa-89a5-704a9dbe7351"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1396.5" y="3586.1816"/> </glyph> <glyph class="state variable" id="_e7ae72c6-c629-42ae-9aa2-f015052b0028"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1433.5294" y="3584.5"/> </glyph> <glyph class="state variable" id="_e2814086-458a-4e40-95ea-4124d82b99d7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1470.5" y="3584.5"/> </glyph> <glyph class="state variable" id="_7c868ca9-4869-41b3-9f04-239f4d9ee518"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1448.3125" y="3584.5"/> </glyph> <glyph class="state variable" id="_a81ec5d4-c424-40b1-b8b6-aa0e4208f218"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1417.8914" y="3584.5"/> </glyph> <glyph class="state variable" id="_c9b6836c-e562-4791-a6ce-7c3879de4cd7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1470.5" y="3610.8582"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3580_emtc_emtc_sa1761"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC"/> <bbox w="40.0" h="20.0" x="1388.797" y="3624.5"/> <glyph class="state variable" id="_71c28dd9-d203-4542-95bf-acec63df7daa"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1401.713" y="3619.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3579_emtc_emtc_sa1760"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1"/> <bbox w="40.0" h="20.0" x="1464.797" y="3625.5"/> <glyph class="state variable" id="_b566f72a-9c72-4734-9efd-0fba92796901"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1477.713" y="3620.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3593_emtc_emtc_csa172" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:AXIN1:DVL1:FRAT1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:16288291 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1/DVL1/FRAT1"/> <bbox w="125.0" h="63.0" x="917.5" y="3537.5"/> <glyph class="macromolecule" id="emtc_emtc_s2060_emtc_emtc_sa995"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: dishevelled, dsh homolog 1 (Drosophila) HUGO:DVL1, HGNC:3084, ENTREZ:1855, UNIPROT:O14640 , GENECARDS:GC01M001262 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding, DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DVL1"/> <bbox w="40.0" h="20.0" x="955.5" y="3560.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2059_emtc_emtc_sa997"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1"/> <bbox w="40.0" h="20.0" x="996.5" y="3561.5"/> <glyph class="state variable" id="_83518003-336e-4a7d-8783-50e4fa1dcd15"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1011.916" y="3556.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3592_emtc_emtc_sa1767"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: frequently rearranged in advanced T-cell lymphomas HUGO:FRAT1 HGNC:3944 ENTREZ:10023 UNIPROT:Q92837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FRAT1"/> <bbox w="52.0" h="20.0" x="948.5" y="3541.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3594_emtc_emtc_csa157" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ITGAV:ITGB3:L1CAM Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:8636223 Integrin aVb3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. aVb3 can also interact with the neural cell adhesion molecule L1CAM; a member of the immunoglobulin superfamily (IgSF). In other words, aVb3 undergoes heterophilic binding with L1CAM M21 cells display some aVb3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and aVb3 was also observed to promote significant haptotactic cell migration. Significant aVb3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. aVb3 may recognize L1 in a cell-cell or cell-substrate interaction. PMID:11553709 Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin aVb3 has been associated with the metastatic potential of tumor cells. In the context of in vitro monolayer of human lung microvascular, L1CAM was shown to serve as a potential ligand for aVb3 during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and aVb3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin aVb3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells. Integrin aVb3 on melanoma cells, and not endothelial cells, is involved in the transmigration process. Because L1 is expressed in both melanoma and endothelial cells, it is possible that L1-L1 homophilic interactions at the heterotypic contacts might play a role in the transmigration of melanoma cells. The data thus indicate that transendothelial migration does not involve L1-L1 homophilic binding. These results led us to speculate that L1 on endothelial cells, and not melanoma cells, has a role during transendothelial migration of melanoma cells PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. PMID:16506207 PMID:11706054 PMID:17952127 PMID:21373966 Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated. A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Integrin aVb3/L1CAM)"/> <bbox w="149.0" h="85.0" x="567.5" y="3736.0"/> <glyph class="macromolecule" id="emtc_emtc_s1639_emtc_emtc_sa891"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="604.0" y="3757.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1640_emtc_emtc_sa892"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="604.0" y="3737.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1642_emtc_emtc_sa893"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: L1 cell adhesion molecule HUGO:L1CAM, HGNC:6470, ENTREZ:3897, GENECARDS:GC0XM153126, UNIPROT:P32004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: ISBN:978-953-51-0410-0 PMID:8893017 PMID:20044598 The adhesion molecule L1CAM (CD171) is a 220 kD transmembrane glyocoprotein and belongs to the immunoglobulin superfamily. The extracellular part of the molecule comprises six Ig-like domains followed by 5 fibronectin type III repeats. The transmembrane domain is followed by a short cytoplasmic tail of 32kD PMID:10413675 L1CAM can be expressed and mediate its effects as a membrane-bound form. L1CAM can also be proteolytically cleaved by different proteases releasing a soluble ectodomain that is likewise functionally active. PMID:16199880 PMID:11706054 The metalloproteases ADAM 10 and 17 as well as plasmin have been described to cleave L1CAM generating a soluble 200 kD and 150 kD form, respectively After ADAM-mediated cleavage, the membrane-bound intracellular C-terminal fragment of L1CAM can be further processed by the presenilin/gamma-secretase complex giving rise of a 28 kD fragment. PMID:19260824 This small intracellular fragment translocates into the nucleus where it is thought to contribute to L1CAM-dependent gene regulation. L1CAM can bind to different substrates/molecules in a cell and context dependent manner. PMID:10469653 LACAM can undergo homophilic binding to itself as a membrane-bound or shedded form. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. PMID:8898967 PMID:8636223 PMID:11553709 PMID:10455125 PMID:16377081 PMID:7613634 PMID:1720120 L1CAM can interact with a plethora of other proteins, e.g. integrins aVb1, aVb3, aVb5, a5b1, neuropilin-1, CD24, neurocan, and axonin-1/TAX-1. PMID:6368220 L1CAM was originally identified in cells of the nervous system PMID:9127006 L1CAM expression has been also found in certain populations of hematopoietic cells. PMID:19273627 Potential role for L1CAM in transendothelial migration and trafficking of murine dendritic cells. PMID:9864376 Furthermore, L1CAM is expressed by renal tubular epithelial cells under physiological conditions being involved in branching of renal tubes in the kidney However, distribution of L1CAM in adults is quite restricted so that its elevated expression in cancerous tissues which is discussed in the next paragraph favours its suitability as therapeutic target in anti-cancer therapy. PMID:19356150 PMID:21195665 L1CAM expression in tumors can be associated with the activation of several signalling pathways that are known to play a pivotal role in tumor progression e.g. the MAPK/ERK and AKT pathway or FAK-mediated signalling PMID:15716380 PMID:17699774 PMID:20501702 L1CAM is a target gene of b-catenin-TCF signaling in colorectal cancer cells. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis The transmembrane localization and shedding of L1CAM by metalloproteases, including ADAM10 could be useful for detection and as target for colon cancer therapy. Expression of L1CAM and ADAM10 in human colon cancer cells induces metastasis. NFkB signaling and ezrin are essential for L1CAM-mediated metastasis of colon cancer cells. PMID:21123622 Gavert and al. showed that L1CAM-mediated colon cancer cell metastasis does not require changes in EMT and cancer stem cell markers. BUT in other context, PMID:19435915 PMID:21109948 Geismann and al. showed that upregulation of L1CAM in pancreatic duct cells is TGFB1- and SNAI2-dependent. Binding of SNAI2 to the L1CAM promoter is essential for TGFB1-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. TGFB1–mediated L1CAM expression is SMAD independent but requires JNK activation. In the context of the human PDAC (pancreatic ductal epithelial cell) line H6c7 which mimics the early steps in PDAC tumorigenesis,TGFB1 induces SNAI2 expression in H6c7 cells through JNK activation. THUS, the impact of L1CAM on EMT might be either tumor specific and/or tumor stage dependent. Further studies are required to elaborate whether upregulation of L1CAM is part of the EMT or even the inducing event. If it is the case, elevated cell migration and apoptosis resistance could be abolished by interfering wih TGFB1 signaling or by supression of SNAI2 or L1CAM. PMID:16506207 PMID:17952127 PMID:21373966 Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated. A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes. Besides its ability to induce Erk1/2 and FAK signalling pathways, L1CAM can also lead to the activation of NF-kB, so that inhibition of NF-kB reduced L1CAM-mediated metastasis of colon cancer cells. PMID:17145883 Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases B-catenin transcriptional activity, thus increases scattering and motility of MCF7 breast carcinoma cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="L1CAM"/> <bbox w="60.0" h="20.0" x="594.0" y="3778.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3595_emtc_emtc_csa109" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:E-Cadherin*:ITGAE:ITGB7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:11413131 E-cadherin dimerization is essential for adhesion to the integrin aEb7 PMID:17325197 Interaction between E-cadherin and aEb7 integrin plays major role in effective tumor cell lysis, during cytolytic granule polarization and subsequent exocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(E-Cadherin*/Integrin aEb7)"/> <bbox w="169.0625" h="83.0" x="595.9375" y="3531.5"/> <glyph class="macromolecule multimer" id="emtc_emtc_s909_emtc_emtc_sa655"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="86.0" h="26.0" x="598.0625" y="3532.5"/> <glyph class="unit of information" id="_4985b345-4848-431a-b87a-ee7c3e4cdfe7"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="631.0625" y="3527.5"/> </glyph> <glyph class="state variable" id="_28b7c18c-b446-4b02-af92-7f7f8cdc6fc5"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="590.5625" y="3528.5918"/> </glyph> <glyph class="state variable" 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class="macromolecule" id="emtc_emtc_s908_emtc_emtc_sa657"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="40.0" h="20.0" x="608.1875" y="3574.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3625_emtc_emtc_csa274" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Desmocolin1 binding partners*:Desmocolin1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Desmocolin 1*/Desmocolin 1 binding partners*)"/> <bbox w="293.0" h="46.0" x="1179.0" y="4266.5"/> <glyph class="macromolecule" id="emtc_emtc_s3626_emtc_emtc_sa1796"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Desmocollin 1 binding partners* desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 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HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocolin1*"/> <bbox w="88.0" h="21.0" x="1380.5" y="4270.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3629_emtc_emtc_csa275" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Desmoglein1 binding partners*:Desmoglein1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Desmoglein 1*/Desmoglein 1 binding partners)"/> <bbox w="295.0" h="43.0" x="1178.0" y="4333.5"/> <glyph class="macromolecule" id="emtc_emtc_s3631_emtc_emtc_sa1799"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Desmoglein 1 binding partners* desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein1 binding partners*"/> <bbox w="199.0" h="18.0" x="1181.5" y="4338.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3630_emtc_emtc_sa1800"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein1*"/> <bbox w="87.0" h="19.0" x="1382.5" y="4338.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3634_emtc_emtc_csa276" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Plakoglobin binding partners*:Plakoglobin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Plakoglobin*/Plakoglobin binding partners)"/> <bbox w="264.0" h="46.0" x="1193.0" y="4540.5"/> <glyph class="macromolecule" id="emtc_emtc_s3635_emtc_emtc_sa1803"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Plakoglobin binding partners* Desmosomal cadherins* Desmocollin* democollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 desmocollin 3 HUGO:DSC3, HGNC:3037, ENTREZ:1825, UNIPROT:Q14574, GENECARDS:GC18M028593 Desmoglein* desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 desmoglein 3 HUGO:DSG3 HGNC:3050 ENTREZ:1830 UNIPROT:P32926 GENECARDS:GC18P029050 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) NGL, "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 Rho GDP dissociation inhibitor (GDI) alpha HUGO:ARHGDIA, HGNC:678, ENTREZ:396, GENECARDS:GC17M079825, UNIPROT:P52565 catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakoglobin binding partners*"/> <bbox w="180.0" h="22.0" x="1196.5" y="4544.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3636_emtc_emtc_sa1804"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakoglobin*"/> <bbox w="80.0" h="21.0" x="1375.5" y="4545.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3640_emtc_emtc_csa277" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Plakophilin2 binding partners*:Plakophilin2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Plakophilin 2*/Plakophilin 2 binding partners)"/> <bbox w="282.0" h="42.0" x="1188.0" y="4682.5"/> <glyph class="macromolecule" id="emtc_emtc_s3641_emtc_emtc_sa1808"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Plakophilin 2 binding partners* desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, UNIPROT:P08670, GENECARDS:GC10P017310 keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343, UNIPROT:P05783 keratin 14 HUGO:KRT14, HGNC:6416, ENTREZ:3861, GENECARDS:GC17M039738, UNIPROT:P02533 keratin 8 HUGO:KRT8 HGNC:6446 ENTREZ:3856 UNIPROT:P05787 GENECARDS:GC12M053290 keratin 5 EBS2, "epidermolysis bullosa simplex 2 Dowling-Meara/Kobner/Weber-Cockayne types", "keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)" HUGO:KRT5 HGNC:6442 ENTREZ:3852 UNIPROT:P13647 GENECARDS:GC12M052908 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin2 binding partners*"/> <bbox w="185.0" h="19.0" x="1190.0" y="4687.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3642_emtc_emtc_sa1809"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin2*"/> <bbox w="91.0" h="17.0" x="1377.0" y="4689.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3644_emtc_emtc_csa278" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Desmoplakin binding partners*:Desmoplakin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="'Desmoplakin*/Desmoplakin binding partners)"/> <bbox w="278.0" h="46.0" x="1187.0" y="4898.5"/> <glyph class="macromolecule" id="emtc_emtc_s3645_emtc_emtc_sa1171"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end Identifiers_begin: Identifiers_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoplakin*"/> <bbox w="83.0" h="20.0" x="1377.0" y="4904.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3646_emtc_emtc_sa1811"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Desmoplakin binding partners* desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 GENECARDS:GC01P201252 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 GENECARDS:GC02P159313 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, UNIPROT:P08670, GENECARDS:GC10P017310 keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343, UNIPROT:P05783 keratin 8 HUGO:KRT8 HGNC:6446 ENTREZ:3856 UNIPROT:P05787 GENECARDS:GC12M053290 keratin 1 EHK1, "epidermolytic hyperkeratosis 1" HUGO:KRT1 HGNC:6412 ENTREZ:3848 UNIPROT:P04264 GENECARDS:GC12M053069 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoplakin binding partners*"/> <bbox w="182.0" h="21.0" x="1193.5" y="4902.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3667_emtc_emtc_csa270" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:APC:AXIN1:_beta_-Catenin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signalingMaps_Modules_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(APC/AXIN1/S33_S37_T41β-Catenin*)"/> <bbox w="226.0" h="75.0" x="1647.0" y="3761.5"/> <glyph class="macromolecule" id="emtc_emtc_s2041_emtc_emtc_sa975"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="74.0" h="28.0" x="1724.0" y="3767.5"/> <glyph class="state variable" id="_d3e6898d-c229-4408-850c-3487bbf3b537"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1716.5" y="3764.1816"/> </glyph> <glyph class="state variable" id="_998f8147-6ba8-494c-8ada-8164948d1a44"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1753.5294" y="3762.5"/> </glyph> <glyph class="state variable" id="_a562c329-db32-4768-bae5-df4b1f931c53"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1793.0" y="3762.5"/> </glyph> <glyph class="state variable" id="_a5ee20ae-7d1b-4a66-bd6d-3ea2ed417840"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1768.3125" y="3762.5"/> </glyph> <glyph class="state variable" id="_63b9a8dd-c44d-4374-af85-448dd18a962d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1737.8914" y="3762.5"/> </glyph> <glyph class="state variable" id="_323bf3b0-1259-4577-9b1b-b8af35837b96"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1793.0" y="3788.8582"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3586_emtc_emtc_sa1763"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC"/> <bbox w="40.0" h="20.0" x="1708.25" y="3796.5"/> <glyph class="state variable" id="_a500f8dc-1dbf-4217-8e1e-1251f62ffa85"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1721.166" y="3791.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3587_emtc_emtc_sa1764"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. 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In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signalingMaps_Modules_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(APC/AXIN1/S45β-Catenin*)"/> <bbox w="165.0625" h="80.0" x="1362.469" y="3759.0"/> <glyph class="macromolecule" id="emtc_emtc_s2043_emtc_emtc_sa949"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. 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Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1"/> <bbox w="40.0" h="20.0" x="1441.531" y="3800.0"/> <glyph class="state variable" id="_6fb625a5-8bb9-4485-9298-62bf92c0e4c8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1454.447" y="3795.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2056_emtc_emtc_sa994"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC"/> <bbox w="40.0" h="20.0" x="1401.531" y="3800.0"/> <glyph class="state variable" id="_c5998fee-425d-4d34-8133-a228111f3947"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1414.447" y="3795.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3669_emtc_emtc_csa272" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:_alpha_-Catenin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Actin cytoskeletal*/α-Catenin*)"/> <bbox w="183.0" h="51.0" x="1633.0" y="3242.5"/> <glyph class="macromolecule" id="emtc_emtc_s3603_emtc_emtc_sa1776"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="1635.5" y="3248.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3604_emtc_emtc_sa1777"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Catenin*"/> <bbox w="73.0" h="23.0" x="1744.5" y="3246.5"/> <glyph class="unit of information" id="_cab13a9d-e842-4d78-a79b-f4cb397791c2"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1771.0" y="3241.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3674_emtc_emtc_csa169" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:LEF1_TCF3_4*:_beta_-Catenin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 -In the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. -In the presence of Wnt lignads, upon ligand binding, DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(β-Catenin*/LEF/TCF*)"/> <bbox w="188.0" h="53.5" x="2172.0" y="3425.0"/> <glyph class="macromolecule" id="emtc_emtc_s2054_emtc_emtc_sa988"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="68.166664" h="27.095238" x="2283.916" y="3431.953"/> <glyph class="state variable" id="_21f094cf-308e-4ebc-bc40-3a727fecabea"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2278.916" y="3428.58"/> </glyph> <glyph class="state variable" id="_2249328a-4b99-4a46-9e3a-7c24d447fe2d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2313.0264" y="3426.953"/> </glyph> <glyph class="state variable" id="_8193c40d-20ff-4678-8834-027f3a13c010"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2347.0828" y="3426.953"/> </glyph> <glyph class="state variable" id="_065e56a0-947c-43e3-a017-0b09da006371"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2326.644" y="3426.953"/> </glyph> <glyph class="state variable" id="_69dc7b8f-fe2f-49a7-b9fc-9860ad1b77ca"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2298.621" y="3426.953"/> </glyph> <glyph class="state variable" id="_44ab9f6f-8d68-424c-aeeb-db3789b0d638"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2347.0828" y="3452.4592"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3589_emtc_emtc_sa1765"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LEF/TCF3* transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 lymphoid enhancer-binding factor 1 HUGO:LEF1, HGNC:6551, ENTREZ:51176, UNIPROT:Q9UJU2, GENECARDS:GC04M108968 transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, UNIPROT:P15923, GENECARDS:GC19M001609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LEF1_TCF3_4*"/> <bbox w="98.0" h="25.0" x="2174.5" y="3428.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3681_emtc_emtc_csa265" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:VE-Cadherin*:_beta_-Catenin*_p120*1_Plakoglobin*_Plakophilin4* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(VE-Cadherin*/β-Catenin*_p120*1_Plakoglobin*_Plakophilin4*)"/> <bbox w="380.0" h="47.0" x="593.0" y="4340.5"/> <glyph class="macromolecule" id="emtc_emtc_s3560_emtc_emtc_sa1742"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VE-Cadherin*"/> <bbox w="84.0" h="19.0" x="596.5" y="4345.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3613_emtc_emtc_sa1784"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: _beta_-Catenin*_p120*_JUP_PKP4* catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*_p120*1_Plakoglobin*_Plakophilin4*"/> <bbox w="290.0" h="20.0" x="680.5" y="4345.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3686_emtc_emtc_csa279" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Cadherin*:_alpha_-Catenin*:_beta_-Catenin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:15609097 CTNNB1 (beta-catenin) binds with high affinity to the distal Cadherin cytoplasmic tail. Cadherin recruits CTNNA1 (alpha-catenin) to the complex. CTNNA1 (alpha-catenin) binds to Actin filaments directly CTNNA1 (alpha-catenin) and can also associate with other actin-binding proteins (MLLT4 or Formin) CTNND1 (delta-catenin or p120) binds directly to Cadherin independently of the other catenins. Catenins/Cadherin complex can further interact with a range of singaling molecules which participate in either cellular signaling or control of cytoskeletal dynamics. Stability of Cadherin/Catenins complex and thereby the integrity of adherens junctions is controlled by phosphorylation/dephosphorylation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(β-Catenin*/Cadherin*/α-Catenin*)"/> <bbox w="236.0" h="55.0" x="935.0" y="3387.5"/> <glyph class="macromolecule" id="emtc_emtc_s3598_emtc_emtc_sa1772"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Catenin*"/> <bbox w="66.0" h="20.0" x="1097.75" y="3398.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3599_emtc_emtc_sa1774"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="66.0" h="28.0" x="941.75" y="3393.5"/> <glyph class="state variable" id="_20de1341-b598-4246-bfc0-7cf2eb60c836"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="936.75" y="3390.1816"/> </glyph> <glyph class="state variable" id="_134a4fe5-d777-479c-b080-2f85acf9743d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="969.7763" y="3388.5"/> </glyph> <glyph class="state variable" id="_b822c0c3-fcd8-4ee1-b1dc-cc9e8054b634"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1002.75" y="3388.5"/> </glyph> <glyph class="state variable" id="_6e252a84-375e-41b3-9abc-92661b0760f4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="982.9611" y="3388.5"/> </glyph> <glyph class="state variable" id="_be1edf0b-ca59-4a8d-8fd4-fe9b70832d31"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="955.8288" y="3388.5"/> </glyph> <glyph class="state variable" id="_3d26688e-12d3-45b6-8325-9782464351b6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1002.75" y="3414.8582"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3683_emtc_emtc_sa1823"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cadherin*"/> <bbox w="75.0" h="20.0" x="1015.5" y="3392.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3687_emtc_emtc_csa271" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Cadherin*:p120* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:15609097 CTNNB1 (beta-catenin) binds with high affinity to the distal Cadherin cytoplasmic tail. Cadherin recruits CTNNA1 (alpha-catenin) to the complex. CTNNA1 (alpha-catenin) binds to Actin filaments directly CTNNA1 (alpha-catenin) and can also associate with other actin-binding proteins (MLLT4 or Formin) CTNND1 (delta-catenin or p120) binds directly to Cadherin independently of the other catenins. Catenins/Cadherin complex can further interact with a range of singaling molecules which participate in either cellular signaling or control of cytoskeletal dynamics. Stability of Cadherin/Catenins complex and thereby the integrity of adherens junctions is controlled by phosphorylation/dephosphorylation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Cadherin*/p120*)"/> <bbox w="162.0" h="48.0" x="1211.0" y="3387.5"/> <glyph class="macromolecule" id="emtc_emtc_s3600_emtc_emtc_sa1773"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p120*"/> <bbox w="52.0" h="16.0" x="1305.75" y="3393.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3684_emtc_emtc_sa1824"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cadherin*"/> <bbox w="75.0" h="20.0" x="1227.5" y="3391.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3709_emtc_emtc_csa136" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR200A:_beta_-Catenin*_ZEB1_ZEB2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19931509 miR-200a downregulates ZEB2 and CTNNB1 This downregulation inhibits carcinoma cell growth, migration and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR200A/β-Catenin*_ZEB1_ZEB2*)"/> <bbox w="216.0" h="58.0" x="2299.5" y="5372.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3696_emtc_emtc_sa1830"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200A"/> <bbox w="78.0" h="18.0" x="2373.5" y="5371.5"/> <glyph class="unit of information" id="_af1c2683-094f-4993-96fc-72d84b3afc3f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2397.5" y="5366.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3708_emtc_emtc_sa1840"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: _beta_-Catenin*_ZEB1_ZEB2* beta catenin HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, GENECARDS:GC03P041236 zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*_ZEB1_ZEB2*"/> <bbox w="214.0" h="19.0" x="2300.5" y="5390.5"/> <glyph class="unit of information" id="_c20541bb-f7b3-4dd4-8d1e-c2c69d461fd9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2397.5" y="5385.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3717_emtc_emtc_csa280" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BIM1_KLF4_SOX2*:MIR183 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20706219 BMI1, KLF4 and SOX2 are targets of MIR183 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR183/BIM1_KLF4_SOX2*)"/> <bbox w="171.0" h="62.0" x="2317.5" y="5539.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3718_emtc_emtc_sa1847"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BMI1_KLF4_SOX2* BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 Kruppel-like factor 4 (gut) HUGO:KLF4, HGNC:6348, ENTREZ:9314, GENECARDS:GC09M110247 SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIM1_KLF4_SOX2*"/> <bbox w="135.0" h="21.0" x="2339.0" y="5560.5"/> <glyph class="unit of information" id="_bcfdf031-0d04-4de8-b792-897ff9cf7e37"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2396.5" y="5555.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3719_emtc_emtc_sa1848"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 183 HUGO:MIR183, HGNC:31554, ENTREZ:406959, GENECARDS:GC07M129416 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR183"/> <bbox w="81.0" h="19.0" x="2365.0" y="5540.5"/> <glyph class="unit of information" id="_e87f52d3-54bc-4547-a1c6-db00fc70e3e1"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2390.5" y="5535.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3722_emtc_emtc_csa116" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR200*:ZEB1_ZEB2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21336307 PMID:21224848 PMID:22286765 Six1 induces ZEB1 and EMT through transcriptional repression of miR200. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR200*/ZEB1_ZEB2*)"/> <bbox w="141.0" h="61.0" x="2150.5" y="5368.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3721_emtc_emtc_sa725"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 microRNA 429 HUGO:MIR429, HGNC:13784, ENTREZ:554210, GENECARDS:GC01P001109 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21336307 PMID:22370643 Regulation of BMI1 and JAG1 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200*"/> <bbox w="72.0" h="20.0" x="2190.5" y="5368.0"/> <glyph class="unit of information" id="_631593f8-cfc2-4422-95be-5e75ef81c7c1"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2211.5" y="5363.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3723_emtc_emtc_sa1850"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ZEB1_ZEB2* zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20706219 ZEB1 and ZEB2 are targeted by all MIR200 family members. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1_ZEB2*"/> <bbox w="108.0" h="20.0" x="2175.5" y="5388.5"/> <glyph class="unit of information" id="_b345e807-a76a-405f-88de-d88dbf84d127"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2219.5" y="5383.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3727_emtc_emtc_csa147" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ETS1_WASF3_WAVE3*:MIR200B Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21081489 miR-200b interacts with the Ets-encoding RNA to exert translational repression PMID:20706219 ETS1, WASF3 and WAVE3 are targeted by MIR-200B References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR200B/ETS1_WASF3_WAVE3*)"/> <bbox w="200.0" h="61.0" x="2521.5" y="5369.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1427_emtc_emtc_sa791"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21081489 miR-200b targets Ets-1 and is down-regulated by Hypoxia to induce Angiogenic response of Endothelial cells Overexpression of Est-1 reverses the phenotypic changes caused by miR-200b, supporting that miR-200b inhibits the angiogenic response via silencing of Est-1 PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200B"/> <bbox w="75.0" h="20.0" x="2591.5" y="5370.5"/> <glyph class="unit of information" id="_471fc3d7-4467-423e-85cb-9f6dbfd964ac"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2614.0" y="5365.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3726_emtc_emtc_sa1852"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: EST1_WASF3_WAVE3* v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) HUGO:ETS1, HGNC:3488, ENTREZ:2113, GENECARDS:GC11M128328 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20706219 ETS1, WASF3 and WAVE3 are targeted by MIR-200B References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ETS1_WASF3_WAVE3*"/> <bbox w="165.0" h="19.0" x="2541.5" y="5392.5"/> <glyph class="unit of information" id="_f9a8786a-a4d7-461c-825d-9f860974e982"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2614.0" y="5387.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3733_emtc_emtc_csa144" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BMI1_BIRC5_KLF4_SOX2_SNAI1_ZEB2*:MIR203A Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 PMID:20706219 BMI1, KLF4 and SOX2 are targets of MIR203 PMID:22514743 SNAI1, ZEB2 are direct targets of MIR203 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR203/BMI1_BIRC5_KLF4_SOX2_SNAI1_ZEB2*)"/> <bbox w="288.0" h="66.0" x="2159.5" y="5724.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3711_emtc_emtc_sa1842"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BMI1_BIRC5_KLF4_SOX2_SNAI1_ZEB2* BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 baculoviral IAP repeat containing 5 HUGO:BIRC5, HGNC:593, ENTREZ:332, GENECARDS:GC17P076210 Kruppel-like factor 4 (gut) HUGO:KLF4, HGNC:6348, ENTREZ:9314, GENECARDS:GC09M110247 SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, GENECARDS:GC20P048599 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1_BIRC5_KLF4_SOX2_SNAI1_ZEB2*"/> <bbox w="271.0" h="20.0" x="2164.5" y="5748.5"/> <glyph class="unit of information" id="_4071103c-6503-41d1-812f-61f3729d6f10"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2290.0" y="5743.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2525_sa2187"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR203A"/> <bbox w="80.0" h="20.0" x="2265.2" y="5726.6"/> <glyph class="unit of information" id="_1ce4a611-904c-42bf-ae8c-cfa29c49258b"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2290.2" y="5721.6"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3740_emtc_emtc_csa281" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR141:SMAD2_TGFBR1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20498632 PMID:22753312 direct regulation of TGFBR1 by miR-141 direct regulation of SMAD2 by miR-141/200c/30e direct regulation of ZEB2 by miR-30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR141/SMAD2_TGFBR1*)"/> <bbox w="164.0" h="61.0" x="3118.0" y="5363.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3736_emtc_emtc_sa1858"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR141"/> <bbox w="83.0" h="18.0" x="3161.5" y="5366.5"/> <glyph class="unit of information" id="_23781486-39bd-4649-ac18-f15b3c93746c"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3188.0" y="5361.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3737_emtc_emtc_sa1859"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: TGFBR1_SMAD2* transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 SMAD family member 2 "MAD, mothers against decapentaplegic homolog 2 (Drosophila)", MADH2, "SMAD, mothers against DPP homolog 2 (Drosophila)" HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20498632 PMID:22753312 direct regulation of TGFBR1 by miR-141 direct regulation of SMAD2 by miR-141/200c/30e direct regulation of ZEB2 by miR-30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_TGFBR1*"/> <bbox w="130.0" h="20.0" x="3133.5" y="5384.5"/> <glyph class="unit of information" id="_4b0b6c50-94f0-43fe-a79c-f332e21bc3f4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3188.5" y="5379.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3744_emtc_emtc_csa282" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR30E:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR30E/SMAD2"/> <bbox w="98.0" h="61.0" x="3288.0" y="5361.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3745_emtc_emtc_sa1864"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 30E HUGO:MIR30E, HGNC:31629, ENTREZ:407034, GENECARDS:GC01P041220 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="82.0" h="20.0" x="3297.5" y="5363.5"/> <glyph class="unit of information" id="_5ae79fea-ed47-4d48-aca4-8081e87d6ca9"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3323.5" y="5358.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3746_emtc_emtc_sa1865"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 2 "MAD, mothers against decapentaplegic homolog 2 (Drosophila)", MADH2, "SMAD, mothers against DPP homolog 2 (Drosophila)" HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="20.0" x="3297.5" y="5383.5"/> <glyph class="unit of information" id="_4d7e1fa4-7f7e-458d-b0d8-2e752112f045"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3327.5" y="5378.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3747_emtc_emtc_csa283" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR30E:ZEB2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22753312 direct regulation of ZEB2 by miR-30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR30E/ZEB2"/> <bbox w="101.0" h="64.0" x="3392.0" y="5360.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3748_emtc_emtc_sa1866"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 30E HUGO:MIR30E, HGNC:31629, ENTREZ:407034, GENECARDS:GC01P041220 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="82.0" h="20.0" x="3404.5" y="5362.5"/> <glyph class="unit of information" id="_c4c7fbd6-f220-4f34-adb0-25d5d4d51e5a"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3430.5" y="5357.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3749_emtc_emtc_sa1867"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB2"/> <bbox w="60.0" h="20.0" x="3411.5" y="5383.5"/> <glyph class="unit of information" id="_9a0936ae-55e3-4286-a133-cd22e3b44eb7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3431.5" y="5378.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3753_emtc_emtc_csa115" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR106B_25*:SMAD7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19726885 PMID:22286770 inhibitory Smad7 mRNA is a target for all 3 members of MIR106B/25 subfamily (MIR106B, MIR93, MIR25) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR106B_25*/SMAD7"/> <bbox w="134.0" h="60.0" x="2157.5" y="5541.5"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1405_emtc_emtc_sa723"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 106b HUGO:MIR106B, HGNC:31495, ENTREZ:406900, GENECARDS:GC07M099695 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth PMID:19726885 PMID:22286770 PMID:21386132 The miR-17 family consists of 3 paralogous polycistronic clusters on different chromosomes: miR-17/92 (miR-17, miR-18a, miR-19a, miR-20a, miR-19b- 1, and miR-92a-1), miR-106b/25 (miR-106b, miR-93, and miR-25) and miR-106a/363 (miR-106a, miR-18b, miR-20b, miR-19b-2, miR-92a-2, and miR-363). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR106B_25*"/> <bbox w="113.0" h="18.0" x="2172.5" y="5543.5"/> <glyph class="unit of information" id="_f1f15005-3d6b-428d-b847-9732cd9b15da"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2214.0" y="5538.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s383_emtc_emtc_sa724"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD7"/> <bbox w="71.66071" h="20.0" x="2216.84" y="5562.5"/> <glyph class="unit of information" id="_aaf517cb-bcc7-4b1c-ab7b-eeeb47523fb6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2242.6704" y="5557.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3754_emtc_emtc_csa284" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD7:TGFBR1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22286770 The inhibitory Smad7 mRNA is repressed by MIR106B, MIR93, MIR25. Smad7 antagonizes TGF-b signaling through multiple mechanisms, including binding to TGFBR1 and interfering with recruitment and downstream phosphorylation and activation of Smad2 and Smad3. Smad7 also functions to recruit E3 ubiquitin ligases to TGRFBR1, resulting in its degradation. Repression of Smad7 therefore activates TGF-beta signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD7/TGFBR1"/> <bbox w="130.0" h="69.0" x="5105.0" y="4305.5"/> <glyph class="macromolecule" id="emtc_emtc_s3755_emtc_emtc_sa1871"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD7"/> <bbox w="60.0" h="20.0" x="5111.5" y="4327.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3756_emtc_emtc_sa1872"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="52.0" h="45.0" x="5180.922" y="4311.238"/> <glyph class="unit of information" id="_d3338c83-0ae7-4a97-bb18-2f80883871de"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5196.922" y="4306.238"/> </glyph> <glyph class="state variable" id="_b014cffc-bfec-4591-9618-030cb220a3f7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5227.922" y="4306.4795"/> </glyph> <glyph class="state variable" id="_a9f5bec2-7dec-4ee9-9f0f-705b8bacf497"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="5168.422" y="4307.284"/> </glyph> <glyph class="unit of information" id="_ca4b23be-7427-45b9-af38-ba3635d0718c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5184.422" y="4306.238"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3760_emtc_emtc_csa63" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIZ1*:MYC Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11283613 Miz-1 regulates expression of p15INK4b The Myc/Miz1 complex binds to the p15 promoter Myc inhibits binding of p300 to Miz-1 Myc inhibits expression of p15INK4B by binding to Miz-1 (Myc represses p15INK4B by interacting with Miz1) PMID:11283614 Disruption of the Myc-Miz1 interaction prevents repression of p15INK4B by Myc. TGFB relieves Myc-mediated repression of p15INK4B by downregulating Myc bound to the p15INK4B transcriptional initiator region. At the same time TGFB induces the formation of a Smad transcriptional complex that recognizes the p15INK4B promoter. Is is proposed that by relieving the Myc-mediated repression of p15INK4B, TGFB allows this gene to be activated by the Smad complex. TGFB signaling controls p15INK4B activation by 2 coupled events: transactivation and relief of repression. PMID:10454538 Myc prevents inhibition of G1 CDKs by TGFB. Inhibition of the p15 promoter by c-Myc. Enforced expression of Myc abrogates p15INK4B induction and CDK inhibition by TGFB Myc downregulation by TGFB is required for Activation of the p15Ink4b G1 Arrest Pathway 3 populations of endogenous CDK4: Latent pools (400 kDa, source of CDK4 for Cyclin D), Active CDK4-CyclinD complex, Inactive monomeric CDK4 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIZ1*/MYC"/> <bbox w="66.5" h="61.0" x="3490.5" y="2180.0"/> <glyph class="macromolecule" id="emtc_emtc_s677_emtc_emtc_sa498"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog (avian) HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748, UNIPROT:P01106 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID :17055429 MYC stimulate P53 and ARF(CDKN2A) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYC"/> <bbox w="40.0" h="20.0" x="3503.5" y="2201.0"/> <glyph class="state variable" id="_fda11de9-98b0-44b6-b557-b382c8304767"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3498.5" y="2205.9841"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s678_emtc_emtc_sa516"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger and BTB domain containing 17 HUGO:ZBTB17, HGNC:12936, ENTREZ:7709, GENECARDS:GC01M016268, UNIPROT:Q13105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIZ1*"/> <bbox w="40.0" h="20.0" x="3504.5" y="2181.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3761_emtc_emtc_csa113" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PARD6A:SMURF1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:21572392 SMURF1 is an homologous to E6AP C-ter (HECT)-type E3 ubiquitin ligase SMURF1 performs a crucial role in the regulation of the BMP signalling pathway in both embryonic development and bone remodelling. PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A/SMURF1"/> <bbox w="128.0" h="69.0" x="1216.0" y="2010.5"/> <glyph class="macromolecule" id="emtc_emtc_s968_emtc_emtc_sa682"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696, UNIPROT:Q9NPB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="55.0" h="39.0" x="1227.0" y="2017.5"/> <glyph class="state variable" id="_4c1ba440-d971-4f22-ac83-3786fd9b5fd2"> <state value="P" variable="S345"/> <bbox w="35.0" h="10.0" x="1231.1615" y="2012.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s969_emtc_emtc_sa683"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1, HGNC:16807, ENTREZ:57154, GENECARDS:GC07M098627, UNIPROT:Q9HCE7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:21572392 SMURF1 is an E3 ubiquitin ligase SMURF1 performs a crucial role in the regulation of the BMP signalling pathway in both embryonic development and bone remodelling. PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity Need more reference 34-36 from PMID15761148: RhoA is an important modulator of cell junction formation and stability. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF1"/> <bbox w="56.5" h="20.0" x="1287.25" y="2019.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3763_emtc_emtc_csa259" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CRK:DOCK1:PXN Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:9808620 Crk–p130Cas complexes regulate cell spreading after integrin stimulation and serve as amolecular switch for induction of cell migration DOCK1 is suggested to be the downstream effector of Crk in integrin signaling: -DOCK1 binds to Crk after integrin stimulation; -DOCK1 colocalizes with the Crk2–p130Cas complexes at focal adhesions and at the sites of membrane spreading; -Expression of DOCK1 accelerates the formation of the Crk–p130Cas complexes. It is likely that the DOCK1 recruited to the Crk–p130Cas complexes on integrin stimulation transduces signals to Rac1 at focal adhesions, which eventually induces cell spreading. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRK/DOCK1/PXN"/> <bbox w="111.0" h="58.0" x="5557.0" y="5519.5"/> <glyph class="macromolecule" id="emtc_emtc_s3484_emtc_emtc_sa1684"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-crk sarcoma virus CT10 oncogene homolog (avian) "v-crk avian sarcoma virus CT10 oncogene homolog" HUGO:CRK HGNC:2362 ENTREZ:1398 UNIPROT:P46108 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRK"/> <bbox w="32.0" h="16.0" x="5593.18" y="5520.875"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3483_emtc_emtc_sa1685"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: paxillin HUGO:PXN HGNC:9718 ENTREZ:5829 UNIPROT:P49023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PXN"/> <bbox w="32.0" h="28.0" x="5559.541" y="5521.125"/> <glyph class="state variable" id="_84dc8ac4-7015-4c38-b9b0-caaaece00fd3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5553.455" y="5516.125"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3486_emtc_emtc_sa1687"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dedicator of cytokinesis 1 "dedicator of cyto-kinesis 1" HUGO:DOCK1 HGNC:2987 ENTREZ:1793 UNIPROT:Q14185 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15308668 DOCK1 (so-called DOCK180) is a GEF of Rac1. DOCK1 together with paxillin-Crk constitutes the main pathway transducing collagen-mediated signals for the activation of Rac1. This signaling pathway is down-regulated when cell migration is counteracted by C3G/Rap1 activation. A balance between Rac1 and Rap1 GTPases in controlling the migratory versus the stationary state of the cell is suggested. PMID:12432077 DOCK1 is a GEF for Rac1 and possibly for CDC42 PMID:9808620 DOCK1 is involved in integrin signaling through Crk-p130Cas complexes. DOCK1 activates JNK in a Rac1, Cdc42 - dependent manner Overexpression of DOCK1 increases the amount of GTP-bound Rac1 Coexpression of Crk2 and p130Cas (BCAR1) enhances this DOCK1-dependent activation of Rac1. Direct binding of DOCK1 to Rac1, but not to RhoA or Cdc42. To sum up, DOCK1 is a novel activator of Rac1 and involved in integrin signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DOCK1"/> <bbox w="48.0" h="19.0" x="5590.0" y="5536.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3792_emtc_emtc_csa124" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR205 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 PMID:22753312 PMID:21209780 PMID:18376396 ZEB1 and ZEB2 contain one and two sites, respectively that are targeted by miRNA-205 PMID:19244118 miR-205 targets N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase C-epsilon. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR205/ZEB1_ZEB2*)"/> <bbox w="156.0" h="62.0" x="2756.5" y="5536.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s1409_emtc_emtc_sa742"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 205 HUGO:MIR205, HGNC:31583, ENTREZ:406988, GENECARDS:GC01P209605 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR205"/> <bbox w="74.0" h="20.0" x="2768.5" y="5536.0"/> <glyph class="unit of information" id="_9af112f0-de3d-49c2-8ce3-a3f79e6d9115"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2790.5" y="5531.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3797_emtc_emtc_csa285" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:HDAC1:HDAC2:SIN3A:SNAI1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1/HDAC2/SIN3A/SNAI1"/> <bbox w="184.0" h="74.0" x="2695.0" y="3406.5"/> <glyph class="macromolecule" id="emtc_emtc_s3798_emtc_emtc_sa1882"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: Feedback loops PMID:22514743 PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="40.0" h="20.0" x="2739.5" y="3436.5"/> <glyph class="state variable" id="_fd8b2029-5ebd-483f-8930-d32da6bee921"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2734.5" y="3432.5222"/> </glyph> <glyph class="state variable" id="_ecea734b-f055-4ae0-a9a1-0aefefedbe96"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2774.5" y="3432.5508"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3800_emtc_emtc_sa1883"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="50.0" h="16.0" x="2734.5" y="3415.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3799_emtc_emtc_sa1884"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 2 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC2"/> <bbox w="53.0" h="17.0" x="2786.5" y="3416.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3802_emtc_emtc_sa1886"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SIN3 transcription regulator homolog A (yeast) SIN3A HUGO:SIN3A HGNC:19353 ENTREZ:25942 UNIPROT:Q96ST3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SIN3A"/> <bbox w="45.0" h="16.0" x="2786.5" y="3437.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3803_emtc_emtc_csa286" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EZH2:HDAC1:HDAC2:SNAI1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:21685935 EZH2 supports carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1 and HDAC2 and Snail to inhibit E-cadherin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH2/HDAC1/HDAC2/SNAI1"/> <bbox w="177.0" h="75.0" x="2697.0" y="3679.5"/> <glyph class="macromolecule" id="emtc_emtc_s3805_emtc_emtc_sa1887"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 2 (Drosophila) "enhancer of zeste (Drosophila) homolog 2" HUGO:EZH2 HGNC:3527 ENTREZ:2146 UNIPROT:Q15910 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH2"/> <bbox w="41.0" h="16.0" x="2790.0" y="3715.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3804_emtc_emtc_sa1888"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 2 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC2"/> <bbox w="53.0" h="17.0" x="2786.0" y="3689.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3807_emtc_emtc_sa1889"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="50.0" h="16.0" x="2732.0" y="3691.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3806_emtc_emtc_sa1890"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: Feedback loops PMID:22514743 PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="40.0" h="20.0" x="2736.0" y="3714.75"/> <glyph class="state variable" id="_d49f98cc-0f1d-4f6d-8b3b-da0baa94ad4a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2731.0" y="3710.7722"/> </glyph> <glyph class="state variable" id="_3132091d-45c8-4987-b654-7bd61a903043"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2771.0" y="3710.8008"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3824_emtc_emtc_csa131" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BIM1_KLF4_SOX2*:MIR200C Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19935649 Targets of miR-200c include stem cell factors, such as Bmi1, Sox2 and KLF4 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR200C/BIM1_KLF4_SOX2*)"/> <bbox w="175.0" h="63.0" x="2734.5" y="5363.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3829_emtc_emtc_sa1912"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BMI1_KLF4_SOX2* BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 Kruppel-like factor 4 (gut) HUGO:KLF4, HGNC:6348, ENTREZ:9314, GENECARDS:GC09M110247 SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIM1_KLF4_SOX2*"/> <bbox w="135.0" h="21.0" x="2764.5" y="5384.5"/> <glyph class="unit of information" id="_e4ba6d8d-6d8c-4885-bf85-566da3d27ec0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2822.0" y="5379.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3830_emtc_emtc_sa1913"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200C"/> <bbox w="84.0" h="17.0" x="2785.5" y="5365.5"/> <glyph class="unit of information" id="_c2ff7e1d-60dc-48dd-ad73-5aeb53aec4a4"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2812.5" y="5360.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3827_emtc_emtc_csa132" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MIR200C:SMAD2_TGFB2* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 PMID:20706219 BIM1 and TGFB2 are targeted by MIR200C PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MIR200C/SMAD2_TGFB2*)"/> <bbox w="165.0" h="60.0" x="2923.5" y="5365.0"/> <glyph class="nucleic acid feature" id="emtc_emtc_s3729_emtc_emtc_sa1853"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200C"/> <bbox w="84.0" h="17.0" x="2981.5" y="5366.5"/> <glyph class="unit of information" id="_be6ea316-20db-4d5a-bde7-2f2d52d1a36f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3008.5" y="5361.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3730_emtc_emtc_sa1855"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD2_TGFB2* SMAD family member 2 "MAD, mothers against decapentaplegic homolog 2 (Drosophila)", MADH2, "SMAD, mothers against DPP homolog 2 (Drosophila)" HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 transforming growth factor, beta 2 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 PMID:20706219 BIM1 and TGFB2 are targeted by MIR200C PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_TGFB2*"/> <bbox w="148.0" h="20.0" x="2938.5" y="5384.5"/> <glyph class="unit of information" id="_1e218f1d-d708-4a30-9266-cdf52d33b474"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3002.5" y="5379.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3832_emtc_emtc_csa288" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BMI1:TWIST1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20818389 Physical interaction between BMI1 and TWIST1 E-Cadherin repression by cooperative BMI1 and TWIST1 p16INK4A repression by cooperative BMI1 and TWIST1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1/TWIST1"/> <bbox w="114.0" h="61.0" x="2310.125" y="3746.13"/> <glyph class="macromolecule" id="emtc_emtc_s3833_emtc_emtc_sa1922"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1 polycomb ring finger oncogene "B lymphoma Mo-MLV insertion region 1 homolog (mouse)", PCGF4, "polycomb group ring finger 4" HUGO:BMI1 HGNC:1066 ENTREZ:648 UNIPROT:P35226 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1"/> <bbox w="34.0" h="19.0" x="2355.625" y="3749.13"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3836_emtc_emtc_sa1923"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: itwist homolog 1 (Drosophila) HUGO:TWIST1 HGNC:12428, ENTREZ:7291, UNIPROT:Q15672, GENECARDS:GC07M019121 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15640618 Twist induces an epithelial-mesenchymal transition to facilitate tumor metastasis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TWIST1"/> <bbox w="104.0" h="19.0" x="2317.625" y="3768.13"/> <glyph class="state variable" id="_ab1f43f3-9626-4638-967b-b514684c214a"> <state value="P" variable="S68"/> <bbox w="30.0" h="10.0" x="2302.625" y="3772.63"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3840_emtc_emtc_csa57" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDK4_6*:p15INK4B* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*/p15INK4B*"/> <bbox w="142.0" h="39.0" x="3498.5" y="1741.5"/> <glyph class="macromolecule" id="emtc_emtc_s4277_emtc_emtc_sa477"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Identifiers_begin: Identifiers_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) HUGO:CDKN2B, HGNC:1788, ENTREZ:1030, GENECARDS:GC09M021992, UNIPROT:P42772 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p15INK4B*"/> <bbox w="80.0" h="16.0" x="3559.5" y="1742.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3838_emtc_emtc_sa1925"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CDK4_6* cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*"/> <bbox w="58.0" h="17.0" x="3501.5" y="1744.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3841_emtc_emtc_csa58" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDK4_6*:p16INK4A* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*/p16INK4A*"/> <bbox w="144.0" h="43.0" x="3498.5" y="1805.5"/> <glyph class="macromolecule" id="emtc_emtc_s3842_emtc_emtc_sa1926"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2A HUGO:CDKN2A, HGNC:1787, ENTREZ:1029, GENECARDS:GC09M021957, UNIPROT:P42771 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest PMID:26592237 P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p16INK4A*"/> <bbox w="78.0" h="19.0" x="3561.5" y="1809.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4278_emtc_emtc_sa1927"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CDK4_6* cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*"/> <bbox w="60.0" h="19.0" x="3501.5" y="1809.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3848_emtc_emtc_csa289" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MDM2:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15140942 Phosphorylations on p53 prevent its binding to MDM2. PMID:15574337 S186 phosphorylation of MDM2 by AKT favors the binding of MDM2 to p53 and its following degradation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2/p53*"/> <bbox w="80.0" h="97.0" x="4147.0" y="2078.5"/> <glyph class="macromolecule" id="emtc_emtc_s3851_emtc_emtc_sa1935"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="50.0" h="48.0" x="4164.0" y="2104.5"/> <glyph class="state variable" id="_cb04367c-408d-48dd-b640-0a91a14017e0"> <state value="" variable="S395"/> <bbox w="30.0" h="10.0" x="4149.0" y="2102.3826"/> </glyph> <glyph class="state variable" id="_4586299c-50a0-4485-826c-74dd89491790"> <state value="P" variable="S186"/> <bbox w="35.0" h="10.0" x="4146.5" y="2144.4822"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3850_emtc_emtc_sa1934"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="39.0" h="19.0" x="4172.5" y="2081.5"/> <glyph class="state variable" id="_8aafc66a-8545-4dba-92e9-fe06022d0246"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4206.5" y="2082.065"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3852_emtc_emtc_csa290" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MDM2:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15140942 Phosphorylations on p53 prevent its binding to MDM2. PMID:15574337 S186 phosphorylation of MDM2 by AKT favors the binding of MDM2 to p53 and its following degradation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2/p53*"/> <bbox w="80.0" h="97.0" x="4146.5" y="1726.0"/> <glyph class="macromolecule" id="emtc_emtc_s3853_emtc_emtc_sa1936"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="50.0" h="48.0" x="4163.5" y="1751.0"/> <glyph class="state variable" id="_6ec91be8-67ef-493e-8425-79baee2a83cf"> <state value="" variable="S395"/> <bbox w="30.0" h="10.0" x="4148.5" y="1748.8827"/> </glyph> <glyph class="state variable" id="_592aa54a-ca1d-449a-a785-88358dbb10b3"> <state value="P" variable="S186"/> <bbox w="35.0" h="10.0" x="4146.0" y="1790.982"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3854_emtc_emtc_sa1937"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="39.0" h="19.0" x="4172.0" y="1729.0"/> <glyph class="state variable" id="_b3da83b4-566d-4b14-a67d-6dc37e087404"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4206.0" y="1729.565"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3857_emtc_emtc_csa291" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MDM2:SNAI2:p53* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15140942 Phosphorylations on p53 prevent its binding to MDM2. PMID:15574337 S186 phosphorylation of MDM2 by AKT favors the binding of MDM2 to p53 and its following degradation. PMID:19448627 Complex of p53, MDM2 and Slug faciliates the proteasomal degradation of Slug by MDM2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2/p53*/SNAI2"/> <bbox w="123.0" h="96.0" x="4130.0" y="2342.5"/> <glyph class="macromolecule" id="emtc_emtc_s3858_emtc_emtc_sa1939"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, UNIPROT:O43623, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="40.0" h="20.0" x="4147.5" y="2344.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3859_emtc_emtc_sa1940"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="39.0" h="19.0" x="4189.5" y="2344.5"/> <glyph class="state variable" id="_caf60822-bc41-4cfe-85d8-95114b05bfd8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4223.5" y="2345.065"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3860_emtc_emtc_sa1941"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="50.0" h="48.0" x="4167.0" y="2367.5"/> <glyph class="state variable" id="_f8e57aa1-2c20-4eaf-a250-65bbe8270102"> <state value="" variable="S395"/> <bbox w="30.0" h="10.0" x="4152.0" y="2365.3826"/> </glyph> <glyph class="state variable" id="_1ec9e90c-a8bb-45e4-ae88-1bee64662cd4"> <state value="P" variable="S186"/> <bbox w="35.0" h="10.0" x="4149.5" y="2407.4822"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3910_emtc_emtc_csa295" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD2:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2/SMAD3"/> <bbox w="131.0" h="137.0" x="5845.5" y="4662.0"/> <glyph class="macromolecule" id="emtc_emtc_s557_emtc_emtc_sa1993"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="109.5" h="46.0" x="5852.25" y="4663.0"/> <glyph class="state variable" id="_b539e1b9-1e0a-4e8e-9c5e-a36d3dae3b68"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="5944.25" y="4688.1953"/> </glyph> <glyph class="state variable" id="_e5ddf018-7d47-4d28-8868-b4b3dca85f80"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5897.9644" y="4704.0"/> </glyph> <glyph class="state variable" id="_2f0a6205-32ec-4e2f-8978-c679159c9e5f"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="5944.25" y="4699.7207"/> </glyph> <glyph class="state variable" id="_c3a6089c-eea7-4ff4-a3c3-af8fc1439f63"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="5946.75" y="4679.1562"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s558_emtc_emtc_sa1994"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="110.0" h="55.0" x="5858.0" y="4715.5"/> <glyph class="state variable" id="_0d1784d1-4b06-40e4-ae89-ec36dcf222b3"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="5843.0" y="4742.1113"/> </glyph> <glyph class="state variable" id="_706c4c97-4100-44a4-927f-3bf31f031f2a"> <state value="" variable="S422"/> <bbox w="30.0" h="10.0" x="5953.0" y="4734.405"/> </glyph> <glyph class="state variable" id="_d6d97dba-b660-41cf-b8be-1ba727cc9369"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="5843.0" y="4760.166"/> </glyph> <glyph class="state variable" id="_a5732266-c70b-4db9-b8ce-c64c3addf64b"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="5950.5" y="4745.4097"/> </glyph> <glyph class="state variable" id="_17fc9dbf-1a67-435a-9772-d1abfd2b2792"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="5950.5" y="4760.3833"/> </glyph> <glyph class="state variable" id="_b78bd1b0-02fa-4b90-93d1-21bb7b5039e3"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="5843.0" y="4729.4453"/> </glyph> <glyph class="state variable" id="_e756f40e-ae4f-4e9f-abe1-c69a397440be"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="5843.0" y="4713.803"/> </glyph> <glyph class="state variable" id="_dd36c15b-9631-4cfd-9d9b-3e3ac6072de9"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5901.7686" y="4765.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3914_emtc_emtc_csa41" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD2_3*:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11792802 -Unphosphorylated Smad proteins exist primarily as monomers -Upon phosphorylation, R-Smads form homo-oligomers, which quickly convert to hetero-oligomers containing Smad4 PMID:11170475 Phosphorylated C-ter tail of R-Smads interacts specifically with the L3 loop of another Smad, which is sufficient to cause their oligomerization PMID:9865696 Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/ Smad4 complexes and nuclear translocation. PMID:8893010 All mammalian R-Smads and Smad4 reside in the cytoplasm Phosphorylated R-Smads quickly form complexes with Smad4 and possibly prior to nuclear translocation PMID:9389648 Nuclear translocation of R-Smads is independent of Smad4 Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-Smad References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*/SMAD4"/> <bbox w="141.0" h="48.0" x="5148.0" y="3821.5"/> <glyph class="macromolecule" id="emtc_emtc_s3917_emtc_emtc_sa392"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="5224.0" y="3825.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3918_emtc_emtc_sa1996"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*"/> <bbox w="67.0" h="19.0" x="5153.5" y="3826.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3919_emtc_emtc_csa45" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD2_3*:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11792802 -Unphosphorylated Smad proteins exist primarily as monomers -Upon phosphorylation, R-Smads form homo-oligomers, which quickly convert to hetero-oligomers containing Smad4 PMID:11170475 Phosphorylated C-ter tail of R-Smads interacts specifically with the L3 loop of another Smad, which is sufficient to cause their oligomerization PMID:9865696 Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/ Smad4 complexes and nuclear translocation. PMID:8893010 All mammalian R-Smads and Smad4 reside in the cytoplasm Phosphorylated R-Smads quickly form complexes with Smad4 and possibly prior to nuclear translocation PMID:9389648 Nuclear translocation of R-Smads is independent of Smad4 Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-SmadPMID:20731704 PMID:21317430 In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h. Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation PMID:22406545 TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways References_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*/SMAD4"/> <bbox w="148.0" h="46.0" x="3402.5" y="3804.5"/> <glyph class="macromolecule" id="emtc_emtc_s556_emtc_emtc_sa414"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3483.5" y="3809.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3915_emtc_emtc_sa1998"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*"/> <bbox w="67.0" h="19.0" x="3407.0" y="3809.25"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3921_emtc_emtc_csa292" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:HMGA2:SMAD2_3*:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HMGA2/SMAD2_3*/SMAD4"/> <bbox w="158.0" h="64.0" x="3192.0" y="3750.5"/> <glyph class="macromolecule" id="emtc_emtc_s3897_emtc_emtc_sa1979"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: high mobility group AT-hook 2 HUGO:HMGA2 HGNC:5009 ENTREZ:8091 UNIPROT:P52926 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HMGA2"/> <bbox w="60.0" h="20.0" x="3196.5" y="3752.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3899_emtc_emtc_sa1984"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3264.5" y="3753.068"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3920_emtc_emtc_sa2001"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*"/> <bbox w="67.0" h="19.0" x="3219.5" y="3776.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3923_emtc_emtc_csa54" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SMAD2_3*:SMAD4:ZEB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20519943 PMID:12743038 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*/SMAD4/ZEB1"/> <bbox w="147.0" h="66.0" x="3399.5" y="3929.0"/> <glyph class="macromolecule" id="emtc_emtc_s594_emtc_emtc_sa455"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="3469.5" y="3931.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s597_emtc_emtc_sa458"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, UNIPROT:P37275, GENECARDS:GC10P031648 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 ZEB1 inhibits MIR200 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1"/> <bbox w="40.0" h="20.0" x="3419.5" y="3931.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3922_emtc_emtc_sa2002"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*"/> <bbox w="67.0" h="19.0" x="3437.5" y="3954.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3924_emtc_emtc_csa298" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ATF3:SMAD2_3*:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ATF3/SMAD2_3*/SMAD4"/> <bbox w="149.0" h="60.0" x="4017.0" y="4053.5"/> <glyph class="macromolecule" id="emtc_emtc_s3927_emtc_emtc_sa2006"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: activating transcription factor 3 HUGO:ATF3, HGNC:785, ENTREZ:467, GENECARDS:GC01P212738, UNIPROT:P18847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ATF3"/> <bbox w="32.0" h="19.0" x="4056.75" y="4075.375"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3925_emtc_emtc_sa2007"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*"/> <bbox w="67.0" h="19.0" x="4026.75" y="4054.625"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3926_emtc_emtc_sa2008"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="4103.25" y="4054.875"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3957_emtc_emtc_csa300" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:I-SMAD*:SMURF* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="I-SMAD*/SMURF*"/> <bbox w="127.0" h="43.0" x="4580.0" y="4422.5"/> <glyph class="macromolecule" id="emtc_emtc_s3963_emtc_emtc_sa2031"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1, HGNC:16807, ENTREZ:57154, GENECARDS:GC07M098627, UNIPROT:Q9HCE7 SMAD specific E3 ubiquitin protein ligase 2 HUGO:SMURF2, HGNC:16809, ENTREZ:64750, GENECARDS:GC17M062540, UNIPROT:Q9HAU4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF*"/> <bbox w="59.0" h="16.0" x="4583.0" y="4425.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3964_emtc_emtc_sa2032"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="I-SMAD*"/> <bbox w="62.0" h="16.0" x="4642.5" y="4425.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3962_emtc_emtc_csa302" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:I-SMAD*:SMURF* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="I-SMAD*/SMURF*"/> <bbox w="127.0" h="43.0" x="4852.5" y="4422.0"/> <glyph class="macromolecule" id="emtc_emtc_s3959_emtc_emtc_sa2034"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1, HGNC:16807, ENTREZ:57154, GENECARDS:GC07M098627, UNIPROT:Q9HCE7 SMAD specific E3 ubiquitin protein ligase 2 HUGO:SMURF2, HGNC:16809, ENTREZ:64750, GENECARDS:GC17M062540, UNIPROT:Q9HAU4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF*"/> <bbox w="59.0" h="16.0" x="4855.5" y="4425.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3958_emtc_emtc_sa2035"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="I-SMAD*"/> <bbox w="60.0" h="17.0" x="4917.0" y="4425.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3972_emtc_emtc_csa303" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:KIT:KITLG Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:15337769 http://www.uniprot.org/uniprot/P21583 KITLG/KIT binding can activate several signaling pathways. -Promotes phosphorylation of PIK3R1, the regulatory subunit of PI3K, and subsequent activation of the kinase AKT1. -Transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. -Promotes activation of STAT family members STAT1, STAT3 and STAT5. -Promotes activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. -Acts synergistically with other cytokines, probably interleukins. PMID:17550342 Activation of KIT by binding to KITLG induces SNAI2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KIT/KITLG"/> <bbox w="98.0" h="117.0" x="819.5" y="120.5"/> <glyph class="macromolecule" id="emtc_emtc_s3974_emtc_emtc_sa2047"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: KIT ligand HUGO:KITLG HGNC:6343 ENTREZ:4254 UNIPROT:P21583 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KITLG"/> <bbox w="42.0" h="18.0" x="847.25" y="123.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4558_emtc_emtc_sa2369"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog HUGO:KIT HGNC:6342 ENTREZ:3815 UNIPROT:P10721 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:15337769 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KIT"/> <bbox w="86.0" h="56.0" x="827.5" y="151.5"/> <glyph class="unit of information" id="_bc6b1f86-78e6-417b-a91e-a1a3eef08537"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="860.5" y="146.5"/> </glyph> <glyph class="unit of information" id="_5a7d54e6-98b5-4361-a90d-9a747d4b35d3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="848.0" y="146.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s3983_emtc_emtc_csa304" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CTBP1_2*:HDAC1:HDAC3:SNAI2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17508028 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTBP1_2*/HDAC1/HDAC3/SNAI2"/> <bbox w="202.0" h="70.0" x="2643.0" y="4219.5"/> <glyph class="macromolecule" id="emtc_emtc_s3979_emtc_emtc_sa2052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: C-terminal binding protein 1 HUGO:CTBP1 HGNC:2494 ENTREZ:1487 UNIPROT:Q13363 C-terminal binding protein 2 HUGO:CTBP2 HGNC:2495 ENTREZ:1488 UNIPROT:P56545 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTBP1_2*"/> <bbox w="62.0" h="22.0" x="2670.5" y="4246.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3981_emtc_emtc_sa2053"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: histone deacetylase 3 HUGO:HDAC3 HGNC:4854 ENTREZ:8841 UNIPROT:O15379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC3"/> <bbox w="56.0" h="17.0" x="2675.0" y="4224.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3980_emtc_emtc_sa2054"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="50.0" h="16.0" x="2737.0" y="4223.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3982_emtc_emtc_sa2055"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, UNIPROT:O43623, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="40.0" h="20.0" x="2754.5" y="4247.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4276_emtc_emtc_csa305" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDK2:CyclinE1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK2/CyclinE1*"/> <bbox w="107.0" h="40.0" x="3029.0" y="1411.5"/> <glyph class="macromolecule" id="emtc_emtc_s4280_emtc_emtc_sa2068"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin E1 HUGO:CCNE1, HGNC:1589, ENTREZ:898, GENECARDS:GC19P030302, UNIPROT:P24864 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinE1*"/> <bbox w="60.0" h="19.0" x="3073.0" y="1413.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4279_emtc_emtc_sa2069"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase 2 HUGO:CDK2, HGNC:1771, ENTREZ:1017, GENECARDS:GC12P056360, UNIPROT:P24941 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK2"/> <bbox w="40.0" h="20.0" x="3030.5" y="1413.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4285_emtc_emtc_csa59" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDK4_6*:CyclinD1*:p27KIP1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*/Cyclin D1*/p27KIP1*"/> <bbox w="183.0" h="60.0" x="3498.0" y="1573.5"/> <glyph class="macromolecule" id="emtc_emtc_s1397_emtc_emtc_sa484"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455, UNIPROT:P24385 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Only several CDK–cyclin complexes are directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="80.0" h="17.0" x="3570.0" y="1594.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1398_emtc_emtc_sa486"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cyclin-dependent kinase inhibitor 1B (p27, Kip1) HUGO:CDKN1B, HGNC:1785, ENTREZ:1027, GENECARDS:GC12P012867, UNIPROT:P46527 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:24954210 p27, p16 and p15 inhibits CDK4_6. This induces a G1 cell cycle arrest. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p27KIP1*"/> <bbox w="64.0" h="17.0" x="3504.0" y="1595.0"/> <glyph class="state variable" id="_0eb43dc9-01a0-497c-9441-b5be4840f429"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3499.0" y="1606.882"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4283_emtc_emtc_sa2072"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CDK4_6* cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*"/> <bbox w="60.0" h="19.0" x="3548.0" y="1574.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4286_emtc_emtc_csa60" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDK4_6*:CyclinD1*:p21CIP1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4/Cyclin D1*/p21CIP1*"/> <bbox w="172.0" h="59.0" x="3498.5" y="1653.5"/> <glyph class="macromolecule" id="emtc_emtc_s643_emtc_emtc_sa487"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cyclin-dependent kinase inhibitor 1A (p21, Cip1) HUGO:CDKN1A, HGNC:1784, ENTREZ:1026, GENECARDS:GC06P036649, UNIPROT:P38936 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:24954210 p27, p16 and p15 inhibits CDK4_6. This induces a G1 cell cycle arrest. PMID:19440234 p21 inhibits CDK2 to induce senescence PMID:10402472 p21 induces metastasis p21 suppresses E2F1-dependent Wnt4 expression, thereby controlling cellular growth. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p21CIP1*"/> <bbox w="63.0" h="16.0" x="3507.0" y="1674.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1399_emtc_emtc_sa489"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455, UNIPROT:P24385 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Only several CDK–cyclin complexes are directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="80.0" h="16.0" x="3569.5" y="1674.5"/> </glyph> <glyph class="macromolecule" id="s2496_sa2171"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CDK4_6* cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*"/> <bbox w="60.0" h="19.0" x="3579.0" y="1654.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4305_emtc_emtc_csa309" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ADAM10:ADAM17 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19726682 PMID:19704010 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ADAM10/ADAM17"/> <bbox w="127.0" h="39.0" x="648.0" y="1934.5"/> <glyph class="macromolecule" id="emtc_emtc_s4311_emtc_emtc_sa2105"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ADAM metallopeptidase domain 17 HUGO:ADAM17, HGNC:195, ENTREZ:6868, UNIPROT:P78536, GENECARDS:GC02M009580 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19726682 PMID:19704010 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ADAM17"/> <bbox w="59.0" h="18.0" x="653.0" y="1937.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s365_emtc_emtc_sa2106"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ADAM metallopeptidase domain 10 HUGO:ADAM10, HGNC:188, ENTREZ:102, UNIPROT:O14672, GENECARDS:GC15M058887 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19726682 PMID:19704010 PMID:19601831 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ADAM10"/> <bbox w="60.0" h="17.0" x="711.0" y="1937.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4306_emtc_emtc_csa311" compartmentRef="emtc_emtc_c21_emtc_emtc_ca21"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:NOTCH1:NUMB Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NUMB/NOTCH"/> <bbox w="112.0" h="45.0" x="798.0" y="1475.0"/> <glyph class="macromolecule" id="emtc_emtc_s517_emtc_emtc_sa2109"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="57.0" h="23.0" x="801.5" y="1479.5"/> <glyph class="unit of information" id="_b785322b-10ee-4181-bfd1-ca29aa80c2fd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="807.5" y="1474.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4336_emtc_emtc_sa2110"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: protein numb homolog HUGO:NUMB, HGNC:8060, ENTREZ:8650, UNIPROT:P49757, GENECARDS:GC14M073741 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NUMB"/> <bbox w="44.0" h="19.0" x="861.5" y="1481.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4350_emtc_emtc_csa293" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:E-protein*:ID* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15121845 PMID:18832382 PMID:15181457 ID proteins can form complexes with TCF3 (E47), and inhibit the process of EMT. PMID:19240756 human E-proteins: E47 (TCF3) and E12 (TCF3) from E2A gene, HEB (TCF12) and E2-2 (TCF4) ID proteins: (ID1, 2, 3, 4), bind all E-proteins ID2 binds to APC/C and CDH1 PMID:21041997 A complex formed by Smad3, Smad4 and ATF3 binds sequences in the ID1 promoter and represses its transcription. The decrease in expression of ID factors then increases activity of E proteins and Twist, resulting in transcriptional repression of the E-Cadherin gene. The transcription factor HMGA2, whose expression increases during TGFB-induced EMT through a Smad3/4-deoendent mechanism, enhances the expression of SNAIL and TWIST and represses the expression of ID2. PMID:17615296 Through constitutive association with bHLH E12/E47 proteins, Id proteins maintain epithelial phenotypes by repressing the function of E12/E47, which acts as a repressor of E-cadherin. Down-regulation of ID1 by Smad2/3/ATF3 complex and of ID2 by TGFB thus relieve this inhibition, permitting conversion of epithelial cells to cells with mesenchymal phenotypes References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID*/E-protein*"/> <bbox w="114.0" h="46.0" x="4185.0" y="4056.5"/> <glyph class="macromolecule" id="emtc_emtc_s3904_emtc_emtc_sa1989"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: inhibitor of DNA binding 1, dominant negative helix-loop-helix protein HUGO:ID1, HGNC:5360, ENTREZ:3397 , UNIPROT:P41134 inhibitor of DNA binding 2, dominant negative helix-loop-helix protein HUGO:ID2, HGNC:5361, ENTREZ:3398, UNIPROT:Q02363, GENECARDS:GC02P008818 inhibitor of DNA binding 3, dominant negative helix-loop-helix protein HUGO:ID3, HGNC:5362, ENTREZ:3399, UNIPROT:Q02535 , GENECARDS:GC01M023884 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15252039 ID is so-called Inhibitor of differentiation/DNA binding proteins ID proteins is frequently deregulated in advanced human malignancies. ID proteins can participate in blocking differentiation, increasing proliferation, tissue invasiveness, and angiogenesis. PMID:17615296 Through constitutive association with bHLH E12/E47 proteins, Id proteins maintain epithelial phenotypes by repressing the function of E12/E47, which acts as a repressor of E-cadherin. Down-regulation of ID1 by Smad2/3/ATF3 complex and of ID2 as well as ID3 by TGFB thus relieve this inhibition, permitting conversion of epithelial cells to cells with mesenchymal phenotypes TGFB induces ETS1 transcriptional expression. TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457) ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1. Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID*"/> <bbox w="25.0" h="22.0" x="4191.416" y="4061.166"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4349_emtc_emtc_sa2163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: E-protein* transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, UNIPROT:P15923, GENECARDS:GC19M001609 transcription factor 12 HUGO:TCF12 HGNC:11623, ENTREZ:6938, UNIPROT:Q99081, GENECARDS:GC15P057210 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19240756 4 human E-proteins from 3 genes: E47 (TCF3) and E12 (TCF3) from E2A gene, HEB (TCF12) and E2-2 (TCF4) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-protein*"/> <bbox w="76.0" h="23.0" x="4219.5" y="4060.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4375_emtc_emtc_csa313" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CBF1*:NICD* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(CBF1* activator complex)"/> <bbox w="114.0" h="57.0" x="2170.0" y="2094.5"/> <glyph class="macromolecule" id="emtc_emtc_s4358_emtc_emtc_sa2171"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: recombination signal binding protein for immunoglobulin kappa J region HUGO:RBPJ, HGNC:5724, ENTREZ:3516, UNIPROT:Q06330 , GENECARDS:GC04P026165 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CBF1*"/> <bbox w="39.0" h="18.0" x="2240.5" y="2104.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4357_emtc_emtc_sa2172"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="49.0" h="21.0" x="2175.5" y="2103.0"/> <glyph class="state variable" id="_e34f81ba-9200-43b5-b3e2-34f016d71e8d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2219.5" y="2098.0"/> </glyph> <glyph class="state variable" id="_c2c899c3-90d3-48ce-ba16-a4808872ad32"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2170.5" y="2098.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4376_emtc_emtc_csa315" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CBF1*:CIR1:HDAC2:SIN3A Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(CBF1* repressor complex 2)"/> <bbox w="188.0" h="43.0" x="2492.0" y="2096.5"/> <glyph class="macromolecule" id="emtc_emtc_s4368_emtc_emtc_sa2180"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 2 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC2"/> <bbox w="53.0" h="17.0" x="2624.5" y="2098.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4370_emtc_emtc_sa2182"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: corepressor interacting with RBPJ, 1 HUGO:CIR1, HGNC:24217, ENTREZ:9541, UNIPROT:Q86X95, GENECARDS:GC02M175212 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CIR1"/> <bbox w="36.0" h="19.0" x="2541.5" y="2099.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4369_emtc_emtc_sa2183"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: recombination signal binding protein for immunoglobulin kappa J region HUGO:RBPJ, HGNC:5724, ENTREZ:3516, UNIPROT:Q06330 , GENECARDS:GC04P026165 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CBF1*"/> <bbox w="39.0" h="18.0" x="2500.5" y="2098.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4372_emtc_emtc_sa2184"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SIN3 transcription regulator homolog A (yeast) SIN3A HUGO:SIN3A HGNC:19353 ENTREZ:25942 UNIPROT:Q96ST3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SIN3A"/> <bbox w="45.0" h="16.0" x="2578.5" y="2099.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4377_emtc_emtc_csa314" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CBF1*:HDAC1:NCOR1:NCOR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(CBF1* repressor complex 1)"/> <bbox w="191.0" h="47.0" x="2292.0" y="2095.5"/> <glyph class="macromolecule" id="emtc_emtc_s4364_emtc_emtc_sa2177"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: nuclear receptor corepressor 1 HUGO:NCOR1, HGNC:7672, ENTREZ:9611, UNIPROT:O75376, GENECARDS:GC17M015933 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCOR1"/> <bbox w="44.0" h="18.0" x="2337.25" y="2102.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4365_emtc_emtc_sa2178"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: nuclear receptor corepressor 2 HUGO:NCOR2, HGNC:7673, ENTREZ:9612, UNIPROT:Q9Y618, GENECARDS:GC12M124808 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCOR2"/> <bbox w="47.0" h="18.0" x="2382.25" y="2103.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4363_emtc_emtc_sa2179"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: recombination signal binding protein for immunoglobulin kappa J region HUGO:RBPJ, HGNC:5724, ENTREZ:3516, UNIPROT:Q06330 , GENECARDS:GC04P026165 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CBF1*"/> <bbox w="39.0" h="18.0" x="2296.25" y="2101.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4366_emtc_emtc_sa2181"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="50.0" h="16.0" x="2431.5" y="2102.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4389_emtc_emtc_csa316" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:HEY1_2*:RUNX2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. PMID:16025100 Heys transcriptional repressors, which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity, independent of histone deacetylase activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY1_2*/RUNX2"/> <bbox w="108.0" h="46.0" x="2525.0" y="2233.5"/> <glyph class="macromolecule" id="emtc_emtc_s4391_emtc_emtc_sa2196"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: runt-related transcription factor 2 HUGO:RUNX2, HGNC:10427, ENTREZ:860, UNIPROT:Q13950 , GENECARDS:GC06P045295 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RUNX2"/> <bbox w="42.0" h="19.0" x="2532.0" y="2234.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4390_emtc_emtc_sa2197"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 1 HUGO:HEY1, HGNC:4880, ENTREZ:23462, UNIPROT:Q9Y5J3, GENECARDS:GC08M080676 hes-related family bHLH transcription factor with YRPW motif 2 HUGO:HEY2, HGNC:4881, ENTREZ:23493, UNIPROT:Q9UBP5, GENECARDS:GC06P126068 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY1_2*"/> <bbox w="56.0" h="21.0" x="2576.0" y="2234.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4410_emtc_emtc_csa318" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:FZD*:LRP5_6*:WNT* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Frizzled/WNT/LRP)"/> <bbox w="154.0" h="96.0" x="834.0" y="6012.5"/> <glyph class="macromolecule" id="emtc_emtc_s4406_emtc_emtc_sa2223"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: wingless-type MMTV integration site family member 1 HUGO:WNT1 HGNC:12774 ENTREZ:7471 UNIPROT:P04628 wingless-type MMTV integration site family member 2 HUGO:WNT2 HGNC:12780 ENTREZ:7472 UNIPROT:P09544 wingless-type MMTV integration site family member 2B HUGO:WNT2B HGNC:12781 ENTREZ:7482 UNIPROT:Q93097 wingless-type MMTV integration site family member 3 HUGO:WNT3 HGNC:12782 ENTREZ:7473 UNIPROT:P56703 wingless-type MMTV integration site family member 3A HUGO:WNT3A HGNC:15983 ENTREZ:89780 UNIPROT:P56704 wingless-type MMTV integration site family member 4 HUGO:WNT4 HGNC:12783 ENTREZ:54361 UNIPROT:P56705 wingless-type MMTV integration site family member 5A HUGO:WNT5A HGNC:12784 ENTREZ:7474 UNIPROT:P41221 wingless-type MMTV integration site family member 5B HUGO:WNT5B HGNC:16265 ENTREZ:81029 UNIPROT:Q9H1J7 wingless-type MMTV integration site family member 6 HUGO:WNT6 HGNC:12785 ENTREZ:7475 UNIPROT:Q9Y6F9 wingless-type MMTV integration site family member 7A HUGO:WNT7A HGNC:12786 ENTREZ:7476 UNIPROT:O00755 wingless-type MMTV integration site family member 7B HUGO:WNT7B HGNC:12787 ENTREZ:7477 UNIPROT:P56706 wingless-type MMTV integration site family member 8A HUGO:WNT8A HGNC:12788 ENTREZ:7478 UNIPROT:Q9H1J5 wingless-type MMTV integration site family member 8B HUGO:WNT8B HGNC:12789 ENTREZ:7479 UNIPROT:Q93098 wingless-type MMTV integration site family member 9A HUGO:WNT9A HGNC:12778 ENTREZ:7483 UNIPROT:O14904 wingless-type MMTV integration site family member 9B HUGO:WNT9B HGNC:12779 ENTREZ:7484 UNIPROT:O14905 wingless-type MMTV integration site family member 10A HUGO:WNT10A HGNC:13829 ENTREZ:80326 UNIPROT:Q9GZT5 wingless-type MMTV integration site family member 10B HUGO:WNT10B HGNC:12775 ENTREZ:7480 UNIPROT:O00744 wingless-type MMTV integration site family member 11 HUGO:WNT11 HGNC:12776 ENTREZ:7481 UNIPROT:O96014 wingless-type MMTV integration site family member 16 HUGO:WNT16 HGNC/16267 ENTREZ:51384 UNIPROT:Q9UBV4 wingless-type MMTV integration site family member 5 WNT5A antisense RNA 1 HUGO:WNT5A-AS1 HGNC:40616 ENTREZ:100874008 HUGO:WNT16 HGNC:16267 ENTREZ:51384 UNIPROT:Q9UBV4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WNT*"/> <bbox w="40.0" h="20.0" x="896.5" y="6015.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4408_emtc_emtc_sa2224"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: low density lipoprotein receptor-related protein 5 HUGO:LRP5 HGNC:6697 ENTREZ:4041 UNIPROT:O75197 low density lipoprotein receptor-related protein 6 HUGO:LRP6 HGNC:6698 ENTREZ:4040 UNIPROT:O75581 HUGO:LRP6 HGNC:6698 ENTREZ:4040 UNIPROT:075581 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17143292 PMID:16443747 WNT3a requires LRP6 to activate wnt PMID:22433869 PMID:19072724 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LRP5_6*"/> <bbox w="63.0" h="49.0" x="922.5" y="6037.25"/> <glyph class="unit of information" id="_5d50786f-105e-4530-b85f-93e3e5a8a3f5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="931.5" y="6032.25"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4409_emtc_emtc_sa2225"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: frizzled family receptor 1 HUGO:FZD1 HGNC:4038 ENTREZ:8321 UNIPROT:Q9UP38 frizzled family receptor 2 HUGO:FZD2 HGNC:4040 ENTREZ:2535 UNIPROT:Q14332 frizzled family receptor 3 HUGO:FZD3 HGNC:4041 ENTREZ:7976 UNIPROT:Q9NPG1 frizzled family receptor 4 HUGO:FZD4 HGNC:4042 ENTREZ:8322 UNIPROT:Q9ULV1 frizzled family receptor 5 HUGO:FZD5 HGNC:4043 ENTREZ:7855 UNIPROT:Q13467 frizzled family receptor 6 HUGO:FZD6 HGNC:4044 ENTREZ:8323 UNIPROT:O60353 frizzled family receptor 7 HUGO:FZD7 HGNC:4045 ENTREZ:8324 UNIPROT:O75084 frizzled family receptor 8 HUGO:FZD8 HGNC:4046 ENTREZ:8325 UNIPROT:Q9H461 frizzled family receptor 9 HUGO:FZD9 HGNC:4047 ENTREZ:8326 UNIPROT:O00144 frizzled family receptor 10 HUGOFZD10 HGNC:4039 ENTREZ:11211 UNIPROT:Q9ULW2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17884187 Activators: Fz1 Fz4 PMID:19020754 PMID:14704854 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FZD*"/> <bbox w="80.0" h="50.0" x="839.0" y="6035.75"/> <glyph class="unit of information" id="_2742e875-7882-4cf5-8aa3-eda5bf3ecfe3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="856.5" y="6030.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4414_emtc_emtc_csa320" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:G_beta_*:G_gamma_* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Gβ/Gγ)"/> <bbox w="99.0" h="43.0" x="1620.0" y="5863.5"/> <glyph class="macromolecule" id="emtc_emtc_s4416_emtc_emtc_sa2228"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: guanine nucleotide binding protein (G protein) beta polypeptide 1 HUGO:GNB1 HGNC:4396 ENTREZ:2782 UNIPROT:P62873 guanine nucleotide binding protein (G protein) beta polypeptide 2 HUGO:GNB2 HGNC:4398 ENTREZ:2783 UNIPROT:P62879 guanine nucleotide binding protein (G protein) beta polypeptide 3 HUGO:GNB3 HGNC:4400 ENTREZ:2784 UNIPROT:P16520 guanine nucleotide binding protein (G protein) beta polypeptide 4 HUGO:GNB4 HGNC:20731 ENTREZ:59345 UNIPROT:Q9HAV0 guanine nucleotide binding protein (G protein) beta 5 HUGO:GNB HGNC:4401 ENTREZ:10681 UNIPROT:O14775 guanine nucleotide binding protein (G protein) beta polypeptide 5 HUGO:GNB5 HGNC:4401 ENTREZ:10681 UNIPROT:O14775 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21640127 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Gβ*"/> <bbox w="40.0" h="20.0" x="1629.0" y="5867.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4417_emtc_emtc_sa2229"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: guanine nucleotide binding protein (G protein) gamma 2 HUGO:GNG2 HGNC:4404 ENTREZ:54331 UNIPROT:P59768 guanine nucleotide binding protein (G protein) gamma 3 HUGO:GNG HGNC:4405 ENTREZ:2785 UNIPROT:P63215 guanine nucleotide binding protein (G protein) gamma 4 HUGO:GNG4 HGNC:4407 ENTREZ:2786 UNIPROT:P50150 guanine nucleotide binding protein (G protein) gamma 5 HUGO:GNG5 HGNC:4408 ENTREZ:2787 UNIPROT:P63218 guanine nucleotide binding protein (G protein) gamma 7 HUGO:GNG7 HGNC:4410 ENTREZ:2788 UNIPROT:O60262 guanine nucleotide binding protein (G protein) gamma 8 HUGO:GNG8 HGNC:19664 ENTREZ:94235 UNIPROT:Q9UK08 guanine nucleotide binding protein (G protein) gamma 10 HUGO:GNG10 HGNC:4402 ENTREZ:2790 UNIPROT:P50151 guanine nucleotide binding protein (G protein) gamma 11 HUGO:GNG11 HGNC:4403 ENTREZ:2791 UNIPROT:P61952 guanine nucleotide binding protein (G protein) gamma 12 HUGO:GNG12 HGNC:19663 ENTREZ:55970 UNIPROT:Q9UBI6 guanine nucleotide binding protein (G protein) gamma 13 HUGO:GNG13 HGNC:14131 ENTREZ:51764 UNIPROT:Q9P2W3 guanine nucleotide binding protein (G protein) gamma transducing activity polypeptide 1 HUGO:GNGT1 HGNC:4411 ENTREZ:2792 UNIPROT:P63211 HUGO:GNG3 HGNC:4405 ENTREZ:2785 UNIPROT:P63215 guanine nucleotide binding protein (G protein) gamma 6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21640127 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Gγ*"/> <bbox w="40.0" h="20.0" x="1671.5" y="5868.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4419_emtc_emtc_csa321" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:DVL1:FZD*:LRP5_6*:WNT* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Dishevelled/Frizzled/WNT/LRP)"/> <bbox w="187.0" h="109.0" x="641.0" y="6008.5"/> <glyph class="macromolecule" id="emtc_emtc_s4424_emtc_emtc_sa984"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dishevelled, dsh homolog 1 (Drosophila) HUGO:DVL1, HGNC:3084, ENTREZ:1855, UNIPROT:O14640 , GENECARDS:GC01M001262 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding, DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DVL1"/> <bbox w="37.0" h="21.0" x="657.0" y="6015.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4421_emtc_emtc_sa2232"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: frizzled family receptor 1 HUGO:FZD1 HGNC:4038 ENTREZ:8321 UNIPROT:Q9UP38 frizzled family receptor 2 HUGO:FZD2 HGNC:4040 ENTREZ:2535 UNIPROT:Q14332 frizzled family receptor 3 HUGO:FZD3 HGNC:4041 ENTREZ:7976 UNIPROT:Q9NPG1 frizzled family receptor 4 HUGO:FZD4 HGNC:4042 ENTREZ:8322 UNIPROT:Q9ULV1 frizzled family receptor 5 HUGO:FZD5 HGNC:4043 ENTREZ:7855 UNIPROT:Q13467 frizzled family receptor 6 HUGO:FZD6 HGNC:4044 ENTREZ:8323 UNIPROT:O60353 frizzled family receptor 7 HUGO:FZD7 HGNC:4045 ENTREZ:8324 UNIPROT:O75084 frizzled family receptor 8 HUGO:FZD8 HGNC:4046 ENTREZ:8325 UNIPROT:Q9H461 frizzled family receptor 9 HUGO:FZD9 HGNC:4047 ENTREZ:8326 UNIPROT:O00144 frizzled family receptor 10 HUGOFZD10 HGNC:4039 ENTREZ:11211 UNIPROT:Q9ULW2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17884187 Activators: Fz1 Fz4 PMID:19020754 PMID:14704854 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FZD*"/> <bbox w="80.0" h="50.0" x="660.0" y="6043.375"/> <glyph class="unit of information" id="_02085205-0884-41f2-8b3d-8b9dc1ce0fff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="677.5" y="6038.375"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4422_emtc_emtc_sa2233"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: low density lipoprotein receptor-related protein 5 HUGO:LRP5 HGNC:6697 ENTREZ:4041 UNIPROT:O75197 low density lipoprotein receptor-related protein 6 HUGO:LRP6 HGNC:6698 ENTREZ:4040 UNIPROT:O75581 HUGO:LRP6 HGNC:6698 ENTREZ:4040 UNIPROT:075581 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17143292 PMID:16443747 WNT3a requires LRP6 to activate wnt PMID:22433869 PMID:19072724 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LRP5_6*"/> <bbox w="63.0" h="49.0" x="747.5" y="6043.875"/> <glyph class="unit of information" id="_6a2dd122-d685-4ce3-9d6e-1ae4c4257f4d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="756.5" y="6038.875"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4423_emtc_emtc_sa2234"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: wingless-type MMTV integration site family member 1 HUGO:WNT1 HGNC:12774 ENTREZ:7471 UNIPROT:P04628 wingless-type MMTV integration site family member 2 HUGO:WNT2 HGNC:12780 ENTREZ:7472 UNIPROT:P09544 wingless-type MMTV integration site family member 2B HUGO:WNT2B HGNC:12781 ENTREZ:7482 UNIPROT:Q93097 wingless-type MMTV integration site family member 3 HUGO:WNT3 HGNC:12782 ENTREZ:7473 UNIPROT:P56703 wingless-type MMTV integration site family member 3A HUGO:WNT3A HGNC:15983 ENTREZ:89780 UNIPROT:P56704 wingless-type MMTV integration site family member 4 HUGO:WNT4 HGNC:12783 ENTREZ:54361 UNIPROT:P56705 wingless-type MMTV integration site family member 5A HUGO:WNT5A HGNC:12784 ENTREZ:7474 UNIPROT:P41221 wingless-type MMTV integration site family member 5B HUGO:WNT5B HGNC:16265 ENTREZ:81029 UNIPROT:Q9H1J7 wingless-type MMTV integration site family member 6 HUGO:WNT6 HGNC:12785 ENTREZ:7475 UNIPROT:Q9Y6F9 wingless-type MMTV integration site family member 7A HUGO:WNT7A HGNC:12786 ENTREZ:7476 UNIPROT:O00755 wingless-type MMTV integration site family member 7B HUGO:WNT7B HGNC:12787 ENTREZ:7477 UNIPROT:P56706 wingless-type MMTV integration site family member 8A HUGO:WNT8A HGNC:12788 ENTREZ:7478 UNIPROT:Q9H1J5 wingless-type MMTV integration site family member 8B HUGO:WNT8B HGNC:12789 ENTREZ:7479 UNIPROT:Q93098 wingless-type MMTV integration site family member 9A HUGO:WNT9A HGNC:12778 ENTREZ:7483 UNIPROT:O14904 wingless-type MMTV integration site family member 9B HUGO:WNT9B HGNC:12779 ENTREZ:7484 UNIPROT:O14905 wingless-type MMTV integration site family member 10A HUGO:WNT10A HGNC:13829 ENTREZ:80326 UNIPROT:Q9GZT5 wingless-type MMTV integration site family member 10B HUGO:WNT10B HGNC:12775 ENTREZ:7480 UNIPROT:O00744 wingless-type MMTV integration site family member 11 HUGO:WNT11 HGNC:12776 ENTREZ:7481 UNIPROT:O96014 wingless-type MMTV integration site family member 16 HUGO:WNT16 HGNC/16267 ENTREZ:51384 UNIPROT:Q9UBV4 wingless-type MMTV integration site family member 5 WNT5A antisense RNA 1 HUGO:WNT5A-AS1 HGNC:40616 ENTREZ:100874008 HUGO:WNT16 HGNC:16267 ENTREZ:51384 UNIPROT:Q9UBV4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WNT*"/> <bbox w="40.0" h="20.0" x="721.5" y="6021.625"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4431_emtc_emtc_csa322" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:AXIN2:GSK3_beta_* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17072303 AXIN2 acts as nucleocytoplasmic chaperon for GSK3B thus increase SNAIL1 stability. PMID:22745173 Control of nuclear activity of GSK3B is AXIN2-dependent. Axin2 serves as a negative regulator of nuclear GSK3B activity that allows for the stabilization of nuclear Snail1 levels and activity References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN2/GSK3β*"/> <bbox w="92.0" h="97.0" x="2979.0" y="2129.5"/> <glyph class="macromolecule" id="emtc_emtc_s4429_emtc_emtc_sa2239"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: axin 2 HUGO:AXIN2, HGNC:904, ENTREZ:8313, GENECARDS:GC17M063524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN2"/> <bbox w="45.0" h="22.0" x="2999.5" y="2185.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4430_emtc_emtc_sa2240"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540, UNIPROT:P49841 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. PMID:15020233 MEK1/2 can phosphorylate tyrosine 216, which stimulates GSK3B kinase activity U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK3B, suggesting that MEK1/2 was involved in the phosphorylation of Tyr216 in GSK3B In vitro kinase interaction showed that GSK3B is phosphorylated by recombinant MEK1 at Y216 PMID:16944320 The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones PMID:9832503 GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1 GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. PMID:14663202 GSK3B is highly activated in nuclei and mitochondria. PMID:11967263 Tyr-216 phosphorylation is required for GSK-mediated down-regulation of b-catenin activity. PMID:8524413 Inactiviation of GSK-3 occurs through Akt phosphorylation of serine 9 of GSK-3b. This phosphorylation may be involved in later phases of neuronal apoptosis. Mutation of Ser9 to Ala did not affect GSK-3 -mediated phosphorylation of b-catenin, whereas mutation of Tyr216 to Phe markedly reduced the in vivo phosphorylation of b-catenin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="71.5" h="42.0" x="2988.5" y="2137.0"/> <glyph class="state variable" id="_9a94d033-0423-4db8-867a-92716e187902"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="2981.0" y="2134.5222"/> </glyph> <glyph class="state variable" id="_427ff06e-9ad2-40e1-8220-fb8196440f5b"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="3052.1724" y="2132.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4447_emtc_emtc_csa325" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EDNRA:Endothelin1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17587812 PMID:19880243 Endothelin1 acts as an autocrine factor selectively through ENDRA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Endotherin1/Endotherin A receptor)"/> <bbox w="107.0" h="94.0" x="1497.0" y="5998.5"/> <glyph class="macromolecule" id="emtc_emtc_s4446_emtc_emtc_sa2252"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: endothelin receptor type A HUGO:EDNRA, HGNC:3179, ENTREZ:1909, GENECARDS:GC04P148401, UNIPROT:P25101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9588211 Endothelin1 is target gene of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EDNRA"/> <bbox w="80.0" h="50.0" x="1512.182" y="6028.5"/> <glyph class="unit of information" id="_c05223bb-12b2-40fb-8af0-01a6ef20358c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1529.682" y="6023.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4449_emtc_emtc_sa2254"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: endothelin 1 HUGO:EDN1, HGNC:3176, ENTREZ:1906, GENECARDS:GC06P012290, UNIPROT:P05305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9588211 Endothelin1 is target gene of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Endothelin1*"/> <bbox w="78.0" h="20.0" x="1515.5" y="6003.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4451_emtc_emtc_csa326" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:G_alpha_*:PLC_beta_* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Gα/PLCβ)"/> <bbox w="62.0" h="100.0" x="1860.0" y="5835.5"/> <glyph class="macromolecule" id="emtc_emtc_s4453_emtc_emtc_sa2256"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: guanine nucleotide binding protein (G protein) alpha 11 (Gq class) HUGO:GNA11 HGNC:4379 ENTREZ:2767 UNIPROT:P29992 guanine nucleotide binding protein (G protein) alpha 12 HUGO:GNA12 HGNC:4380 ENTREZ:2768 UNIPROT:Q03113 guanine nucleotide binding protein (G protein) alpha 13 HUGO:GNA13 HGNC:4381 ENTREZ:10672 UNIPROT:Q14344 guanine nucleotide binding protein (G protein) alpha 14 HUGO:GNA14 HGNC:4382 ENTREZ:9630 UNIPROT:O95837 guanine nucleotide binding protein (G protein) alpha 15 (Gq class) HUGO:GNA15 HGNC:4383 ENTREZ:2769 UNIPROT:P30679 guanine nucleotide binding protein (G protein) alpha inhibiting activity polypeptide 1 HUGO:GNAI1 HGNC:4384 ENTREZ:2770 UNIPROT:P63096 guanine nucleotide binding protein (G protein) alpha inhibiting activity polypeptide 2 HUGO:GNAI2 HGNC:4385 ENTREZ:2771 UNIPROT:P04899 guanine nucleotide binding protein (G protein) alpha inhibiting activity polypeptide 3 HUGO:GNAI3 HGNC:4387 ENTREZ:2773 UNIPROT:P08754 guanine nucleotide binding protein (G protein) alpha activating activity polypeptide olfactory type HUGO:GNAL HGNC:4388 ENTREZ:2774 UNIPROT:P38405 guanine nucleotide binding protein (G protein) alpha activating activity polypeptide O HUGO:GNAO1 HGNC:4389 ENTREZ:2775 UNIPROT:P09471 guanine nucleotide binding protein (G protein) q polypeptide HUGO:GNAQ HGNC:4390 ENTREZ:2776 UNIPROT:P50148 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21640127 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Gα*"/> <bbox w="40.0" h="20.0" x="1873.0" y="5866.75"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s4454_emtc_emtc_sa2257"> <label text="GTP"/> <bbox w="28.0" h="27.0" x="1877.5" y="5837.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4456_emtc_emtc_sa2259"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phospholipase C, beta 1 (phosphoinositide-specific) HUGO:PLCB1, HGNC:15917, ENTREZ:23236, GENECARDS:GC20P008061, UNIPROT:Q9NQ66 phospholipase C, beta 2 HUGO:PLCB2, HGNC:9055, ENTREZ:5330, GENECARDS:GC15M040580, UNIPROT:Q00722 phospholipase C, beta 3 (phosphatidylinositol-specific) HUGO:PLCB3, HGNC:9056, ENTREZ:5331, GENECARDS:GC11P064019, UNIPROT:Q01970 phospholipase C, beta 4 HUGO:PLCB4, HGNC:9059, ENTREZ:5332, GENECARDS:GC20P009024, UNIPROT:Q15147 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PLCβ*"/> <bbox w="41.0" h="18.0" x="1872.5" y="5894.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4452_emtc_emtc_csa319" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:GTP:G_alpha_* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Gα-GTP)"/> <bbox w="67.0" h="69.0" x="1750.0" y="5865.5"/> <glyph class="macromolecule" id="emtc_emtc_s4412_emtc_emtc_sa2226"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: guanine nucleotide binding protein (G protein) alpha 11 (Gq class) HUGO:GNA11 HGNC:4379 ENTREZ:2767 UNIPROT:P29992 guanine nucleotide binding protein (G protein) alpha 12 HUGO:GNA12 HGNC:4380 ENTREZ:2768 UNIPROT:Q03113 guanine nucleotide binding protein (G protein) alpha 13 HUGO:GNA13 HGNC:4381 ENTREZ:10672 UNIPROT:Q14344 guanine nucleotide binding protein (G protein) alpha 14 HUGO:GNA14 HGNC:4382 ENTREZ:9630 UNIPROT:O95837 guanine nucleotide binding protein (G protein) alpha 15 (Gq class) HUGO:GNA15 HGNC:4383 ENTREZ:2769 UNIPROT:P30679 guanine nucleotide binding protein (G protein) alpha inhibiting activity polypeptide 1 HUGO:GNAI1 HGNC:4384 ENTREZ:2770 UNIPROT:P63096 guanine nucleotide binding protein (G protein) alpha inhibiting activity polypeptide 2 HUGO:GNAI2 HGNC:4385 ENTREZ:2771 UNIPROT:P04899 guanine nucleotide binding protein (G protein) alpha inhibiting activity polypeptide 3 HUGO:GNAI3 HGNC:4387 ENTREZ:2773 UNIPROT:P08754 guanine nucleotide binding protein (G protein) alpha activating activity polypeptide olfactory type HUGO:GNAL HGNC:4388 ENTREZ:2774 UNIPROT:P38405 guanine nucleotide binding protein (G protein) alpha activating activity polypeptide O HUGO:GNAO1 HGNC:4389 ENTREZ:2775 UNIPROT:P09471 guanine nucleotide binding protein (G protein) q polypeptide HUGO:GNAQ HGNC:4390 ENTREZ:2776 UNIPROT:P50148 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21640127 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Gα*"/> <bbox w="40.0" h="20.0" x="1764.5" y="5897.0"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s4413_emtc_emtc_sa2227"> <label text="GTP"/> <bbox w="28.0" h="27.0" x="1769.0" y="5868.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4507_emtc_emtc_csa340" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PI3KC3-catalytic*:PI3KC3-regulator* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(PI3KC3)"/> <bbox w="112.0" h="59.0" x="5364.0" y="918.5"/> <glyph class="macromolecule" id="emtc_emtc_s4509_emtc_emtc_sa2327"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphatidylinositol 3-kinase, catalytic subunit type 3 HUGO:PIK3C3 HGNC:8974 ENTREZ:5289 UNIPROT:Q8NEB9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC3-catalytic*"/> <bbox w="107.0" h="17.0" x="5368.0" y="920.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4510_emtc_emtc_sa2328"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphoinositide-3-kinase, regulatory subunit 4 HUGO:PIK3R4 HGNC:8982 ENTREZ:30849 UNIPROT:Q99570 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC3-regulator*"/> <bbox w="110.0" h="19.0" x="5366.0" y="940.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4522_emtc_emtc_csa343" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PDPK1:PI Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(PDPK1/PIP3)"/> <bbox w="94.0" h="75.0" x="4780.0" y="890.5"/> <glyph class="macromolecule" id="emtc_emtc_s4524_emtc_emtc_sa2337"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: 3-phosphoinositide dependent protein kinase-1 HUGO:PDPK1 HGNC:8816 ENTREZ:5170 UNIPROT:O15530 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:18802401 PMID:17680028 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDPK1"/> <bbox w="58.0" h="17.0" x="4785.0" y="921.5"/> <glyph class="state variable" id="_7763c864-98bb-40a3-a131-dc6baac4cd1d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4780.0" y="924.98645"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4524_emtc_emtc_sa2338"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: 3-phosphoinositide dependent protein kinase-1 HUGO:PDPK1 HGNC:8816 ENTREZ:5170 UNIPROT:O15530 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:18802401 PMID:17680028 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDPK1"/> <bbox w="58.0" h="17.0" x="4803.5" y="927.0"/> <glyph class="state variable" id="_13bc0ddc-d864-44c1-9132-a72fbb9dffbb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4798.5" y="930.48645"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s4523_emtc_emtc_sa2339"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: phosphatidylinositol-3,4,5-triphosphate CAS:N/A PUBCHEM:8260 CHEBI:16618 KEGGCOMPOUND:C05981 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end</body> </html> </notes> <label text="PI(3,4,5)P3"/> <bbox w="70.0" h="25.0" x="4795.5" y="895.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4625_emtc_emtc_csa347" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PDGF family*:PDGFR family* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(PDGF/PDGFR)"/> <bbox w="105.0" h="120.0" x="2694.0" y="5990.5"/> <glyph class="macromolecule multimer" id="emtc_emtc_s4629_emtc_emtc_sa2419"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFR family*"/> <bbox w="86.0" h="56.0" x="2702.0" y="6031.5"/> <glyph class="unit of information" id="_388639e1-f775-45a9-876e-9e0e089457dd"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2735.0" y="6026.5"/> </glyph> <glyph class="unit of information" id="_a88fac2b-7d67-40c6-9dc0-20fc90308ef7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2722.5" y="6026.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4632_emtc_emtc_sa2422"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: platelet-derived growth factor alpha polypeptide HUGO:PDGFA HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet-derived growth factor beta polypeptide HUGO:PDGFA HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 platelet derived growth factor D HUGO:PDGFD HGNC:30620 ENTREZ:80310 UNIPROT:Q9GZP0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGF family*"/> <bbox w="97.0" h="33.0" x="2696.625" y="5992.625"/> <glyph class="unit of information" id="_c1f774e9-2882-4638-89cb-8081295a9cfc"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2735.125" y="5987.625"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4652_emtc_emtc_csa348" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:FGF family*:FGFR family*:Heparin Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Heparin/FGF/FGFR)"/> <bbox w="123.0" h="142.0" x="3191.0" y="5983.5"/> <glyph class="macromolecule" id="emtc_emtc_s4653_emtc_emtc_sa2444"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Fibroblas growth factors FGF fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 fms-related tyrosine kinase 1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR family*"/> <bbox w="80.0" h="50.0" x="3215.5" y="6053.0"/> <glyph class="unit of information" id="_af2dca3b-6cd1-4c12-9dc7-9a661e7dadca"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3233.0" y="6048.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4654_emtc_emtc_sa2445"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 fibroblast growth factor 3 "fibroblast growth factor 3 (murine mammary tumor virus integration site (v-int-2) oncogene homolog)", INT2, HBGF-3, "INT-2 proto-oncogene protein", "murine mammary tumor virus integration site 2, mouse", HUGO:FGF3 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 fibroblast growth factor 4 "heparin secretory transforming protein 1", HSTF1 HUGO:FGF4 HGNC:3682 ENTREZ:2249 UNIPROT:P08620 fibroblast growth factor 6 HUGO:FGF6 HGNC:3684 ENTREZ:2251 UNIPROT:P10767 fibroblast growth factor 7 HUGO:FGF7 HGNC:3685 ENTREZ:2252 UNIPROT:P21781 fibroblast growth factor 8 (androgen-induced) HUGO:FGF8 HGNC:3686 ENTREZ:2253 UNIPROT:P55075 "fibroblast growth factor 9 (glia-activating factor)" HUGO:FGF9 HGNC:3687 ENTREZ:2254 UNIPROT:P31371 fibroblast growth factor 10 HUGO:FGF10 HGNC:3666 ENTREZ:2255 UNIPROT:O15520 fibroblast growth factor 16 HUGO:FGF16 HGNC:3672 ENTREZ:8823 UNIPROT:O43320 fibroblast growth factor 19 HUGO:FGF19 HGNC:3675 ENTREZ:9965 UNIPROT:O95750 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF family*"/> <bbox w="78.0" h="28.0" x="3218.0" y="6019.5"/> <glyph class="unit of information" id="_9e1eaa02-b6ac-4672-bd06-cc4b15b2e46f"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3247.0" y="6014.5"/> </glyph> </glyph> <glyph class="simple chemical multimer" id="emtc_emtc_s4655_emtc_emtc_sa2446"> <label text="Heparin"/> <bbox w="66.0" h="31.0" x="3222.0" y="5984.0"/> <glyph class="unit of information" id="_1695094f-7b53-42c9-95ae-7d2cdeea4fa3"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3245.0" y="5979.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4671_emtc_emtc_csa299" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EGF family*:EGFR family*:GRB2:SHC1_p66_p52*:SOS* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos Phosphorylation of SCH1 at tyrosine forms docking sitess for GRB2 adaptator protein via ist SH2 domain The SH3 domain of GRB2 then binds to the proline-rich motifs in SOS, which is the GTP exchange factor for RAS Via this process that SOS is recruited to the membrane and colocalizes with Ras. Upon ligand (EGF, TGFA) binding, or upon transactiviation by Endothelin via HB-EGF ligand, EGFR is dimerized, then phosphorylated and thus activated by c-Src, which also phosphorylates and activates Shc1 (p66, p52). EGFR binds to Shc (p66, p52) and both proteins bind to GRB2. Both Shc and GRB2 bind to and thus recruit SOS to the membrane to colocalize and thus activate Ras. Activation of Ras results in activation of ERK1_2, which is signal tranducer and activator of SP1, STAT3, STAT5, EGR1 and c-Fos transcription factors SP1 stimulates expression of Collagen 1 (PMID:15240825). STAT3 induces transcriptional expression of VEGFA, TIMP1 and TWIST (PMID:17909010). EGR1 induces transcriptional expression of TIMP1. c-Fos induces transcriptional expression of Endothelin1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(GRB2/SOS*/SHC1_p66_p52/EGFR family)"/> <bbox w="254.0" h="112.0" x="6042.0" y="3340.5"/> <glyph class="macromolecule" id="emtc_emtc_s3941_emtc_emtc_sa2020"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SHC (Src homology 2 domain containing) transforming protein 1 HUGO:SHC1, HGNC:10840, ENTREZ:6464, UNIPROT:P29353 , GENECARDS:GC01M154934 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SHC1_p66_p52*"/> <bbox w="101.0" h="31.0" x="6050.625" y="3392.0"/> <glyph class="state variable" id="_651dccbe-8994-4da1-82dc-3337d0b0b985"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="6041.2466" y="3387.0"/> </glyph> <glyph class="state variable" id="_b3f2259a-102e-402f-b788-74c3b09cde43"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="6141.162" y="3387.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3942_emtc_emtc_sa2019"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: son of sevenless homolog 1 (Drosophila) HUGO:SOS1, HGNC:11187, ENTREZ:6654, UNIPROT:Q07889 , GENECARDS:GC02M039208 son of sevenless homolog 2 (Drosophila) HUGO:SOS2, HGNC:11188, ENTREZ:6655, UNIPROT:Q07890, GENECARDS:GC14M050583 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos SOS is an GTP-exchange factor for Ras References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOS*"/> <bbox w="35.0" h="17.0" x="6075.875" y="3367.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3943_emtc_emtc_sa2018"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: growth factor receptor-bound protein 2 HUGO:GRB2, HGNC:4566, ENTREZ:2885, UNIPROT:P62993, GENECARDS:GC17M073313 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos GRB2 is an adaptator for Ras References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GRB2"/> <bbox w="38.0" h="17.0" x="6114.875" y="3368.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4582_emtc_emtc_sa2378"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR family*"/> <bbox w="86.0" h="56.0" x="6171.0" y="3372.0"/> <glyph class="unit of information" id="_f588af86-dd3e-446f-8bf7-d2fdc305e603"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6204.0" y="3367.0"/> </glyph> <glyph class="state variable" id="_86f2a8ee-2f2c-452e-9d08-62d7698535c1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6205.6743" y="3367.0"/> </glyph> <glyph class="unit of information" id="_fcfe0556-69c3-4cdc-9ad1-8f2967af0c87"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6191.5" y="3367.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2526_sa2188"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, alpha HUGO:TGFA HGNC:11765 ENTREZ:7039 UNIPROT:P01135 heparin-binding EGF-like growth factor HUGO:HBEGF, HGNC:3059, ENTREZ:1839, UNIPROT:Q99075 , GENECARDS:GC05M139694 epidermal growth factor "epidermal growth factor (beta-urogastrone)" HUGO:EGF HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGF family*"/> <bbox w="78.0" h="21.0" x="6173.077" y="3347.5386"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4688_emtc_emtc_csa350" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:Formin* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Actin/Formin)"/> <bbox w="121.0" h="66.0" x="1085.0" y="3779.5"/> <glyph class="macromolecule" id="emtc_emtc_s4689_emtc_emtc_sa2473"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="1091.5" y="3783.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4690_emtc_emtc_sa2474"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: formin 1 FMN, "formin (limb deformity)", LD HUGO:FMN1 HGNC:3768 ENTREZ:342184 UNIPROT:Q68DA7 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Formin*"/> <bbox w="62.0" h="17.0" x="1098.5" y="3808.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4703_emtc_emtc_csa352" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Laminin 1 partners*:Laminin1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Laminin1/Laminin 1 partners)"/> <bbox w="176.0" h="64.0" x="5969.0" y="6488.0"/> <glyph class="macromolecule" id="emtc_emtc_s4705_emtc_emtc_sa2487"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:114518 Laminin-1: LAMA1, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin1*"/> <bbox w="74.0" h="18.0" x="6027.75" y="6490.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4704_emtc_emtc_sa2488"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 fibulin 1 HUGO:FBLN1 HGNC:3600 ENTREZ:2192 UNIPROT:P23142 fibulin 2 HUGO:FBLN2 HGNC:3601 ENTREZ:2199 UNIPROT:P98095 elastin HUGO:ELN HGNC:3327 ENTREZ:2006 UNIPROT:P15502 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin 1 partners*"/> <bbox w="121.0" h="22.0" x="5998.75" y="6509.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4708_emtc_emtc_csa353" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Elastin partners*:Elastin* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Elastin/Elastin partners)"/> <bbox w="145.0" h="65.0" x="5724.0" y="6493.0"/> <glyph class="macromolecule" id="emtc_emtc_s4710_emtc_emtc_sa2491"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: elastin HUGO:ELN HGNC:3327 ENTREZ:2006 UNIPROT:P15502 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Elastin*"/> <bbox w="49.0" h="18.0" x="5773.75" y="6496.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4709_emtc_emtc_sa2492"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 fibulin 1 HUGO:FBLN1 HGNC:3600 ENTREZ:2192 UNIPROT:P23142 fibulin 2 HUGO:FBLN2 HGNC:3601 ENTREZ:2199 UNIPROT:P98095 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:114518 Laminin-1: LAMA1, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Elastin partners*"/> <bbox w="107.0" h="22.0" x="5745.75" y="6516.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4711_emtc_emtc_csa351" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Galectin 3 partners*:Galectin 3* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Galectin 3/Galectin 3 partners)"/> <bbox w="189.0" h="67.0" x="3371.0" y="6500.0"/> <glyph class="macromolecule" id="emtc_emtc_s4696_emtc_emtc_sa2479"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: lectin, galactoside-binding, soluble, 3 HUGO:LGALS3 HGNC:6563 ENTREZ:3958 UNIPROT:P17931 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Galectin 3*"/> <bbox w="74.0" h="19.0" x="3410.75" y="6504.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4695_emtc_emtc_sa2480"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Galectin 3 partners*"/> <bbox w="124.0" h="21.0" x="3389.75" y="6526.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4721_emtc_emtc_csa356" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Fibronectin partners*:Fibronectin* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Fibronectin/Fibronectin partners)"/> <bbox w="193.0" h="64.0" x="5251.0" y="6452.0"/> <glyph class="macromolecule" id="emtc_emtc_s4723_emtc_emtc_sa2500"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end Identifiers_begin: Identifiers_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:2409071 Fibronectin is located on the apical and basal cell surfaces. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="72.0" h="20.0" x="5317.0" y="6456.234"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4722_emtc_emtc_sa2501"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Fibronectin partners NAME:a5b1* ITGA5/ITGB1 integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 NAME:a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 NAME:a10b1* ITGA10/ITGB1 integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin partners*"/> <bbox w="135.0" h="19.0" x="5287.5" y="6478.766"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4725_emtc_emtc_csa357" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Talin partners*:Talin* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Talin/Talin partners)"/> <bbox w="129.0" h="62.0" x="4906.0" y="5643.5"/> <glyph class="macromolecule" id="emtc_emtc_s4726_emtc_emtc_sa2503"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: HUGO:FERMT1 HUGO:FERMT2 HUGO:FERMT3 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Talin partners*"/> <bbox w="97.0" h="19.0" x="4908.5" y="5666.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4727_emtc_emtc_sa2504"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Talin* talin 1 HUGO:TLN1 HGNC:11845 ENTREZ:7094 UNIPROT:Q9Y490 talin 2 HUGO:TLN2 HGNC:15447 ENTREZ:83660 UNIPROT:Q9Y4G6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: Identifiers_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Talin*"/> <bbox w="39.0" h="16.0" x="4934.5" y="5647.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4740_emtc_emtc_csa358" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MMP13*:TIMP family* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MMP12/TIMP)"/> <bbox w="100.0" h="76.0" x="1649.0" y="6654.0"/> <glyph class="macromolecule" id="emtc_emtc_s4745_emtc_emtc_sa2521"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: matrix metallopeptidase 13 (membrane-inserted) HUGO:MMP13, HGNC:7159, ENTREZ:4322, GENECARDS:GC11M102847, UNIPROT:P45452 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 MMP13 activates TGFB by cleavage of LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP13*"/> <bbox w="64.0" h="17.0" x="1664.5" y="6686.0"/> <glyph class="unit of information" id="_99e49ea9-8a82-4d5e-8a78-09e8508721e4"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1671.5" y="6681.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4746_emtc_emtc_sa2522"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: TIMP metallopeptidase inhibitor 1 "tissue inhibitor of metalloproteinase 1" HUGO:TIMP1 HGNC:11820 ENTREZ:7076 UNIPROT:P01033 TIMP metallopeptidase inhibitor 2 "tissue inhibitor of metalloproteinase 2" HUGO:TIMP2 HGNC:11821 ENTREZ:7077 UNIPROT:P16035 TIMP metallopeptidase inhibitor 3 SFD, "tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory)" HUGO:TIMP3 HGNC:11822 ENTREZ:7078 UNIPROT:P35625 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP family*"/> <bbox w="87.0" h="20.0" x="1655.5" y="6657.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4742_emtc_emtc_csa359" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MMP1*:TIMP1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(MMP1/TIMP1)"/> <bbox w="102.0" h="83.0" x="1457.0" y="6651.0"/> <glyph class="macromolecule" id="emtc_emtc_s4744_emtc_emtc_sa2519"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: TIMP metallopeptidase inhibitor 1 "tissue inhibitor of metalloproteinase 1" HUGO:TIMP1 HGNC:11820 ENTREZ:7076 UNIPROT:P01033 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP1"/> <bbox w="38.0" h="18.0" x="1487.5" y="6655.625"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4743_emtc_emtc_sa2520"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: HUGO:MMP1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP1*"/> <bbox w="54.0" h="18.0" x="1479.0" y="6685.375"/> <glyph class="unit of information" id="_97a2a4b4-2b4e-40a0-bd3b-6f06b39861ef"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1481.0" y="6680.375"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4750_emtc_emtc_csa349" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:FGFR family*:FRS2:GRB2:SOS* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(FRS2/GRB2/SOS/FGFR family)"/> <bbox w="250.0" h="112.0" x="6044.0" y="3202.5"/> <glyph class="macromolecule" id="emtc_emtc_s4673_emtc_emtc_sa2460"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: fibroblast growth factor receptor substrate 2 HUGO:FRS2, HGNC:16971, ENTREZ:10818, UNIPROT:Q8WU20 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FRS2"/> <bbox w="51.0" h="19.0" x="6095.5" y="3209.0"/> <glyph class="state variable" id="_1962a145-ae68-4bfc-845d-4c90fe719d81"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6088.0" y="3213.4849"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4675_emtc_emtc_sa2461"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: son of sevenless homolog 1 (Drosophila) HUGO:SOS1, HGNC:11187, ENTREZ:6654, UNIPROT:Q07889 , GENECARDS:GC02M039208 son of sevenless homolog 2 (Drosophila) HUGO:SOS2, HGNC:11188, ENTREZ:6655, UNIPROT:Q07890, GENECARDS:GC14M050583 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos SOS is an GTP-exchange factor for Ras References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOS*"/> <bbox w="35.0" h="17.0" x="6051.75" y="3228.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4674_emtc_emtc_sa2462"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: growth factor receptor-bound protein 2 HUGO:GRB2, HGNC:4566, ENTREZ:2885, UNIPROT:P62993, GENECARDS:GC17M073313 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos GRB2 is an adaptator for Ras References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GRB2"/> <bbox w="38.0" h="17.0" x="6090.75" y="3229.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4678_emtc_emtc_sa2463"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Fibroblas growth factors FGF fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 fms-related tyrosine kinase 1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR family*"/> <bbox w="80.0" h="50.0" x="6155.285" y="3212.785"/> <glyph class="unit of information" id="_44819947-a0af-4a1a-829c-514a88dbc663"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6172.785" y="3207.785"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4759_emtc_emtc_csa360" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:IGF binding partners*:IGF family* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(IGF family/IGF binding partners)"/> <bbox w="198.0" h="69.0" x="1979.0" y="6616.0"/> <glyph class="macromolecule" id="emtc_emtc_s4757_emtc_emtc_sa2530"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: IGF family* insulin-like growth factor 1 (somatomedin C) HUGO:IGF1 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 insulin-like growth factor 2 (somatomedin A) HUGO:IGF2 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF family*"/> <bbox w="70.0" h="19.0" x="2049.5" y="6645.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4756_emtc_emtc_sa2531"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: IGF binding partners* insulin-like growth factor binding protein 1 HUGO:IGFBP1 HGNC:5469 ENTREZ:3484 UNIPROT:P08833 insulin-like growth factor binding protein 2 HUGO:IGFBP2 HGNC:5471 ENTREZ:3485 UNIPROT:P18065 insulin-like growth factor binding protein 3 HUGO:IGFBP3 HGNC:5472 ENTREZ:3486 UNIPROT:P17936 insulin-like growth factor binding protein 4 HUGO:IGFBP4 HGNC:5473 ENTREZ:3487 UNIPROT:P22692 insulin-like growth factor binding protein 5 HUGO:IGFBP5 HGNC:5474 ENTREZ:3488 UNIPROT:P24593 insulin-like growth factor binding protein 6 HUGO:IGFBP6 HGNC:5475 ENTREZ:3489 UNIPROT:P24592 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF binding partners*"/> <bbox w="144.0" h="19.0" x="2011.5" y="6620.0"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4782_emtc_emtc_csa364" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:BAD:BAD_binding partners* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(BAD/BAD_binding partner)"/> <bbox w="172.0" h="72.0" x="4717.0" y="1174.5"/> <glyph class="macromolecule" id="emtc_emtc_s4783_emtc_emtc_sa2545"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BAD_binding partner* B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAD_binding partners*"/> <bbox w="142.0" h="20.0" x="4731.5" y="1206.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4784_emtc_emtc_sa2546"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-associated agonist of cell death HUGO:BAD, HGNC:936, ENTREZ:572, UNIPROT:Q92934, GENECARDS:GC11M064037 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAD"/> <bbox w="38.0" h="20.0" x="4782.5" y="1183.5"/> <glyph class="state variable" id="_7a9265e9-0b11-44f6-a64a-08ac53c71e77"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4796.895" y="1178.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4791_emtc_emtc_csa366" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:14-3-3*:FOXO3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19564415 The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression. This explains the role of FOXO3 in promoting tumor invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(FOXO3/14-3-3 family)"/> <bbox w="141.0" h="66.0" x="3097.0" y="2347.5"/> <glyph class="macromolecule" id="emtc_emtc_s4792_emtc_emtc_sa2552"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: 14-3-3* tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide HUGO:YWHAQ HGNC:12854 ENTREZ:10971 UNIPROT:P27348 GENECARDS:YWHAQ REACTOME:48915 KEGG:10971 ATLASONC:GC_YWHAQ WIKI:YWHAQ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide HUGO:YWHAZ HGNC:12855 ENTREZ:7534 UNIPROT:P63104 GENECARDS:YWHAZ REACTOME:48917 KEGG:7534 ATLASONC:GC_YWHAZ WIKI:YWHAZ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide HUGO:YWHAE HGNC:12851 ENTREZ:7531 UNIPROT:P62258 GENECARDS:YWHAE REACTOME:48891 KEGG:7531 ATLASONC:GC_YWHAE WIKI:YWHAE tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide HUGO:YWHAB HGNC:12849 ENTREZ:7529 UNIPROT:P31946 GENECARDS:YWHAB REACTOME:48889 KEGG:7529 ATLASONC:GC_YWHAB WIKI:YWHAB stratifin HUGO:SFN HGNC:10773 ENTREZ:2810 UNIPROT:P31947 GENECARDS:SFN REACTOME:48913 KEGG:2810 ATLASONC:GC_SFN WIKI:SFN tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma polypeptide HUGO:YWHAG HGNC:12852 ENTREZ:7532 UNIPROT:P61981 GENECARDS:YWHAG REACTOME:48907 KEGG:7532 ATLASONC:GC_YWHAG WIKI:YWHAG tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide HUGO:YWHAH HGNC:12853 ENTREZ:7533 UNIPROT:Q04917 GENECARDS:YWHAH REACTOME:48905 KEGG:7533 ATLASONC:GC_YWHAH WIKI:YWHAH Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: YWHAB is so-called 14-3-3 alpha/beta PMID:9069260 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="14-3-3*"/> <bbox w="105.0" h="17.0" x="3118.5" y="2374.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4793_emtc_emtc_sa2553"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: forkhead box O3 HUGO:FOXO3, HGNC:3821, ENTREZ:2309, GENECARDS:GC06P108881, UNIPROT:O43524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19564415 The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression. This explains the role of FOXO3 in promoting tumor invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXO3"/> <bbox w="45.0" h="19.0" x="3146.5" y="2350.5"/> <glyph class="state variable" id="_7913a4f9-dbb0-4c94-9df9-1e77ffc604ae"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3141.5" y="2345.572"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4795_emtc_emtc_csa365" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:14-3-3*:BAD Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(BAD/14-3-3 family)"/> <bbox w="128.0" h="67.0" x="5412.0" y="1108.5"/> <glyph class="macromolecule" id="emtc_emtc_s4787_emtc_emtc_sa2548"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: 14-3-3* tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide HUGO:YWHAQ HGNC:12854 ENTREZ:10971 UNIPROT:P27348 GENECARDS:YWHAQ REACTOME:48915 KEGG:10971 ATLASONC:GC_YWHAQ WIKI:YWHAQ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide HUGO:YWHAZ HGNC:12855 ENTREZ:7534 UNIPROT:P63104 GENECARDS:YWHAZ REACTOME:48917 KEGG:7534 ATLASONC:GC_YWHAZ WIKI:YWHAZ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide HUGO:YWHAE HGNC:12851 ENTREZ:7531 UNIPROT:P62258 GENECARDS:YWHAE REACTOME:48891 KEGG:7531 ATLASONC:GC_YWHAE WIKI:YWHAE tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide HUGO:YWHAB HGNC:12849 ENTREZ:7529 UNIPROT:P31946 GENECARDS:YWHAB REACTOME:48889 KEGG:7529 ATLASONC:GC_YWHAB WIKI:YWHAB stratifin HUGO:SFN HGNC:10773 ENTREZ:2810 UNIPROT:P31947 GENECARDS:SFN REACTOME:48913 KEGG:2810 ATLASONC:GC_SFN WIKI:SFN tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma polypeptide HUGO:YWHAG HGNC:12852 ENTREZ:7532 UNIPROT:P61981 GENECARDS:YWHAG REACTOME:48907 KEGG:7532 ATLASONC:GC_YWHAG WIKI:YWHAG tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide HUGO:YWHAH HGNC:12853 ENTREZ:7533 UNIPROT:Q04917 GENECARDS:YWHAH REACTOME:48905 KEGG:7533 ATLASONC:GC_YWHAH WIKI:YWHAH Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: YWHAB is so-called 14-3-3 alpha/beta PMID:9069260 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="14-3-3*"/> <bbox w="105.0" h="17.0" x="5430.5" y="1136.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4788_emtc_emtc_sa2549"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: BCL2-associated agonist of cell death HUGO:BAD, HGNC:936, ENTREZ:572, UNIPROT:Q92934, GENECARDS:GC11M064037 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. 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PMID:17496910 PMID:22128289 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-MET*"/> <bbox w="86.0" h="56.0" x="1136.5" y="152.5"/> <glyph class="unit of information" id="_73ac173e-3fc5-4f1c-a745-8fdb2e35f265"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1169.5" y="147.5"/> </glyph> <glyph class="unit of information" id="_6325dfa9-02e7-4a79-bb4b-a0ece19c2910"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1157.0" y="147.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4825_emtc_emtc_csa369" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EPHB2:Ephrin-B1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Ephrin-B1/EPHB2)"/> <bbox w="123.0" h="106.0" x="2709.5" y="109.5"/> <glyph class="macromolecule multimer" id="emtc_emtc_s4828_emtc_emtc_sa2580"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: EPH receptor B2 "EphB2" HUGO:EPHB2 HGNC:3393 ENTREZ:2048 UNIPROT:P29323 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20179713 E-cadherin promotes EPHA2– ephrin-A1 localization at epithelial cell junctions EPHA2 is upregulated in many cancers and its expression has been linked to increased malignancy and a poor clinical prognosis. EPHA2 seems to be preferentially expressed in malignant breast and prostate cancers with a basal phenotype. EPHA1 is downregulated in advanced human skin and colorectal cancers, EphB receptors are downregulated in advanced colorectal cancer and ephrin-A5 is downregulated in glioblastomas TNF-alpha, VEGFA and HIF2A upregulate ephrin-A1 in cultured endothelial cells. Endothelial ephrin-B2 is upregulated by VEGF through the Notch pathway. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EPHB2"/> <bbox w="86.0" h="56.0" x="2727.5" y="136.5"/> <glyph class="unit of information" id="_c17e328e-f0ba-4cba-be10-c131fd32d9c7"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2760.5" y="131.5"/> </glyph> <glyph class="state variable" id="_22651888-540f-4e50-8b54-3847e8aa47ca"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2806.0" y="154.98137"/> </glyph> <glyph class="unit of information" id="_34b10b04-e58e-4d7a-8471-eacf50f11aff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2748.0" y="131.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4829_emtc_emtc_sa2581"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ephrin-B1 EPLG2 HUGO:EFNB1 HGNC:3226 ENTREZ:1947 UNIPROT:P98172 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Ephrin-B1*"/> <bbox w="83.0" h="16.0" x="2728.0" y="112.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4824_emtc_emtc_csa368" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EPHA2:Epherin-A1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20179713 E-cadherin promotes EPHA2– ephrin-A1 localization at epithelial cell junctions EPHA2 is upregulated in many cancers and its expression has been linked to increased malignancy and a poor clinical prognosis. EPHA2 seems to be preferentially expressed in malignant breast and prostate cancers with a basal phenotype. EPHA1 is downregulated in advanced human skin and colorectal cancers, EphB receptors are downregulated in advanced colorectal cancer and ephrin-A5 is downregulated in glioblastomas TNF-alpha, VEGFA and HIF2A upregulate ephrin-A1 in cultured endothelial cells. Endothelial ephrin-B2 is upregulated by VEGF through the Notch pathway. PMID:19074825 PMID:24003208 “Forward” signaling corresponds to the proto- typical RTK mode of signaling, which is triggered by ligand binding and involves activation of the kinase domain. However, the activation mechanisms of Eph receptors have unique features as compared to other RTK families. Binding between Eph receptors and ephrins on juxtaposed cell surfaces leads to oligomerization through not only Eph receptor – ephrin interfaces but also receptor – receptor cis interfaces located in multiple domains Phosphorylation of the conserved tyrosine in the activation loop appears to be less critical for Eph receptor activation than it is for many other RTKs, although it may be important for maximal activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Ephrin-A1/EPHA2)"/> <bbox w="118.0" h="97.0" x="2275.5" y="113.5"/> <glyph class="macromolecule" id="emtc_emtc_s4826_emtc_emtc_sa2578"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ephrin-A1 EPLG1, TNFAIP4 HUGO:EFNA1 HGNC:3221 ENTREZ:1942 UNIPROT:P20827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:19074825 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Epherin-A1*"/> <bbox w="79.0" h="16.0" x="2298.0" y="116.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4827_emtc_emtc_sa2579"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: EPH receptor A2 "EphA2" HUGO:EPHA2 HGNC:3386 ENTREZ:1969 UNIPROT:P29317 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20179713 E-cadherin promotes EPHA2– ephrin-A1 localization at epithelial cell junctions EPHA2 is upregulated in many cancers and its expression has been linked to increased malignancy and a poor clinical prognosis. 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PMID:19074825 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EPHA2"/> <bbox w="86.0" h="56.0" x="2293.5" y="135.5"/> <glyph class="unit of information" id="_1355e6df-3832-4756-afcd-c590e334c77e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2326.5" y="130.5"/> </glyph> <glyph class="state variable" id="_4d523984-23f8-41be-91d6-898b29ac6267"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2286.0" y="153.06879"/> </glyph> <glyph class="unit of information" id="_6bb26448-8d1a-468d-a25c-7d4400984882"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2314.0" y="130.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2265_csa310" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARF6:DNM2_GTP:NME2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12447393 Activation of (activated) ARF6 is required for dynamin-dependent endocytosis of E-cadherin. Nm23-H1 binds ARF6-GTP and mediates dynamin-dependent vesicle fission. (I has not however be tested wheter, NM23H2 (NME2) binds ARF6 as well, nut is is strongly suggested) PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARF6/DNM2_GTP/NME2"/> <bbox w="230.0" h="200.0" x="1315.0" y="805.0"/> <glyph class="macromolecule" id="s2258_sa2003"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NME2"/> <bbox w="80.0" h="40.0" x="1455.0" y="915.0"/> </glyph> <glyph class="macromolecule" id="s2259_sa2004"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:12447393 Activation of (activated) ARF6 is required for dynamin-dependent endocytosis of E-cadherin. Nm23-H1 binds ARF6-GTP and mediates dynamin-dependent vesicle fission. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARF6"/> <bbox w="80.0" h="40.0" x="1455.0" y="835.0"/> </glyph> </glyph> <glyph class="complex" id="s2266_csa309" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:ARF6:DNM2_GTP:NME1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12447393 Activation of (activated) ARF6 is required for dynamin-dependent endocytosis of E-cadherin. Nm23-H1 binds ARF6-GTP and mediates dynamin-dependent vesicle fission. PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) DNM2 induces E-cadherin internalisation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARF6/DNM2_GTP/NME1"/> <bbox w="230.0" h="180.0" x="1315.0" y="595.0"/> <glyph class="macromolecule" id="s2252_sa1999"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:12447393 Activation of (activated) ARF6 is required for dynamin-dependent endocytosis of E-cadherin. Nm23-H1 binds ARF6-GTP and mediates dynamin-dependent vesicle fission. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARF6"/> <bbox w="80.0" h="40.0" x="1450.0" y="615.0"/> </glyph> <glyph class="macromolecule" id="s2253_sa2000"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:25234227 Nm23-h1(NME1) binds to gelsolin and inactivates its actin-severing capacity to promote tumor cell motility and metastasis. Dynamin 2 act on the actin cytoskeleton by Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) NPDK-A and dynamin associate during cytokinesis to promote chromosome stability. Loss of NDPK-A is linked to cytokinesis failure and tetraploidy PMID:18470881 Nm23-H1 binds Dbl-1(MCF2) and thus interferes with the ability of Dbl-1 to load GTP onto CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NME1"/> <bbox w="80.0" h="40.0" x="1450.0" y="675.0"/> </glyph> </glyph> <glyph class="complex" id="s2267_csa306" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:DNM2:GTP Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) DNM2 induces E-cadherin internalisation - Promoting cytokinesis and chromosome stability thanks to NDPKA Loss of NDPK-A is linked to cytokinesis failure and tetraploidy References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DNM2_GTP"/> <bbox w="100.0" h="120.0" x="590.0" y="858.0"/> <glyph class="macromolecule" id="s2256_sa1984"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) DNM2 induces E-cadherin internalisation - Promoting cytokinesis and chromosome stability thanks to NDPKA Loss of NDPK-A is linked to cytokinesis failure and tetraploidy References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DNM2"/> <bbox w="80.0" h="40.0" x="600.0" y="878.0"/> </glyph> <glyph class="simple chemical" id="s2257_sa1985"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="605.0" y="905.5"/> </glyph> </glyph> <glyph class="complex" id="s2268_csa307" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:DNM2:GDP Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) DNM2 induces E-cadherin internalisation - Promoting cytokinesis and chromosome stability thanks to NDPKA Loss of NDPK-A is linked to cytokinesis failure and tetraploidy References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DNM2_GDP"/> <bbox w="100.0" h="120.0" x="594.0" y="1267.0"/> <glyph class="macromolecule" id="s2233_sa1989"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) DNM2 induces E-cadherin internalisation - Promoting cytokinesis and chromosome stability thanks to NDPKA Loss of NDPK-A is linked to cytokinesis failure and tetraploidy References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DNM2"/> <bbox w="80.0" h="40.0" x="604.0" y="1287.0"/> </glyph> <glyph class="simple chemical" id="s2240_sa1990"> <label text="GDP"/> <bbox w="70.0" h="25.0" x="609.0" y="1314.5"/> </glyph> </glyph> <glyph class="complex" id="s2270_emtc_emtc_csa273" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Actin cytoskeletal*:Cadherin*:_alpha_-Catenin*:_beta_-Catenin*:p120* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:15609097 CTNNB1 (beta-catenin) binds with high affinity to the distal Cadherin cytoplasmic tail. Cadherin recruits CTNNA1 (alpha-catenin) to the complex. CTNNA1 (alpha-catenin) binds to Actin filaments directly CTNNA1 (alpha-catenin) and can also associate with other actin-binding proteins (MLLT4 or Formin) CTNND1 (delta-catenin or p120) binds directly to Cadherin independently of the other catenins. Catenins/Cadherin complex can further interact with a range of singaling molecules which participate in either cellular signaling or control of cytoskeletal dynamics. Stability of Cadherin/Catenins complex and thereby the integrity of adherens junctions is controlled by phosphorylation/dephosphorylation. PMID:16099633 Phosphorylation of beta-catenin (CTNNB1) by receptor and no-receptor tyrosine kinases results in dissociation of CTNNA1 from CTNNB1 with concomitant loss of cadherin adhesion. Dephosphoryaltion of CTNNB1 by tyrosine phosphatases ensure or restore the integrity of Cadherin-mediated adhesions. PMID :10402472 We conclude that a pool of surface E-cadherin is constantly trafficked through an endocytic, recycling pathway and that this may provide a mechanism for regulating the availability of E-cadherin for junction formation in development, tissue remodeling, and tumorigenesis. PMID:22674073 Cadherin internalization can occur through either clathrin-mediated, caveolin-mediated, or macropinocytosis-like pathways. Internalized cadherin is then sorted either for lysosomal degradation or recycling back to the plasma membrane. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(α-Catenin*/β-Catenin*/p120*/Actin cytoskeletal/Cadherin*)"/> <bbox w="370.0" h="65.5" x="1442.0" y="3383.5"/> <glyph class="macromolecule" id="emtc_emtc_s3608_emtc_emtc_sa1778"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Catenin*"/> <bbox w="69.0" h="18.0" x="1525.75" y="3387.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3606_emtc_emtc_sa1779"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="66.0" h="28.0" x="1447.75" y="3404.0"/> <glyph class="state variable" id="_f4526521-6ebc-42c2-8e0e-9ec50ce4587a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1442.75" y="3400.6816"/> </glyph> <glyph class="state variable" id="_32a69d64-2c18-4ee9-b1a0-f6adb662ceec"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1475.7762" y="3399.0"/> </glyph> <glyph class="state variable" id="_c1b1bc24-b148-4164-95ad-d8b3d2afecc5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1508.75" y="3399.0"/> </glyph> <glyph class="state variable" id="_49c62483-26a9-4134-a167-b9018cccd5d6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1488.961" y="3399.0"/> </glyph> <glyph class="state variable" id="_3fa476db-f823-459c-98e2-ba53a2f77182"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1461.8287" y="3399.0"/> </glyph> <glyph class="state variable" id="_5d0490c3-f719-4073-b7a3-ca7cd41bd2f3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1508.75" y="3425.3582"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3607_emtc_emtc_sa1780"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p120*"/> <bbox w="52.0" h="16.0" x="1596.0" y="3411.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3685_emtc_emtc_sa1825"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cadherin*"/> <bbox w="75.0" h="20.0" x="1519.5" y="3406.5"/> </glyph> <glyph class="macromolecule" id="s2269_sa2007"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="110.0" h="20.0" x="1607.0" y="3389.0"/> </glyph> </glyph> <glyph class="complex" id="s2279_emtc_emtc_csa47" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:TGFB1:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Reference_bigin: PMID:22943793 TGFb binds to homodimer TGFBR2 first TGFBR2 phosphorylates the GS domain of homodimeric TFGBR1 on serine residues This phosphorylation leads to incorporation of TGFBR1 and formation of a large ligand-receptor complex of fimeric TGFB and two pairs of TGFBR1 and TGFBR2 PMID:12809600 PMID:22710166 The active ligand–receptor complex is a heterotetrameric complex This complex consists of an active dimer of TGFB and homodimers of both TGFBRI and TGFBR2. Within the active receptor complex, TGFBR2autophosphorylates itself and catalyzes transphosphorylation of the TGFBR1. Transphosphorylation of the TGFBRI activates its kinase activity. Reference_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1/TGFBR1/TGFBR2"/> <bbox w="70.375" h="139.5" x="6162.812" y="4104.75"/> <glyph class="macromolecule multimer" id="emtc_emtc_s1653_emtc_emtc_sa420"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="52.0" h="43.0" x="6174.562" y="4108.75"/> <glyph class="unit of information" id="_b5c2a63e-3c73-4550-9e28-9d5f2eb03000"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6190.562" y="4103.75"/> </glyph> <glyph class="state variable" id="_6c40f819-0398-40f7-8bd6-2b08f8f53fdb"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6162.062" y="4106.3325"/> </glyph> <glyph class="unit of information" id="_bc4a15a1-1567-4f54-9518-b2df80a92e6d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6178.062" y="4103.75"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s2280_emtc_emtc_sa421"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="50.0" h="26.0" x="6177.562" y="4150.25"/> <glyph class="unit of information" id="_4067f0a3-80d5-42c5-a67c-cbbc8f6d009c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6192.562" y="4145.25"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1655_emtc_emtc_sa422"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="53.75" h="46.0" x="6174.812" y="4179.25"/> <glyph class="unit of information" id="_9c26c21e-083d-4bd1-b404-0454ed84bf8c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6191.687" y="4174.25"/> </glyph> <glyph class="state variable" id="_f50d16f4-95ad-447d-8579-1886fea6fc63"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6223.562" y="4174.497"/> </glyph> <glyph class="state variable" id="_cc3e25b3-10a1-409e-b639-8cc00c2ac4d8"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6162.312" y="4175.32"/> </glyph> <glyph class="unit of information" id="_425a63b8-5419-46cd-981d-466d8dbb8732"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6179.187" y="4174.25"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2281_emtc_emtc_csa40" compartmentRef="emtc_emtc_c33_emtc_emtc_ca33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SARA*:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*/SMAD2"/> <bbox w="109.0" h="96.0" x="5980.5" y="4255.5"/> <glyph class="macromolecule" id="s2282_emtc_emtc_sa389"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger, FYVE domain containing 9 HUGO:ZFYVE9, HGNC:6775, ENTREZ:9372, UNIPROT:O95405, GENECARDS:GC01P052608 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:11792802 -SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. -Several other proteins with possible roles in Smad anchoring: PMID:10678166 Microtubules can anchor inactive Smads in the cytoplasm Activation by a ligand results in dissociation of the Smads from the microtubule network It is possible that microtubules serve as tracks for intracellular Smad movement PMID:11278410 Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*"/> <bbox w="60.0" h="20.0" x="5997.0" y="4255.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s481_emtc_emtc_sa390"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="107.0" h="51.0" x="5981.5" y="4275.5"/> <glyph class="state variable" id="_0ba8fafa-17e4-4d1e-be4f-c4d254ee88f4"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="6071.0" y="4303.977"/> </glyph> <glyph class="state variable" id="_d8e5650a-3e9e-4c4e-9e95-e80eece3714e"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="6025.9424" y="4321.5"/> </glyph> <glyph class="state variable" id="_a51a35f8-5d24-4217-84c1-06f6a996cae6"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="6071.0" y="4316.7554"/> </glyph> <glyph class="state variable" id="_20fb98b5-3c41-4061-8130-2431147ebf77"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="6073.5" y="4293.9556"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2283_emtc_emtc_csa44" compartmentRef="emtc_emtc_c33_emtc_emtc_ca33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SARA*:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*/SMAD3"/> <bbox w="115.0" h="98.0" x="5723.0" y="4253.5"/> <glyph class="macromolecule" id="s2284_emtc_emtc_sa406"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger, FYVE domain containing 9 HUGO:ZFYVE9, HGNC:6775, ENTREZ:9372, UNIPROT:O95405, GENECARDS:GC01P052608 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:11792802 -SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. -Several other proteins with possible roles in Smad anchoring: PMID:10678166 Microtubules can anchor inactive Smads in the cytoplasm Activation by a ligand results in dissociation of the Smads from the microtubule network It is possible that microtubules serve as tracks for intracellular Smad movement PMID:11278410 Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*"/> <bbox w="60.0" h="20.0" x="5757.406" y="4253.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s508_emtc_emtc_sa411"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="115.0" h="49.0" x="5723.0" y="4274.5"/> <glyph class="state variable" id="_de30edd3-9c9e-476c-bdf8-d2423ee5ddfc"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="5708.0" y="4297.663"/> </glyph> <glyph class="state variable" id="_f2852005-76f1-4606-8875-6b717cc06005"> <state value="" variable="S422"/> <bbox w="30.0" h="10.0" x="5823.0" y="4290.797"/> </glyph> <glyph class="state variable" id="_cdad0141-13c9-46f0-924b-073b27f75558"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="5708.0" y="4313.7476"/> </glyph> <glyph class="state variable" id="_2b59e593-4f80-427c-8c3d-5081eb876926"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="5820.5" y="4300.601"/> </glyph> <glyph class="state variable" id="_f7daa377-93ea-404b-8582-be031869fab0"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="5820.5" y="4313.9414"/> </glyph> <glyph class="state variable" id="_0813c462-9bc8-45ec-bd95-34dca3f6830c"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="5708.0" y="4286.3784"/> </glyph> <glyph class="state variable" id="_61b9ca60-8eaa-4c2a-afc7-ed7e474ec9a8"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="5708.0" y="4272.443"/> </glyph> <glyph class="state variable" id="_b33e5818-6809-4bb6-92ee-ce4040bdfb41"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5769.2124" y="4318.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2285_emtc_emtc_csa345" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EGF family*:EGFR family* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(EGF family/EGFR)"/> <bbox w="101.0" h="109.0" x="2423.25" y="6010.5"/> <glyph class="macromolecule" id="s2286_emtc_emtc_sa2371"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, alpha HUGO:TGFA HGNC:11765 ENTREZ:7039 UNIPROT:P01135 heparin-binding EGF-like growth factor HUGO:HBEGF, HGNC:3059, ENTREZ:1839, UNIPROT:Q99075 , GENECARDS:GC05M139694 epidermal growth factor "epidermal growth factor (beta-urogastrone)" HUGO:EGF HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGF family*"/> <bbox w="78.0" h="21.0" x="2434.75" y="6015.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4581_emtc_emtc_sa2377"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR family*"/> <bbox w="86.0" h="56.0" x="2430.0" y="6040.5"/> <glyph class="unit of information" id="_95b1ad75-da69-4474-b94b-96f5c5fc286f"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2463.0" y="6035.5"/> </glyph> <glyph class="state variable" id="_f635b789-1c4f-498c-be3d-ec9f63fc2fcd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2464.674" y="6035.5"/> </glyph> <glyph class="unit of information" id="_96b4cdc7-0b5b-4352-82f6-b160b9b21bc9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2450.5" y="6035.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2287_emtc_emtc_csa267" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:APC:AXIN1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10581160 PMID:17318175 PMID:10421629 Recruitment of CTNNB1 via the degradation complex of APC/AXIN1 is regulated by a series of ordered phosphorylation events. Phosphorylation of AXIN1 by CSNK1 (casein kinase 1) and GSK3B can increase axin binding to CTNNB1. PMID:8638126 PMID:11487578 PMID:15327768 AXIN1 also promotes phosphorylation of APC by CSNK1 and GSK3B. Phosphorylated APC has higher affinity to CTNNB1. PMID:12554650 Finally, these phosphorylation events allo CTNNB1 to be a more efficient substrate of both CSNK1 (at S45) and the GSK3B (at T41, S33, S37). The affinity of phosphorylated APC to CTNNB1 is higher than that of phosphorylated AXIN1. Therefore upon phosphorylation, APC can displace AXIN1 from CTNNB1, allowing AXIN1 to bind another molecule of CTNNB1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC/AXIN1"/> <bbox w="88.0" h="44.0" x="1261.5" y="3617.5"/> <glyph class="macromolecule" id="emtc_emtc_s3572_emtc_emtc_sa1751"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC"/> <bbox w="40.0" h="20.0" x="1265.0" y="3621.0"/> <glyph class="state variable" id="_0f46947e-a818-4d17-8eb7-614333385289"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1277.916" y="3616.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3573_emtc_emtc_sa1752"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1"/> <bbox w="40.0" h="20.0" x="1306.0" y="3621.0"/> <glyph class="state variable" id="_f2d8a776-6738-47d3-936f-6d858c58e157"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1318.916" y="3616.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2288_emtc_emtc_csa355" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:COL2A1:Collagen2 partners* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Collagen1/Collagen1 partners)"/> <bbox w="189.0" h="64.0" x="5030.0" y="6451.0"/> <glyph class="macromolecule" id="emtc_emtc_s4719_emtc_emtc_sa2497"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type II, alpha 1 "collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital)", SEDC HUGO:COL2A1 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL2A1"/> <bbox w="46.0" h="18.0" x="5101.125" y="6455.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4718_emtc_emtc_sa2498"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME: a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 NAME:a10b1* ITGA10/ITGB1 integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. 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Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen2 partners*"/> <bbox w="120.0" h="20.0" x="5065.375" y="6476.25"/> </glyph> </glyph> <glyph class="complex" id="s2289_emtc_emtc_csa362" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:IGF family*:IGF1R Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(IGF family/IGF1R)"/> <bbox w="100.0" h="120.0" x="1978.5" y="5998.5"/> <glyph class="macromolecule" id="s2290_emtc_emtc_sa2535"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: IGF family* insulin-like growth factor 1 (somatomedin C) HUGO:IGF1 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 insulin-like growth factor 2 (somatomedin A) HUGO:IGF2 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. 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Rac1 seems to modulate the amout of Adherens junction according to the biological context. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IQGAP1/Rac_GTP"/> <bbox w="113.0" h="131.0" x="1704.0" y="1718.0"/> <glyph class="macromolecule" id="s2318_sa2035"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:15263019 Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IQGAP1"/> <bbox w="80.0" h="40.0" x="1724.0" y="1779.0"/> </glyph> <glyph class="macromolecule" id="s2316_sa2036"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="42.0" h="18.0" x="1745.0" y="1753.0"/> </glyph> <glyph class="simple chemical" id="s2317_sa2037"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end</body> </html> </notes> <label text="GTP"/> <bbox w="40.0" h="20.0" x="1742.0" y="1726.0"/> </glyph> </glyph> <glyph class="complex" id="s2322_csa316" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:CDC42:GTP:IQGAP1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15263019 Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42_ATP/IQGAP1"/> <bbox w="135.0" h="131.0" x="1677.0" y="1483.0"/> <glyph class="simple chemical" id="s2325_sa2038"> <label text="GTP"/> <bbox w="40.0" h="20.0" x="1733.5" y="1520.0"/> </glyph> <glyph class="macromolecule" id="s2326_sa2039"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: cell division cycle 42 HUGO:CDC42, HGNC:1736, ENTREZ:998, UNIPROT:P60953, GENECARDS:GC01P022379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 is a member of the RAS superfamily of small GTPases and plays an essential role in control of cell polarity, actin cytoskeleton rearrangements, protein traffickinf and directed cell movements. PMID:10934474 PMID:11248548 PMID:11340065 PMID:15003621 CDC42 and cell polarity: PMID:15020669 CDC42 functions in vivo: PMID:18719708 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42"/> <bbox w="45.0" h="19.0" x="1731.5" y="1496.0"/> <glyph class="state variable" id="_8b465986-1541-4395-a79c-9daed0389b35"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1771.5" y="1491.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2323_sa2040"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:15263019 Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IQGAP1"/> <bbox w="80.0" h="40.0" x="1712.0" y="1549.0"/> </glyph> </glyph> <glyph class="complex" id="s2334_csa317" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:MAP3K7:TAB1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K7/NLK"/> <bbox w="80.0" h="110.0" x="5134.0" y="2423.0"/> <glyph class="macromolecule" id="s2355_sa2052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: mitogen-activated protein kinase kinase kinase 7 TAK1 HUGO:MAP3K7 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:21041997 TGFB has been shown to induce p38 and JNK MAP kinase signaling through activation of TAK1 (MAP3K7) by the ubiquitin ligase TRAF6 that interacts with the TGFB receptor complex PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K7"/> <bbox w="62.0" h="22.0" x="5143.0" y="2452.0"/> </glyph> <glyph class="macromolecule" id="s2362_sa2059"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TAB1"/> <bbox w="50.0" h="20.0" x="5149.0" y="2483.0"/> </glyph> </glyph> <glyph class="complex" id="s2343_emtc_emtc_csa12" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:TGFB1:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Reference_bigin: PMID:22943793 TGFb binds to homodimer TGFBR2 first TGFBR2 phosphorylates the GS domain of homodimeric TFGBR1 on serine residues This phosphorylation leads to incorporation of TGFBR1 and formation of a large ligand-receptor complex of fimeric TGFB and two pairs of TGFBR1 and TGFBR2 PMID:12809600 PMID:22710166 The active ligand–receptor complex is a heterotetrameric complex This complex consists of an active dimer of TGFB and homodimers of both TGFBRI and TGFBR2. Within the active receptor complex, TGFBR2autophosphorylates itself and catalyzes transphosphorylation of the TGFBR1. Transphosphorylation of the TGFBRI activates its kinase activity. Reference_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1/TGFBR1/TGFBR2"/> <bbox w="71.5" h="157.0" x="6162.906" y="3878.5"/> <glyph class="macromolecule multimer" id="emtc_emtc_s606_emtc_emtc_sa240"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="58.0" h="46.5" x="6167.906" y="3880.25"/> <glyph class="unit of information" id="_efec7127-6e4f-426a-a7c5-c20bdfe53979"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6186.906" y="3875.25"/> </glyph> <glyph class="state variable" id="_cf0f9ba3-4d3b-45b3-aeac-80aae3406703"> <state value="P" variable="Ser"/> <bbox w="30.0" h="10.0" x="6152.906" y="3878.0425"/> </glyph> <glyph class="unit of information" id="_7c11d113-354a-4dea-b3d9-012b285639df"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6174.406" y="3875.25"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s2344_emtc_emtc_sa241"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. 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PMID:11792802 -SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. -Several other proteins with possible roles in Smad anchoring: PMID:10678166 Microtubules can anchor inactive Smads in the cytoplasm Activation by a ligand results in dissociation of the Smads from the microtubule network It is possible that microtubules serve as tracks for intracellular Smad movement PMID:11278410 Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals. 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After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="111.0" h="49.0" x="5978.5" y="4086.0"/> <glyph class="state variable" id="_c5945ce6-003b-4f9e-9654-c2fe391dd3ae"> <state value="" variable="S465"/> <bbox w="30.0" h="10.0" x="6074.5" y="4113.1646"/> </glyph> <glyph class="state variable" id="_e433c84d-ba00-490f-8c57-34735ca86aaa"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="6024.9775" y="4130.0"/> </glyph> <glyph class="state variable" id="_63ab6aa0-0943-4862-b835-e8fff5ff19c4"> <state value="" variable="S467"/> <bbox w="30.0" h="10.0" x="6074.5" y="4125.4414"/> </glyph> <glyph class="state variable" id="_b15a7bd9-0b44-4b58-aef7-a09db68cf307"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="6074.5" y="4103.5356"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2347_emtc_emtc_csa43" compartmentRef="emtc_emtc_c33_emtc_emtc_ca33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:SARA*:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*/SMAD3"/> <bbox w="115.0" h="92.0" x="5723.0" y="4064.5"/> <glyph class="macromolecule" id="s2348_emtc_emtc_sa404"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: zinc finger, FYVE domain containing 9 HUGO:ZFYVE9, HGNC:6775, ENTREZ:9372, UNIPROT:O95405, GENECARDS:GC01P052608 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:11792802 -SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. -Several other proteins with possible roles in Smad anchoring: PMID:10678166 Microtubules can anchor inactive Smads in the cytoplasm Activation by a ligand results in dissociation of the Smads from the microtubule network It is possible that microtubules serve as tracks for intracellular Smad movement PMID:11278410 Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*"/> <bbox w="60.0" h="20.0" x="5759.0" y="4065.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s504_emtc_emtc_sa410"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="111.0" h="46.0" x="5727.0" y="4086.5"/> <glyph class="state variable" id="_46b904a7-7158-464d-a941-b42140c7ec85"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="5712.0" y="4107.9385"/> </glyph> <glyph class="state variable" id="_1b6b4e13-bb16-4f22-a133-a63b17587598"> <state value="" variable="S422"/> <bbox w="30.0" h="10.0" x="5823.0" y="4101.493"/> </glyph> <glyph class="state variable" id="_d0adee79-ac0c-44e5-a3e3-3687e676fc76"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="5712.0" y="4123.0386"/> </glyph> <glyph class="state variable" id="_4b951947-9ff4-4bf5-affa-32db608146ee"> <state value="" variable="S423"/> <bbox w="30.0" h="10.0" x="5823.0" y="4110.697"/> </glyph> <glyph class="state variable" id="_d7c68e5d-dc69-4b40-809c-9f790973b1b8"> <state value="" variable="S425"/> <bbox w="30.0" h="10.0" x="5823.0" y="4123.2207"/> </glyph> <glyph class="state variable" id="_f647f78b-5915-42f8-a050-1876fa208db5"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="5712.0" y="4097.345"/> </glyph> <glyph class="state variable" id="_c38cf359-72f3-4d12-b7f1-e90a0579a08d"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="5712.0" y="4084.2625"/> </glyph> <glyph class="state variable" id="_a3b07873-b651-4280-b812-6794d850a2ce"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5771.2573" y="4127.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2349_emtc_emtc_csa344" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:EGF family*:EGFR family* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(EGF family/EGFR)"/> <bbox w="101.0" h="109.0" x="2273.0" y="6008.5"/> <glyph class="macromolecule" id="s2350_emtc_emtc_sa2352"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, alpha HUGO:TGFA HGNC:11765 ENTREZ:7039 UNIPROT:P01135 heparin-binding EGF-like growth factor HUGO:HBEGF, HGNC:3059, ENTREZ:1839, UNIPROT:Q99075 , GENECARDS:GC05M139694 epidermal growth factor "epidermal growth factor (beta-urogastrone)" HUGO:EGF HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGF family*"/> <bbox w="78.0" h="21.0" x="2284.5" y="6013.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4578_emtc_emtc_sa2376"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR family*"/> <bbox w="86.0" h="56.0" x="2280.0" y="6037.0"/> <glyph class="unit of information" id="_54b35a91-76f5-48d5-9b1b-9882aa66d33c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2313.0" y="6032.0"/> </glyph> <glyph class="state variable" id="_dbef5047-e75d-4ca6-80cd-c6f696aa5a9b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2317.174" y="6032.0"/> </glyph> <glyph class="unit of information" id="_765b019f-21fb-4f3a-ba90-9e8960c2272e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2300.5" y="6032.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2351_emtc_emtc_csa266" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:APC:AXIN1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10581160 PMID:17318175 PMID:10421629 Recruitment of CTNNB1 via the degradation complex of APC/AXIN1 is regulated by a series of ordered phosphorylation events. Phosphorylation of AXIN1 by CSNK1 (casein kinase 1) and GSK3B can increase axin binding to CTNNB1. PMID:8638126 PMID:11487578 PMID:15327768 AXIN1 also promotes phosphorylation of APC by CSNK1 and GSK3B. Phosphorylated APC has higher affinity to CTNNB1. PMID:12554650 Finally, these phosphorylation events allo CTNNB1 to be a more efficient substrate of both CSNK1 (at S45) and the GSK3B (at T41, S33, S37). The affinity of phosphorylated APC to CTNNB1 is higher than that of phosphorylated AXIN1. Therefore upon phosphorylation, APC can displace AXIN1 from CTNNB1, allowing AXIN1 to bind another molecule of CTNNB1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC/AXIN1"/> <bbox w="88.0" h="44.0" x="1020.0" y="3617.5"/> <glyph class="macromolecule" id="emtc_emtc_s3569_emtc_emtc_sa1749"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC"/> <bbox w="40.0" h="20.0" x="1023.5" y="3621.0"/> <glyph class="state variable" id="_8234b0d0-0082-499c-9a2c-d9dd41389977"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1038.916" y="3616.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3568_emtc_emtc_sa1750"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1"/> <bbox w="40.0" h="20.0" x="1064.5" y="3621.0"/> <glyph class="state variable" id="_68591e80-bf4a-4eb4-964d-73aa8141ef2d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1079.916" y="3616.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4506_emtc_emtc_csa339" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PI3KC1-catalytic*:PI3KC1-regulator* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(PI3KC1)"/> <clone/> <bbox w="118.0" h="66.0" x="5017.0" y="877.5"/> <glyph class="macromolecule" id="emtc_emtc_s4502_emtc_emtc_sa2322"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphoinositide-3-kinase catalytic alpha polypeptide HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 phosphoinositide-3-kinase catalytic beta polypeptide HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 phosphoinositide-3-kinase catalytic delta polypeptide HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 phosphoinositide-3-kinase catalytic gamma polypeptide HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:16847462 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC1-catalytic*"/> <clone/> <bbox w="114.0" h="21.0" x="5019.0" y="879.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4503_emtc_emtc_sa2323"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphoinositide-3-kinase regulatory subunit 1 (alpha) HUGO:PIK3R1 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 phosphoinositide-3-kinase regulatory subunit 2 (beta) HUGO:PIK3R2 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 phosphoinositide-3-kinase regulatory subunit 3 (gamma) HUGO:PIK3R3 HGNC:8981 ENTREZ:8503 UNIPROT:Q92569 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:16847462 PMID:19568798 PMID:12040186 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC1-regulator*"/> <clone/> <bbox w="114.0" h="19.0" x="5021.0" y="902.5"/> </glyph> </glyph> <glyph class="complex" id="emtc_emtc_s4506_emtc_emtc_csa342" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:PI3KC1-catalytic*:PI3KC1-regulator* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(PI3KC1)"/> <clone/> <bbox w="118.0" h="66.0" x="5017.5" y="1066.0"/> <glyph class="macromolecule" id="emtc_emtc_s4502_emtc_emtc_sa2332"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphoinositide-3-kinase catalytic alpha polypeptide HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 phosphoinositide-3-kinase catalytic beta polypeptide HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 phosphoinositide-3-kinase catalytic delta polypeptide HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 phosphoinositide-3-kinase catalytic gamma polypeptide HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:16847462 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC1-catalytic*"/> <clone/> <bbox w="114.0" h="21.0" x="5019.5" y="1068.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4503_emtc_emtc_sa2333"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphoinositide-3-kinase regulatory subunit 1 (alpha) HUGO:PIK3R1 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 phosphoinositide-3-kinase regulatory subunit 2 (beta) HUGO:PIK3R2 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 phosphoinositide-3-kinase regulatory subunit 3 (gamma) HUGO:PIK3R3 HGNC:8981 ENTREZ:8503 UNIPROT:Q92569 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:16847462 PMID:19568798 PMID:12040186 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC1-regulator*"/> <clone/> <bbox w="114.0" h="19.0" x="5020.5" y="1090.0"/> </glyph> </glyph> <glyph class="complex" id="s2352_emtc_emtc_csa354" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Collagen1 partners*:Collagen1* Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(Collagen1/Collagen1 partners)"/> <bbox w="187.0" h="66.0" x="4830.0" y="6451.0"/> <glyph class="macromolecule" id="emtc_emtc_s4715_emtc_emtc_sa2494"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Collagen 1* collagen, type I, alpha 1 HUGO:COL1A1 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023, UNIPROT:P08123 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen1*"/> <bbox w="79.0" h="20.0" x="4886.75" y="6457.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4714_emtc_emtc_sa2495"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: a1b1*_a2b1* NAME:a1b1* ITGA1/ITGB1 integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME: a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen1 partners*"/> <bbox w="132.0" h="20.0" x="4855.75" y="6478.0"/> </glyph> </glyph> <glyph class="complex" id="s2353_emtc_emtc_csa361" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:IGF family*:IGF1R Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="(IGF family/IGF1R)"/> <bbox w="100.0" h="120.0" x="1824.0" y="5993.5"/> <glyph class="macromolecule" id="s2354_emtc_emtc_sa2532"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: IGF family* insulin-like growth factor 1 (somatomedin C) HUGO:IGF1 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 insulin-like growth factor 2 (somatomedin A) HUGO:IGF2 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF family*"/> <bbox w="70.0" h="19.0" x="1839.0" y="6005.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4768_emtc_emtc_sa2534"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: insulin-like growth factor 1 receptor HUGO:IGF1R HGNC:5465 ENTREZ:3480 UNIPROT:P08069 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF1R"/> <bbox w="86.0" h="56.0" x="1831.0" y="6028.5"/> <glyph class="unit of information" id="_21516002-4f4e-42e0-b6d0-a03d451eb4c7"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1864.0" y="6023.5"/> </glyph> <glyph class="state variable" id="_cb2c91a6-2dfe-447a-afe6-1e0da0e710bf"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="1867.3944" y="6023.5"/> </glyph> <glyph class="unit of information" id="_dcedafff-909e-4e57-89d9-3e479276ce4d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1851.5" y="6023.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="emtc_emtc_s147_emtc_emtc_sa143" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="degradation of CRB3"/> <bbox w="30.0" h="30.0" x="3662.0" y="1378.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s988_emtc_emtc_sa686" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of RHOA by Ubiquitin-Proteasome complex"/> <bbox w="30.0" h="30.0" x="3557.0" y="1386.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s989_emtc_emtc_sa687" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of PALS1"/> <bbox w="30.0" h="30.0" x="3607.0" y="1258.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s1327_emtc_emtc_sa694" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Proteasomal degradation of TWIST1"/> <bbox w="30.0" h="30.0" x="3536.0" y="1382.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s1614_emtc_emtc_sa868" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of HIF1A by Ubiquitin/Proteasome pathway"/> <bbox w="30.0" h="30.0" x="3617.0" y="1385.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s1956_emtc_emtc_sa962" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of phosphorylated Snai1"/> <bbox w="30.0" h="30.0" x="3469.0" y="1315.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s1968_emtc_emtc_sa972" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of cyclin D1 after in nucleus phosphorylated by GSK3B"/> <bbox w="30.0" h="30.0" x="3518.0" y="1374.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s1971_emtc_emtc_sa974" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of Cyclin E after in nucleus phosphorylation by GSK3B or CDK2"/> <bbox w="30.0" h="30.0" x="3496.0" y="1368.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s2042_emtc_emtc_sa978" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Degradation of beta-catenin upon phosphorylation by GSK3B"/> <bbox w="30.0" h="30.0" x="3480.0" y="1353.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s2899_emtc_emtc_sa1407" compartmentRef="emtc_emtc_c24_emtc_emtc_ca24"> <label text="CRB3 degradation by endocytosis"/> <bbox w="30.0" h="30.0" x="1525.25" y="1424.0"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s3046_emtc_emtc_sa1554" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>References_begin: PMID:11989976 PMID:17959595 Caspase1,3 promote proteosomal degradation of ARHGDIB References_end</body> </html> </notes> <label text="ARHGDIB proteosomal degradation"/> <bbox w="30.0" h="30.0" x="3713.0" y="1291.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s3758_emtc_emtc_sa1874" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Proteasomal degradation of TGFBR1"/> <bbox w="30.0" h="30.0" x="3689.0" y="1372.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s3855_emtc_emtc_sa1938" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="p53 degradation in proteasome by MDM2"/> <bbox w="30.0" h="30.0" x="3710.0" y="1358.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s3861_emtc_emtc_sa1942" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="p53 is required for protosomal degradation of SNAI2 by MDM2"/> <bbox w="30.0" h="30.0" x="3641.0" y="1384.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s3967_emtc_emtc_sa2038" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Proteasomal degradation of I-SMAD*"/> <bbox w="30.0" h="30.0" x="3596.0" y="1388.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s4288_emtc_emtc_sa2074" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="Protosomal degradation of p27KIP1*"/> <bbox w="30.0" h="30.0" x="3469.0" y="1337.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s4344_emtc_emtc_sa2157" compartmentRef="emtc_emtc_c41_emtc_emtc_ca41"> <label text="p53 nuclear proteasomal degradation"/> <bbox w="30.0" h="30.0" x="4292.0" y="2197.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s4345_emtc_emtc_sa2158" compartmentRef="emtc_emtc_c41_emtc_emtc_ca41"> <label text="NICD nuclear prteasomal degradation"/> <bbox w="30.0" h="30.0" x="4257.0" y="2211.5"/> </glyph> <glyph class="source and sink" id="emtc_emtc_s4811_emtc_emtc_sa2565" compartmentRef="emtc_emtc_c21_emtc_emtc_ca21"> <label text="E-Cadherin degradation in lysosome"/> <bbox w="30.0" h="30.0" x="931.0" y="1634.0"/> </glyph> <glyph class="source and sink" id="s2367_sa2065" compartmentRef="emtc_emtc_c36_emtc_emtc_ca36"> <label text="s2367"/> <bbox w="30.0" h="30.0" x="3737.0" y="1344.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1_emtc_emtc_sa1" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="40.0" h="20.0" x="3187.5" y="3694.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2_emtc_emtc_sa3" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="40.0" h="20.0" x="3082.5" y="4044.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3_emtc_emtc_sa4" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 ZEB1 inhibits MIR200 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1"/> <bbox w="40.0" h="20.0" x="3769.0" y="3872.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4_emtc_emtc_sa5" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB2"/> <bbox w="40.0" h="20.0" x="2991.5" y="3925.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s5_emtc_emtc_sa6" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: itwist homolog 1 (Drosophila) HUGO:TWIST1 HGNC:12428, ENTREZ:7291, GENECARDS:GC07M019121 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TWIST1"/> <bbox w="60.0" h="20.0" x="3054.5" y="3694.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s11_emtc_emtc_sa12" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 3 (stromelysin 1, progelatinase) HUGO:MMP3, HGNC:7173, ENTREZ:4314, GENECARDS:GC11M102706 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP3"/> <bbox w="39.5" h="20.0" x="2561.5" y="4879.688"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s16_emtc_emtc_sa17" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: itwist homolog 2 (Drosophila) HUGO:TWIST2, HGNC:20670, ENTREZ:117581, GENECARDS:GC02P239757 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TWIST2"/> <bbox w="60.0" h="20.0" x="3639.0" y="3692.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s42_emtc_emtc_sa43" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 1 (interstitial collagenase) HUGO:MMP1, HGNC:7155, ENTREZ:4312, GENECARDS:GC11M102660 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP1"/> <bbox w="40.0" h="20.0" x="2561.0" y="4800.562"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s43_emtc_emtc_sa44" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA, HGNC:12680, ENTREZ:7422, GENECARDS:GC06P043737 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:11166270 VEGF stands for the vascular Endothelial Growth Factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults PMID:13678960 VEGFs belong to a family of homodimeric glycoproteins that containts five members (VEGF-A, B, C, D, and Placenta growth factor PLGF). VEGFs bind to 3 different VEGF-receptor tyrosine kinases (VEGFR-1, 2, 3). Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular functions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFA"/> <bbox w="40.0" h="19.5" x="4534.0" y="5030.375"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s54_emtc_emtc_sa711" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 200a HUGO:MIR200A, HGNC:31578, ENTREZ:406983, GENECARDS:GC01P001101 microRNA 200b HUGO:MIR200B, HGNC:31579, ENTREZ:406984, GENECARDS:GC01P001100 microRNA 200c HUGO:MIR200C, HGNC:31580, ENTREZ:406985, GENECARDS:GC12P007072 microRNA 141 HUGO:MIR141, HGNC:31528, ENTREZ:406933, GENECARDS:GC12P007073 microRNA 429 HUGO:MIR429, HGNC:13784, ENTREZ:554210, GENECARDS:GC01P001109 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 p53 activates MIR200C PMID:21483453 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR200*"/> <bbox w="60.0" h="20.0" x="2945.5" y="4410.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s68_emtc_emtc_sa65" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, GENECARDS:GC19M001609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TCF3"/> <bbox w="40.0" h="20.0" x="3423.0" y="4266.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s71_emtc_emtc_sa68" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="20.0" x="2378.0" y="3350.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s75_emtc_emtc_sa72" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: crumbs homolog 3 (Drosophila) HUGO:CRB3, HGNC:20237, ENTREZ:92359, GENECARDS:GC19P006414 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3"/> <bbox w="40.0" h="20.0" x="4431.5" y="2865.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s77_emtc_emtc_sa74" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: InaD-like (Drosophila) HUGO:INADL, HGNC:28881, ENTREZ:10207, GENECARDS:GC01P062208 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 PATJ* is target of and thus repressed by ZEB1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PATJ*"/> <bbox w="40.0" h="20.0" x="4429.5" y="2795.25"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s80_emtc_emtc_sa77" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="60.0" h="20.0" x="2409.0" y="2534.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s83_emtc_emtc_sa80" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 7 HUGO:CLDN7, HGNC:2049, ENTREZ:1366, GENECARDS:GC17M007163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin7*"/> <bbox w="60.0" h="20.0" x="2409.0" y="3114.582"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s86_emtc_emtc_sa83" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="40.0" h="20.0" x="2429.0" y="2420.9"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s89_emtc_emtc_sa86" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO3*"/> <bbox w="40.0" h="20.0" x="2429.0" y="2639.36"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s93_emtc_emtc_sa89" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 2, 26kDa HUGO:GJB2, HGNC:4284, ENTREZ:2706, GENECARDS:GC13M020761 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB2"/> <bbox w="38.0" h="20.0" x="2473.0" y="4482.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s96_emtc_emtc_sa92" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 3, 31kDa HUGO:GJB3, HGNC:4285, ENTREZ:2707, GENECARDS:GC01P035246 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB3"/> <bbox w="38.0" h="19.0" x="2473.0" y="4510.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s99_emtc_emtc_sa95" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, GENECARDS:GC07P073213 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin4*"/> <bbox w="60.0" h="20.0" x="2409.0" y="3029.512"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s102_emtc_emtc_sa98" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, GENECARDS:GC06P007541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoplakin*"/> <bbox w="100.0" h="20.0" x="2411.0" y="4457.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s105_emtc_emtc_sa101" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, GENECARDS:GC11P000394 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin3*"/> <bbox w="100.0" h="20.0" x="2411.0" y="4419.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s108_emtc_emtc_sa104" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, GENECARDS:GC18M025465 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="N-Cadherin*"/> <bbox w="80.0" h="20.0" x="2394.5" y="3842.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s111_emtc_emtc_sa107" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, GENECARDS:GC16P068679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="P-Cadherin*"/> <bbox w="80.0" h="20.0" x="2394.5" y="3922.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s114_emtc_emtc_sa110" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, GENECARDS:GC10P017310 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Vimentin is a putative direct HIF1 target gene http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vimentin*"/> <bbox w="60.0" h="20.0" x="4307.5" y="2929.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s117_emtc_emtc_sa113" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, GENECARDS:GC20P059827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="R-Cadherin*"/> <bbox w="80.0" h="20.0" x="2394.5" y="4002.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s120_emtc_emtc_sa116" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, GENECARDS:GC18M028670 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocollin2*"/> <bbox w="100.0" h="20.0" x="2396.5" y="4181.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s123_emtc_emtc_sa119" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) HUGO:MMP2, HGNC:7166, ENTREZ:4313, GENECARDS:GC16P055478 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP2"/> <bbox w="39.5" h="20.0" x="2561.5" y="4840.125"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s127_emtc_emtc_sa123" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) HUGO:MMP9, HGNC:7176, ENTREZ:4318, GENECARDS:GC20P044637 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP9"/> <bbox w="39.5" h="20.0" x="2558.5" y="4945.25"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s131_emtc_emtc_sa127" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 14 (membrane-inserted) HUGO:MMP14, HGNC:7160, ENTREZ:4323, GENECARDS:GC14P023305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP14"/> <bbox w="40.0" h="20.0" x="2558.0" y="5056.375"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s133_emtc_emtc_sa129" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="69.0" h="20.5" x="2532.0" y="5095.938"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s144_emtc_emtc_sa140" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: membrane protein, palmitoylated 5 (MAGUK p55 subfamily member 5) HUGO:MPP5, HGNC:18669, ENTREZ:64398, GENECARDS:GC14P067708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PALS1*"/> <bbox w="60.0" h="20.0" x="2409.0" y="2313.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s179_emtc_emtc_sa166" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: calcium/calmodulin-dependent serine protein kinase (MAGUK family) HUGO:CASK, HGNC:1497, ENTREZ:8573, GENECARDS:GC0XM041374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN2*"/> <bbox w="40.0" h="20.0" x="4310.5" y="3285.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s182_emtc_emtc_sa169" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lin-7 homolog C (C. elegans) HUGO:LIN7C, HGNC:17789, ENTREZ:55327, GENECARDS:GC11M027472 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN7C"/> <bbox w="35.0" h="17.0" x="4310.5" y="3347.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s185_emtc_emtc_sa172" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: chromosome 16 open reading frame 70 HUGO:C16orf70, HGNC:29564, ENTREZ:80262, GENECARDS:GC16P067143 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN10*"/> <bbox w="55.0" h="17.0" x="4310.5" y="3241.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s250_emtc_emtc_sa701" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 106b HUGO:MIR106B, HGNC:31495, ENTREZ:406900, GENECARDS:GC07M099695 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. PMID:19726885 PMID:22286770 PMID:21386132 The miR-17 family consists of 3 paralogous polycistronic clusters on different chromosomes: miR-17/92 (miR-17, miR-18a, miR-19a, miR-20a, miR-19b- 1, and miR-92a-1), miR-106b/25 (miR-106b, miR-93, and miR-25) and miR-106a/363 (miR-106a, miR-18b, miR-20b, miR-19b-2, miR-92a-2, and miR-363). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR106B_25*"/> <bbox w="84.0" h="20.0" x="2945.5" y="4471.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s285_emtc_emtc_sa243" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA1"/> <bbox w="40.0" h="20.0" x="3505.5" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s286_emtc_emtc_sa244" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2"/> <bbox w="40.0" h="20.0" x="3552.76" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s287_emtc_emtc_sa245" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2B"/> <bbox w="40.0" h="20.0" x="3600.02" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s288_emtc_emtc_sa246" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA3"/> <bbox w="40.0" h="20.0" x="3650.28" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s289_emtc_emtc_sa247" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="40.0" h="20.0" x="3697.54" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s290_emtc_emtc_sa248" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="40.0" h="20.0" x="3744.799" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s291_emtc_emtc_sa249" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="40.0" h="20.0" x="3792.059" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s292_emtc_emtc_sa250" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 7 HUGO:ITGA7 HGNC:6143 ENTREZ:3679 UNIPROT:Q13683 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA7"/> <bbox w="40.0" h="20.0" x="3839.316" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s293_emtc_emtc_sa251" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 8 HUGO:ITGA8 HGNC:6144 ENTREZ:8516 UNIPROT:P53708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA8"/> <bbox w="40.0" h="20.0" x="3886.576" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s294_emtc_emtc_sa252" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 9 HUGO:ITGA9 HGNC:6145 ENTREZ:3680 UNIPROT:Q13797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA9"/> <bbox w="40.0" h="20.0" x="3933.836" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s295_emtc_emtc_sa253" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA10"/> <bbox w="40.0" h="20.0" x="3981.096" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s296_emtc_emtc_sa254" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 11 HUGO:ITGA11 HGNC:6136 ENTREZ:22801 UNIPROT:Q9UKX5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA11"/> <bbox w="40.0" h="20.0" x="4032.355" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s297_emtc_emtc_sa255" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha D HUGO:ITGAD HGNC:6146 ENTREZ:3681 UNIPROT:Q13349 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAD"/> <bbox w="40.0" h="20.0" x="4083.615" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s298_emtc_emtc_sa256" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha E (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide) HUGO:ITGAE HGNC:6147 ENTREZ:3682 UNIPROT:P38570 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAE"/> <bbox w="40.0" h="20.0" x="4130.875" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s299_emtc_emtc_sa257" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide) CD11A HUGO:ITGAL HGNC:6148 ENTREZ:3683 UNIPROT:P20701 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAL"/> <bbox w="40.0" h="20.0" x="4178.135" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s300_emtc_emtc_sa258" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha M (complement component 3 receptor 3 subunit) CD11B, CR3A, "integrin, alpha M (complement component receptor 3, alpha; also known as CD11b (p170), macrophage antigen alpha polypeptide)" HUGO:ITGAM HGNC:6149 ENTREZ:3684 UNIPROT:P11215 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAM"/> <bbox w="40.0" h="20.0" x="4225.395" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s301_emtc_emtc_sa259" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha X (complement component 3 receptor 4 subunit) CD11C, "integrin, alpha X (antigen CD11C (p150), alpha polypeptide)" HUGO:ITGAX HGNC:6152 ENTREZ:3687 UNIPROT:P20702 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAX"/> <bbox w="40.0" h="20.0" x="4272.654" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s302_emtc_emtc_sa260" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4319.914" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s303_emtc_emtc_sa261" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) FNRB, MDF2, MSK12 HUGO:ITGB1 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4367.174" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s304_emtc_emtc_sa262" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2 HGNC:6155 ENTREZ:3689 UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16716598 PMID:15235127 Hypoxia induces leukocyte beta-2 integrin expression and function by transcriptional mechanisms dependent upon HIF-1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4414.434" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s305_emtc_emtc_sa263" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="4461.691" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s306_emtc_emtc_sa264" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB4"/> <bbox w="40.0" h="20.0" x="4508.953" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s307_emtc_emtc_sa265" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB5"/> <bbox w="40.0" h="20.0" x="4556.21" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s308_emtc_emtc_sa266" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 6 HUGO:ITGB6 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB6"/> <bbox w="40.0" h="20.0" x="4603.47" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s309_emtc_emtc_sa267" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="40.0" h="20.0" x="4650.73" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s310_emtc_emtc_sa268" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 8 HUGO:ITGB8 HGNC:6163 ENTREZ:3696 UNIPROT:P26012 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB8"/> <bbox w="40.0" h="20.0" x="4697.99" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s417_emtc_emtc_sa713" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 1-1 HUGO:MIR1-1, HGNC:31499, ENTREZ:406904, GENECARDS:GC20P061153 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR1-1"/> <bbox w="60.0" h="20.0" x="2945.5" y="4961.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s452_emtc_emtc_sa365" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 1 "MAD, mothers against decapentaplegic homolog 1 (Drosophila)", MADH1, "SMAD, mothers against DPP homolog 1 (Drosophila)" HUGO:SMAD1 HGNC:6767 ENTREZ:4086 UNIPROT:Q15797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD1"/> <bbox w="60.0" h="19.0" x="4565.0" y="4139.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s454_emtc_emtc_sa367" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 2 "MAD, mothers against decapentaplegic homolog 2 (Drosophila)", MADH2, "SMAD, mothers against DPP homolog 2 (Drosophila)" HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="58.0" h="22.0" x="4565.0" y="4011.375"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s456_emtc_emtc_sa369" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 3 "MAD, mothers against decapentaplegic homolog 3 (Drosophila)", MADH3, "SMAD, mothers against DPP homolog 3 (Drosophila)" HUGO:SMAD3 HGNC:6769 ENTREZ:4088 UNIPROT:P84022 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="53.0" h="20.0" x="4565.0" y="3946.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s458_emtc_emtc_sa371" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 4 "MAD, mothers against decapentaplegic homolog 4 (Drosophila)", MADH4, "SMAD, mothers against DPP homolog 4 (Drosophila)" HUGO:SMAD4 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="4571.0" y="4513.75"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s461_emtc_emtc_sa374" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 5 "MAD, mothers against decapentaplegic homolog 5 (Drosophila)", MADH5, "SMAD, mothers against DPP homolog 5 (Drosophila)" HUGO:SMAD5 HGNC:6771 ENTREZ:4090 UNIPROT:Q99717 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD5"/> <bbox w="59.0" h="21.0" x="4565.0" y="4086.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s464_emtc_emtc_sa377" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD6"/> <bbox w="60.0" h="20.0" x="4565.0" y="4258.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s467_emtc_emtc_sa380" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD7"/> <bbox w="60.0" h="20.0" x="4565.0" y="4291.25"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s470_emtc_emtc_sa383" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 9 "MAD, mothers against decapentaplegic homolog 9 (Drosophila)", MADH9, "SMAD, mothers against DPP homolog 9 (Drosophila)" HUGO:SMAD9 HGNC:6774 ENTREZ:4093 UNIPROT:O15198 GENECARDS:GC13M037418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD9"/> <bbox w="60.0" h="20.0" x="4565.0" y="4113.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s540_emtc_emtc_sa426" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="63.0" h="18.0" x="2406.0" y="2347.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s579_emtc_emtc_sa440" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19597490 CAR: a tight-junction-associated cell adhesion molecule CAR is downregulated in human cancer and in TGF-b-induced EMT PMID:15820557 CAR: a virus receptor within the tight junction CAR: a transmembrane protein PMID:12727824 CAR: down-stream target of Rag-MEK-ERK pathway PMID:16542650 In epithelial cell, CAR localizes with ZO1 and Occludin References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: coxsackie virus and adenovirus receptor HUGO:CXADR, HGNC:2559, ENTREZ:1525, GENECARDS:GC21P018884 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:19597490 CAR: a tight-junction-associated cell adhesion molecule CAR is downregulated in human cancer and in TGF-b-induced EMT PMID:15820557 CAR: a virus receptor within the tight junction CAR: a transmembrane protein PMID:12727824 CAR: down-stream target of Rag-MEK-ERK pathway PMID:16542650 In epithelial cell, CAR localizes with ZO1 and OccludinMaps_Modules_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CAR*"/> <bbox w="40.0" h="20.0" x="2429.0" y="2498.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s584_emtc_emtc_sa446" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="40.0" h="16.0" x="2429.0" y="2568.277"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s587_emtc_emtc_sa449" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 1 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO2*"/> <bbox w="40.0" h="20.0" x="2429.0" y="2603.818"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s590_emtc_emtc_sa452" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="60.0" h="20.0" x="2409.0" y="2843.25"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s611_emtc_emtc_sa465" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) HUGO:CDKN2B, HGNC:1788, ENTREZ:1030, GENECARDS:GC09M021992 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p15INK4B*"/> <bbox w="72.0" h="20.0" x="3542.334" y="2122.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s650_emtc_emtc_sa492" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Human cells contain multiple loci encoding CDKs and cyclins (13 and 25 loci, respectively). A subset of CDK–cyclin complexes is directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="64.0" h="20.0" x="2806.0" y="2518.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s652_emtc_emtc_sa494" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="56.0" h="19.0" x="2781.0" y="2058.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s663_emtc_emtc_sa506" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1A (p21, Cip1) HUGO:CDKN1A, HGNC:1784, ENTREZ:1026, GENECARDS:GC06P036649 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9618481 p21 is regulated by 3 classes of signals that result in arrest of cell growth: (i) p53 (activated by DNA damage), p73, or the tumor suppressor protein BRCA1. (ii) Extracellular growth factors acting in a p53-independent mechanism, e.g. TGFB (iii) Factors that induce cellular differentiation -Smad4 transactivated the proximal p21 promoter 1.3-fold -Smad2 transactivated the proximal p21 promoter 3-fold -Smad2/4 transactivated the proximal p21 promoter 12-fold -Smad3 transactivated the proximal p21 promoter 25-fold -Smad3/Smad2 transactivated the proximal p21 promoter 40-fold -Smad3/Smad4 transactivated the proximal p21 promoter 110-fold -Smad2/Smad3/Smad4 transactivated the proximal p21 promoter 140-fold Smad proteins act as Transcriptional Activators via functional interactions with the Transcription factor Sp1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p21CIP1*"/> <bbox w="66.0" h="19.0" x="3437.666" y="2123.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s667_emtc_emtc_sa508" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin E1 HUGO:CCNE1, HGNC:1589, ENTREZ:898, GENECARDS:GC19P030302 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinE1*"/> <bbox w="60.0" h="20.0" x="2891.0" y="2519.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s695_emtc_emtc_sa525" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL1A2"/> <bbox w="60.0" h="20.0" x="4745.25" y="5197.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s786_emtc_emtc_sa588" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 13 (membrane-inserted) HUGO:MMP13, HGNC:7159, ENTREZ:4322, GENECARDS:GC11M102847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP13"/> <bbox w="40.0" h="20.0" x="2558.0" y="5016.812"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1328_emtc_emtc_sa695" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) HUGO:ETS1, HGNC:3488, ENTREZ:2113, GENECARDS:GC11M128328 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16391805 Ets-1 is a transcription factor Ets-1 involves in inducing MMP2 expression by EMT in human squamous carcinoma cells References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ETS1"/> <bbox w="40.0" h="20.0" x="2561.0" y="4761.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1335_emtc_emtc_sa702" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 21 HUGO:MIR21, HGNC:31586, ENTREZ:406991, GENECARDS:GC17P057918 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR21"/> <bbox w="60.0" h="20.0" x="2945.5" y="5022.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1336_emtc_emtc_sa703" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 205 HUGO:MIR205, HGNC:31583, ENTREZ:406988, GENECARDS:GC01P209605 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR205"/> <bbox w="60.0" h="20.0" x="2945.5" y="4593.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1339_emtc_emtc_sa707" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 192 HUGO:MIR192, HGNC:31562, ENTREZ:406967, GENECARDS:GC11M064676 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR192"/> <bbox w="60.0" h="20.0" x="2945.5" y="4715.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1340_emtc_emtc_sa708" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 34a HUGO:MIR34A, HGNC:31635, ENTREZ:407040, GENECARDS:GC01M009211 microRNA 34b HUGO:MIR34B, HGNC:31636, ENTREZ:407041, GENECARDS:GC11P111383 microRNA 34c HUGO:MIR34C, HGNC:31637, ENTREZ:407042, GENECARDS:GC11P111384 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34*"/> <bbox w="60.0" h="20.0" x="2945.5" y="5144.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1345_emtc_emtc_sa715" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 31 HUGO:MIR31, HGNC:31630, ENTREZ:407035, GENECARDS:GC09M021507 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR31"/> <bbox w="60.0" h="20.0" x="2945.5" y="4900.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1348_emtc_emtc_sa718" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 449a HUGO:MIR449A, HGNC:27645, ENTREZ:554213, GENECARDS:GC05M054466 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR449A"/> <bbox w="60.0" h="20.0" x="2945.5" y="4839.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1352_emtc_emtc_sa722" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 34a HUGO:MIR34A, HGNC:31635, ENTREZ:407040, GENECARDS:GC01M009211 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR34A"/> <bbox w="60.0" h="20.0" x="2945.5" y="5083.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1428_emtc_emtc_sa792" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF1"/> <bbox w="40.0" h="20.0" x="4534.0" y="5082.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1443_emtc_emtc_sa796" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: kinase insert domain receptor (a type III receptor tyrosine kinase) HUGO:KDR, HGNC:6307, ENTREZ:3791, GENECARDS:GC04M055944 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:11166270 VEGFR2 is highly specific towards VEGFA. PMID:11741095 PMID:13678960 However VEGFR2 also binds to processed forms of VEGF-C, D, E. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR2*"/> <bbox w="60.0" h="20.0" x="4534.0" y="4985.84"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1600_emtc_emtc_sa855" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 14 HUGO:KRT14, HGNC:6416, ENTREZ:3861, GENECARDS:GC17M039738 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT14"/> <bbox w="60.0" h="20.0" x="4310.5" y="3125.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1603_emtc_emtc_sa858" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT18"/> <bbox w="60.0" h="20.0" x="4310.5" y="3085.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1606_emtc_emtc_sa861" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 19 HUGO:KRT19, HGNC:6436, ENTREZ:3880, GENECARDS:GC17M039679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19, Vimentin are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT19"/> <bbox w="60.0" h="20.0" x="4309.5" y="3045.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1615_emtc_emtc_sa869" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 3 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, GENECARDS:GC14M076424 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:11790723 Whereas TGFB1 and 2 are proscarring growth factors, TGFB3 is antiscarring TGFB1, 2, and 3 are embryonically expressed in skin and up-regulated at adult wound sites Overlapping expression patterns of HIF1Aand TGFB3 in vivo TGFB1 mRNA expression was serum- but not hypoxia-inducible. In contrast, TGF-b3 mRNA expression was hypoxia-inducible, but not serum- inducible TGFB3 might be a HIF1A target gene References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB3"/> <bbox w="40.0" h="20.0" x="4534.0" y="5139.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1617_emtc_emtc_sa871" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fms-related tyrosine kinase 1 HUGO:FLT1, HGNC:3763, ENTREZ:2321, GENECARDS:GC13M028874 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11528470 VEGFR1 (FLT1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, EG-VEGF, and Erythoproietin PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 PMID:1312256 PMID:7929268 PMID:9751730 VEGFR1 is a hight-affinnity receptor for VEGF-A, B and PLGF PMID:11166270 PMID:11312109 VEGFR1 is expressed in vascular endothelial and some non-endothelial cells including harmatopoietic stem cells, macrophages and monocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR1*"/> <bbox w="60.0" h="20.0" x="4534.0" y="4932.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1620_emtc_emtc_sa874" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: prokineticin 1 HUGO:PROK1, HGNC:18454, ENTREZ:84432, GENECARDS:GC01P110994 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11528470 EG-VEGF (Prokinecticin 1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, VEGFR1, and Erythoproietin PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EG-VEGF*"/> <bbox w="60.0" h="20.0" x="4534.0" y="4892.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2150_emtc_emtc_sa1015" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-3 partitioning defective 3 homolog (C. elegans) HUGO:PARD3, HGNC:16051, ENTREZ:56288, GENECARDS:GC10M034438 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR3*"/> <bbox w="38.0" h="18.0" x="2431.0" y="2394.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2459_emtc_emtc_sa1290" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, GENECARDS:GC03M190023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1*"/> <bbox w="62.0" h="16.0" x="2407.0" y="2714.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2461_emtc_emtc_sa1292" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="60.0" h="17.0" x="2409.0" y="2779.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2878_emtc_emtc_sa1399" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D3 HUGO:CCND3, HGNC:1585, ENTREZ:896, GENECARDS:GC06M041949 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21777377 Further studies are required to investigate the mechanism by which Cx31.1 repress cyclin D3 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD3*"/> <bbox w="60.0" h="20.0" x="2644.0" y="2518.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2935_emtc_emtc_sa1440" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN HUGO:PTEN, HGNC:9588, ENTREZ:5728, UNIPROT:P60484, GENECARDS:GC10P089613 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTEN"/> <bbox w="42.0" h="17.0" x="4039.0" y="2059.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2937_emtc_emtc_sa1442" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D2 HUGO:CCND2, HGNC:1583, ENTREZ:894, GENECARDS:GC12P004382 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD2*"/> <bbox w="57.0" h="18.0" x="2729.0" y="2518.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3700_emtc_emtc_sa1833" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYC"/> <bbox w="36.0" h="18.0" x="3248.0" y="2460.25"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3714_emtc_emtc_sa1844" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 183 HUGO:MIR183, HGNC:31554, ENTREZ:406959, GENECARDS:GC07M129416 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR183"/> <bbox w="56.0" h="20.0" x="2945.5" y="4654.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3739_emtc_emtc_sa1861" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="53.0" h="21.0" x="4570.0" y="3792.291"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3742_emtc_emtc_sa1862" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: microRNA 30E HUGO:MIR30E, HGNC:31629, ENTREZ:407034, GENECARDS:GC01P041220 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="57.0" h="23.0" x="2945.5" y="4776.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3793_emtc_emtc_sa1878" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, epsilon HUGO:PRKCE, HGNC:9401, ENTREZ:5581, UNIPROT:Q02156, GENECARDS:GC02P045790 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCE"/> <bbox w="46.0" h="20.0" x="2552.0" y="5133.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3819_emtc_emtc_sa1906" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21224848 PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1"/> <bbox w="37.0" h="17.0" x="2404.0" y="4101.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3820_emtc_emtc_sa1910" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOX2"/> <bbox w="70.0" h="25.0" x="4083.0" y="4623.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3844_emtc_emtc_sa1928" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2A HUGO:CDKN2A, HGNC:1787, ENTREZ:1029, GENECARDS:GC09M021957, UNIPROT:P42771 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:20818389 Physical interaction between BMI1 and TWIST1 E-Cadherin repression by cooperative BMI1 and TWIST1 p16INK4A repression by cooperative BMI1 and TWIST1 PMID:23140366 p16INK4A expression induced by ROS PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF PMID:24954210 RAS activates p16 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDKN2A"/> <bbox w="52.0" h="18.0" x="3653.0" y="2120.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3866_emtc_emtc_sa1948" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box C2 (MFH-1, mesenchyme forkhead 1) HUGO:FOXC2, HGNC:3801, ENTREZ:2303 , UNIPROT:Q99958 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17537911 Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXC2"/> <bbox w="43.0" h="19.0" x="3423.0" y="4343.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3870_emtc_emtc_sa1952" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 1, dominant negative helix-loop-helix protein HUGO:ID1, HGNC:5360, ENTREZ:3397 , UNIPROT:P41134 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17490644 Snai1 and TCF3 (E47) upregulate both mRNA and protein level of ID1 This upregulation depends on SP1 or AP1 co-transcription factors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID1"/> <bbox w="32.0" h="18.0" x="3925.0" y="4338.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3873_emtc_emtc_sa1955" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="44.0" h="16.0" x="2554.0" y="5203.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3885_emtc_emtc_sa1968" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: endothelin 1 HUGO:EDN1, HGNC:3176, ENTREZ:1906, GENECARDS:GC06P012290, UNIPROT:P05305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9588211 Endothelin1 is target gene of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Endothelin1*"/> <bbox w="87.0" h="18.0" x="4534.0" y="4806.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3888_emtc_emtc_sa1971" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 2, dominant negative helix-loop-helix protein HUGO:ID2, HGNC:5361, ENTREZ:3398, UNIPROT:Q02363, GENECARDS:GC02P008818 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11708773 PMID:15252039 ID2 is target of HIF1 upon hypoxic conditions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID2"/> <bbox w="28.0" h="18.0" x="3925.0" y="4386.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3906_emtc_emtc_sa1990" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: activating transcription factor 3 HUGO:ATF3, HGNC:785, ENTREZ:467, GENECARDS:GC01P212738, UNIPROT:P18847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ATF3"/> <bbox w="35.0" h="17.0" x="3925.0" y="4291.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3928_emtc_emtc_sa2009" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: jun B proto-oncogene HUGO:JUNB, HGNC:6205, ENTREZ:3726, GENECARDS:GC19P012902, UNIPROT:P17275 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JUNB"/> <bbox w="42.0" h="19.0" x="3423.0" y="4208.25"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3984_emtc_emtc_sa2056" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="70.0" h="25.0" x="3649.0" y="2301.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3986_emtc_emtc_sa2058" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="70.0" h="25.0" x="3097.0" y="3566.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3988_emtc_emtc_sa2060" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 2 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC2"/> <bbox w="46.0" h="18.0" x="2488.0" y="3513.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3990_emtc_emtc_sa2062" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SIN3 transcription regulator homolog A (yeast) SIN3A HUGO:SIN3A HGNC:19353 ENTREZ:25942 UNIPROT:Q96ST3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. 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</glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3994_emtc_emtc_sa2067" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: beta catenin HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="81.0" h="20.0" x="2393.0" y="3898.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4290_emtc_emtc_sa2076" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html 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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 3, dominant negative helix-loop-helix protein HUGO:ID3, HGNC:5362, ENTREZ:3399, UNIPROT:Q02535, GENECARDS:GC01M023884 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11708773 PMID:15252039 ID2 is target of HIF1 upon hypoxic conditions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID3"/> <bbox w="29.0" h="19.0" x="3925.0" y="4428.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4379_emtc_emtc_sa2186" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 1 HUGO:HEY1, HGNC:4880, ENTREZ:23462, UNIPROT:Q9Y5J3, GENECARDS:GC08M080676 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY1"/> <bbox w="42.0" h="17.0" x="2217.0" y="2175.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4381_emtc_emtc_sa2188" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 2 HUGO:HEY2, HGNC:4881, ENTREZ:23493, UNIPROT:Q9UBP5, GENECARDS:GC06P126068 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY2"/> <bbox w="44.0" h="19.0" x="2215.0" y="2210.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4385_emtc_emtc_sa2192" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: runt-related transcription factor 2 HUGO:RUNX2, HGNC:10427, ENTREZ:860, UNIPROT:Q13950 , GENECARDS:GC06P045295 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RUNX2"/> <bbox w="46.0" h="21.0" x="2214.0" y="2247.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4393_emtc_emtc_sa2199" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP10"/> <bbox w="54.0" h="18.0" x="2555.0" y="4984.75"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4397_emtc_emtc_sa2203" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 2 (Drosophila) "enhancer of zeste (Drosophila) homolog 2" HUGO:EZH2 HGNC:3527 ENTREZ:2146 UNIPROT:Q15910 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH2"/> <bbox w="39.0" h="22.0" x="2560.0" y="3330.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4399_emtc_emtc_sa2205" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 1 (Drosophila) "enhancer of zeste (Drosophila) homolog 1" HUGO:EZH1 HGNC:3526 ENTREZ:2145 UNIPROT:Q92800 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16567498 PMID:17587822 EZH1 and EZH2 are targets of HEYs-mediated transcriptional repression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH1"/> <bbox w="39.0" h="18.0" x="2503.0" y="3250.5"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4426_emtc_emtc_sa2236" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: axin 2 HUGO:AXIN2, HGNC:904, ENTREZ:8313, GENECARDS:GC17M063524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN2"/> <bbox w="50.0" h="20.0" x="2171.0" y="3780.0"/> </glyph> <glyph class="nucleic 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<notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 2 "tissue inhibitor of metalloproteinase 2" HUGO:TIMP2 HGNC:11821 ENTREZ:7077 UNIPROT:P16035 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP2"/> <bbox w="45.0" h="18.0" x="2466.0" y="4660.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4616_emtc_emtc_sa2407" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 3 SFD, "tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory)" HUGO:TIMP3 HGNC:11822 ENTREZ:7078 UNIPROT:P35625 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP3"/> <bbox w="48.0" h="19.0" x="2463.0" y="4694.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4621_emtc_emtc_sa2412" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOS"/> <bbox w="70.0" h="25.0" x="3773.0" y="2979.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4680_emtc_emtc_sa2465" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor alpha polypeptide HUGO:PDGFA HGNC:8799 ENTREZ:5154 UNIPROT:P04085 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFA"/> <bbox w="52.0" h="17.0" x="2459.0" y="4545.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4683_emtc_emtc_sa2468" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFR family*"/> <bbox w="97.0" h="21.0" x="2414.0" y="4570.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4803_emtc_emtc_sa2561" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine phosphatase type IVA, member 3 HUGO:PTP4A3 HGNC:9636 ENTREZ:11156 UNIPROT:O75365 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:24376839 PTP4A3 is implicated in cell adhesion and the regulation of focal adhesion components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. http://d-scholarship.pitt.edu/18634/1/Zimmerman_ETD-2013.pdf c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3. Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTP4A3"/> <bbox w="53.0" h="20.0" x="2458.0" y="4601.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4805_emtc_emtc_sa2563" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUP Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakoglobin*"/> <bbox w="81.0" h="19.0" x="2423.0" y="4368.0"/> </glyph> <glyph class="nucleic acid feature" id="s2364_sa2062" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYB"/> <bbox w="70.0" h="25.0" x="4037.0" y="2646.5"/> </glyph> <glyph class="nucleic acid feature" id="s2368_sa2066" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTSD"/> <bbox w="50.0" h="20.625" x="4302.0" y="3438.375"/> </glyph> <glyph class="nucleic acid feature" id="s2371_sa2069" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:24335145 β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="miR96"/> <bbox w="55.0" h="22.5" x="2944.5" y="5197.75"/> </glyph> <glyph class="nucleic acid feature" id="s2372_sa2070" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:24335145 β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="miR182"/> <bbox w="55.0" h="22.5" x="2944.5" y="5247.75"/> </glyph> <glyph class="nucleic acid feature" id="s2381_sa2079" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BCL2L11 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:18281283 production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIM*"/> <bbox w="70.0" h="25.0" x="4247.0" y="2036.5"/> </glyph> <glyph class="nucleic acid feature" id="s2383_sa2081" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="70.0" h="25.0" x="4377.0" y="2036.5"/> </glyph> <glyph class="nucleic acid feature" id="s2388_sa2086" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: p16INK4a activates the pRB tumor suppressor, which silences certain proproliferative genes by heterochromatinization, thereby instituting a stringent arrest of cell proliferation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RB1"/> <bbox w="45.0" h="22.0" x="2619.5" y="2027.75"/> </glyph> <glyph class="nucleic acid feature" id="s2393_sa2091" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP7"/> <bbox w="47.0" h="20.0" x="2560.0" y="4912.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s13_emtc_emtc_sa14" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EMT"/> <bbox w="45.0" h="27.0" x="2066.5" y="1028.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s45_emtc_emtc_sa46" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Adherens junctions"/> <bbox w="130.0" h="20.0" x="686.0" y="3326.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s46_emtc_emtc_sa47" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Proliferation"/> <bbox w="100.0" h="20.0" x="2200.0" y="1165.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s47_emtc_emtc_sa48" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cytoskeleton remodeling"/> <bbox w="160.0" h="20.0" x="4581.0" y="2163.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s67_emtc_emtc_sa64" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:22039431 Apoptosis or programmed cell death is a key regulatory process involved in major biological pathways in which its dysregulation is linked to cancer, autoimmunity, and neurodegenerative disorders References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Apoptosis"/> <bbox w="75.0" h="20.0" x="3578.5" y="1149.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s136_emtc_emtc_sa132" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:15151915 Tight cell juntions serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets. Multicellular organisms are separated from the external environment by a layer of epithelial cells The integrity of these epithelial cells is maintained by intercellular junctional complexes (tight junctions, adherens junctions, and desmosomes, whereas gap junctions provide for intercellular communication. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Tight junctions"/> <bbox w="110.0" h="20.0" x="364.0" y="2731.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s137_emtc_emtc_sa133" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmosomes"/> <bbox w="108.0" h="27.0" x="703.5" y="4129.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s138_emtc_emtc_sa134" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Self-renewal"/> <bbox w="117.5" h="20.0" x="2029.25" y="1175.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s139_emtc_emtc_sa135" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Invasiveness"/> <bbox w="117.5" h="20.0" x="2030.25" y="858.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s140_emtc_emtc_sa136" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Metastasis"/> <bbox w="77.5" h="20.0" x="1768.25" y="957.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s143_emtc_emtc_sa139" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Gap junctions"/> <bbox w="100.0" h="20.0" x="732.0" y="5389.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s619_emtc_emtc_sa472" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html 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y="1167.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s910_emtc_emtc_sa658" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Exocytosis"/> <bbox w="80.0" h="20.0" x="376.0" y="3514.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s1417_emtc_emtc_sa787" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Angiogenesis Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:21081489 Angiogenesis is the formation of vessels from the existing vascular structure Angiogenesis is a crucial biological response in wound healing, menstrual cycle, tumor aggression, and diabetic retinopathy. Endothelial sprouting, which requires extracellular matrix remodeling and endothelial cell migration, is the prerequisite process of angiogenic response. Such biological response relies on highly coordinated gene expression in a temporal and spatial manner. Increasing evidence revealed that miRs play a pivotal role in the angiogenic process. miR200b, one member of miR200, is hypoxia-inducible and down-regulates ETS1 transcription factor, subsequently promoting angiogenesis in HMECs. HMECs are Human Microvascular Endothelial Cells PMID:7512751 Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin aVb3 was identified as a marker of angiogenic vascular tissue. Integrin aVb3 was expressed on blood vessels in human wound granulation tissue but not in normal skill. Integrin aVb3 provides a specific trasmembrane signal that potentiates the survival of angiogenic vascular cells in vivo. PMID:19208835 Angiogenesis is the development of new blood vessels from existing ones. Angiogenesis is central to a variety of physiologic phenomena, including tissue growth and repair, fetal development, and the female reproductive cycle Angiogenesis is crucial for supplying oxygen and nutrients to specific pathologic tissues such as neoplasms. PMID:15501236 Angiogenic signals can be matrix attached or freely diffusible Endothelial cells (ECs) are activated by angiogenic factors such as VEGFs or FGF2 upon which they release matrix metalloproteinases that degrade the extracellular matrix in the immediate surrounding. ECs are now free to migrate. ECs align and form tubes that anastomose and to which parenchymal cells are recruited to form stable new blood vessels. Later angiogenic ECs return to quiescenceMaps_Modules_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Angiogenesis"/> <bbox w="85.0" h="20.0" x="4601.5" y="2383.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2848_emtc_emtc_sa1384" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="G0 phase"/> <bbox w="80.0" h="20.0" x="3016.0" y="1167.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2882_emtc_emtc_sa1402" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin polymerization"/> <bbox w="140.0" h="20.0" x="4590.0" y="2274.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2883_emtc_emtc_sa1403" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Microtubule stability"/> <bbox w="140.0" h="20.0" x="4590.0" y="485.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2884_emtc_emtc_sa1404" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Stress fiber formation"/> <bbox w="140.0" h="20.0" x="4754.0" y="484.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2885_emtc_emtc_sa1405" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Lamellipodium formation"/> <bbox w="170.0" h="20.0" x="4930.0" y="485.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2886_emtc_emtc_sa1406" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Filopodium formation"/> <bbox w="140.0" h="20.0" x="5129.0" y="485.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2929_emtc_emtc_sa1431" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CELL_MATRIX_ADHESIONS Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin Laminin-8 interacts with integrins. PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cell-matrix adhesions"/> <bbox w="142.0" h="27.0" x="4336.0" y="6771.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2930_emtc_emtc_sa1432" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cell-cell adhesions"/> <bbox w="137.0" h="38.0" x="366.0" y="1914.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2962_emtc_emtc_sa1463" compartmentRef="emtc_emtc_c24_emtc_emtc_ca24"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: Overexpression of Numb promotes sorting of Notch1 through late endosomes for degradation, whereas depletion of Numb facilitates Notch1 recycling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Endosomal trafficking"/> <bbox w="151.25" h="20.0" x="1465.625" y="1232.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s2974_emtc_emtc_sa1472" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JNK pathway"/> <bbox w="100.0" h="20.0" x="5775.0" y="2396.5"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s3487_emtc_emtc_sa1688" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Membrane spreading"/> <bbox w="145.0" h="22.0" x="1963.5" y="1386.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s3862_emtc_emtc_sa1944" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NF-κB pathway"/> <bbox w="113.0" h="28.0" x="2938.5" y="594.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s3881_emtc_emtc_sa1964" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Hypoxia Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Hypoxia"/> <bbox w="71.0" h="21.0" x="3889.0" y="1631.5"/> </glyph> <glyph class="phenotype" id="s2245_sa1994" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label 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Confidence_begin: Confidence_end</body> </html> </notes> <label text="Clathrin Coated pit"/> <bbox w="130.0" h="25.0" x="591.5" y="1457.5"/> </glyph> <glyph class="phenotype" id="s2247_sa1996" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Clathrin dependent endosomal pathway"/> <bbox w="267.5" h="33.75" x="767.25" y="982.0"/> </glyph> <glyph class="phenotype" id="emtc_emtc_s44_emtc_emtc_sa45" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:TIGHT_JUNCTIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: Migration = motility References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cell motility"/> <bbox w="108.0" h="29.0" x="1862.0" y="1162.5"/> </glyph> <glyph class="phenotype" id="s2307_sa2028" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin mediated endocytosis"/> <bbox w="210.0" h="25.0" x="669.0" y="761.5"/> </glyph> 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</html> </notes> <label text="Senescence"/> <bbox w="90.0" h="25.0" x="2762.0" y="1425.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s6_emtc_emtc_sa7" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: Feedback loops PMID:22514743 PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="50.0" h="20.0" x="3412.5" y="3694.0"/> <glyph class="state variable" id="_e23e2c5c-c7b7-469b-850b-46793822d8d8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3407.5" y="3690.0222"/> </glyph> <glyph class="state variable" id="_94110d78-f49c-462e-90ff-74799fe58a72"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3457.5" y="3690.0508"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s7_emtc_emtc_sa8" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, UNIPROT:O43623, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="40.0" h="20.0" x="3410.5" y="4044.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s8_emtc_emtc_sa9" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, UNIPROT:P37275, GENECARDS:GC10P031648 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 ZEB1 inhibits MIR200 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1"/> <bbox w="40.0" h="20.0" x="3649.0" y="3972.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s9_emtc_emtc_sa10" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, UNIPROT:O60315, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB2"/> <bbox w="40.0" h="20.0" x="2717.5" y="4024.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s10_emtc_emtc_sa11" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: itwist homolog 1 (Drosophila) HUGO:TWIST1 HGNC:12428, ENTREZ:7291, UNIPROT:Q15672, GENECARDS:GC07M019121 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15640618 Twist induces an epithelial-mesenchymal transition to facilitate tumor metastasis. 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id="emtc_emtc_s35_emtc_emtc_sa36" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="117.0" h="55.0" x="4858.5" y="3929.0"/> <glyph class="state variable" id="_5110b031-a53a-466a-bc3c-836112dff2ce"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="4843.5" y="3955.6113"/> </glyph> <glyph class="state 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require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="119.5" h="56.0" x="4864.75" y="3995.5"/> <glyph class="state variable" id="_718d4f01-b385-44fa-9be0-878eeab5b47d"> <state value="" variable="S465"/> <bbox w="30.0" h="10.0" x="4969.25" y="4027.2593"/> </glyph> <glyph class="state variable" id="_f4819af6-a4ab-4403-b170-12e5b38846e7"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="4915.5522" y="4046.5"/> </glyph> <glyph class="state variable" id="_a9eeaa27-12b1-4e0b-822b-dc70536f53b1"> <state value="" variable="S467"/> <bbox w="30.0" h="10.0" x="4969.25" y="4041.2905"/> </glyph> <glyph class="state variable" id="_f14d963f-a861-45e4-b2ce-0d7ebfe1124d"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="4969.25" y="4016.2551"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s41_emtc_emtc_sa42" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 1 "MAD, mothers against decapentaplegic homolog 1 (Drosophila)", MADH1, "SMAD, mothers against DPP homolog 1 (Drosophila)" HUGO:SMAD1 HGNC:6767 ENTREZ:4086 UNIPROT:Q15797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD1"/> <bbox w="60.0" h="20.0" x="4864.75" y="4140.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s48_emtc_emtc_sa49" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 1 (interstitial collagenase) HUGO:MMP1, HGNC:7155, ENTREZ:4312, GENECARDS:GC11M102660, UNIPROT:P08254 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP1"/> <bbox w="40.0" h="20.0" x="2076.0" y="4800.566"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s70_emtc_emtc_sa67" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, UNIPROT:P15923, GENECARDS:GC19M001609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17299729 E47 or TCF3 is upregulated in gastric cancer. PMID:22564737 E47 or TCF3 or EA2 is upregulated in prostate cancer. It could be an upstream regulator of Id1 and c-Myc which are highly expressed in prostate cancer. It could acts as a tumor promoter at least in prostate cancer. PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TCF3"/> <bbox w="40.0" h="20.0" x="3800.5" y="4266.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s73_emtc_emtc_sa70" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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</html> </notes> <label text="ZO3*"/> <bbox w="40.0" h="20.0" x="1105.5" y="2636.36"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s98_emtc_emtc_sa94" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 3, 31kDa HUGO:GJB3, HGNC:4285, ENTREZ:2707, UNIPROT:O75712, GENECARDS:GC01P035246 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB3"/> <bbox w="36.0" h="19.0" x="611.0" y="5742.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s101_emtc_emtc_sa97" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, UNIPROT:O14493, GENECARDS:GC07P073213 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin4*"/> <bbox w="59.0" h="16.75" x="596.0" y="3041.482"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s104_emtc_emtc_sa100" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoplakin*"/> <bbox w="100.0" h="20.0" x="1604.0" y="4798.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s107_emtc_emtc_sa103" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin3*"/> <bbox w="94.0" h="17.0" x="1928.0" y="4421.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s110_emtc_emtc_sa106" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="N-Cadherin*"/> <bbox w="80.0" h="20.0" x="2055.0" y="3842.5"/> <glyph class="state variable" id="_699a546c-c286-47c6-891c-67efe1e36601"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2130.0" y="3857.0654"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s113_emtc_emtc_sa109" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="P-Cadherin*"/> <bbox w="80.0" h="20.0" x="2055.0" y="3922.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s116_emtc_emtc_sa112" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, UNIPROT:P08670, GENECARDS:GC10P017310 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:13130303 Vimentin is a putative direct HIF1 target gene http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vimentin*"/> <bbox w="60.0" h="20.0" x="4833.5" y="2930.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s119_emtc_emtc_sa115" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="R-Cadherin*"/> <bbox w="80.0" h="20.0" x="2055.0" y="4002.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s122_emtc_emtc_sa118" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocollin2*"/> <bbox w="88.0" h="20.0" x="1934.5" y="4181.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s125_emtc_emtc_sa121" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) HUGO:MMP2, HGNC:7166, ENTREZ:4313, GENECARDS:GC16P055478, P08253 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP2"/> <bbox w="40.0" h="20.0" x="2076.0" y="4840.635"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s129_emtc_emtc_sa125" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) HUGO:MMP9, HGNC:7176, ENTREZ:4318, UNIPROT:P14780, GENECARDS:GC20P044637 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP9"/> <bbox w="40.0" h="20.0" x="2073.0" y="4945.768"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s130_emtc_emtc_sa126" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 14 (membrane-inserted) HUGO:MMP14, HGNC:7160, ENTREZ:4323, UNIPROT:P50281, GENECARDS:GC14P023305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:23737743 The characterization of ECM degradation by MT1-MMP indicate a dynamic nature of MMP14 (MT1-MMP) at invadopodia and its importance in the degradation of the ECM References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP14"/> <bbox w="40.0" h="20.0" x="2073.0" y="5056.902"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s146_emtc_emtc_sa142" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11927608 PALS1 is an adapter linking Crumbs and PATJ* PALS1 contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate kinase domain Interaction PALS1 -LIN7 via the C-terminal L27 domain of PALS1 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: membrane protein, palmitoylated 5 (MAGUK p55 subfamily member 5) HUGO:MPP5, HGNC:18669, ENTREZ:64398, UNIPROT:Q8NI35, GENECARDS:GC14P067708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11927608 PALS1 is an adapter linking Crumbs and PATJ* PALS1 contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate kinase domain Interaction PALS1 -LIN7 via the C-terminal L27 domain of PALS1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PALS1*"/> <bbox w="45.0" h="20.0" x="601.5" y="2314.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s181_emtc_emtc_sa168" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: calcium/calmodulin-dependent serine protein kinase (MAGUK family) HUGO:CASK, HGNC:1497, ENTREZ:8573, UNIPROT:O14936, GENECARDS:GC0XM041374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN2*"/> <bbox w="51.0" h="19.0" x="4833.5" y="3285.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s187_emtc_emtc_sa174" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: chromosome 16 open reading frame 70 HUGO:C16orf70, HGNC:29564, ENTREZ:80262, UNIPROT:Q9BSU1, GENECARDS:GC16P067143 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN10*"/> <bbox w="55.0" h="20.0" x="4834.5" y="3240.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s203_emtc_emtc_sa171" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lin-7 homolog C (C. elegans) HUGO:LIN7C, HGNC:17789, ENTREZ:55327, UNIPROT:Q9NUP9, GENECARDS:GC11M027472 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN7C"/> <bbox w="51.0" h="17.0" x="4828.0" y="3346.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s206_emtc_emtc_sa188" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 PATJ* is repressed by ZEB1 PMID:10102271 PATJ* is a component of the Crb complex. The L27 domain of PATJ* binds to the L27 domain of PALS1* PMID:22881460 Apical recuritment if PATJ* depends on the CRB3/PALS1* complex PMID:18005931 PATJ contains one L27 domain (interacting with the N-ter L27 of PALS1) and has up to 10 PDZ domains. The 6th PDZ interacts with ZO3 and the 8th interacts with Claudin1. The ZO3 cytoplasmic protein is linked to tight junctions via its association with Occludin. Occludin and Claudin1 are transmembrane proteins PMID:16129888 PATJ expression affects the localization of ZO1, ZO3, Occludin, CRB3 and PALS1 PATJ provides a link between the lateral (Occludin and ZO3) and apical (PALS1 and CRB3) components of tight junctions and stabilizes the CRB3 complex References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: InaD-like (Drosophila) HUGO:INADL, HGNC:28881, ENTREZ:10207, UNIPROT:Q8NI35, GENECARDS:GC01P062208 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 PATJ* is repressed by ZEB1 PMID:10102271 PATJ* is a component of the Crb complex. The L27 domain of PATJ* binds to the L27 domain of PALS1* PMID:22881460 Apical recuritment if PATJ* depends on the CRB3/PALS1* complex PMID:18005931 PATJ contains one L27 domain (interacting with the N-ter L27 of PALS1) and has up to 10 PDZ domains. The 6th PDZ interacts with ZO3 and the 8th interacts with Claudin1. The ZO3 cytoplasmic protein is linked to tight junctions via its association with Occludin. Occludin and Claudin1 are transmembrane proteins PMID:16129888 PATJ expression affects the localization of ZO1, ZO3, Occludin, CRB3 and PALS1 PATJ provides a link between the lateral (Occludin and ZO3) and apical (PALS1 and CRB3) components of tight junctions and stabilizes the CRB3 complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PATJ*"/> <bbox w="45.0" h="16.0" x="6172.5" y="2797.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s227_emtc_emtc_sa61" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LIM domain only 2 (rhombotin-like 1) HUGO:LMO2, HGNC:6642, ENTREZ:4005, UNIPROT:P25791, GENECARDS:GC11M033880 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Complex ZEB1-LMO2 PMID:20731704 PMID:22349261 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LMO2"/> <bbox w="40.0" h="20.0" x="3849.5" y="3913.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s229_emtc_emtc_sa204" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 2 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB2"/> <bbox w="40.0" h="20.0" x="1459.0" y="6775.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s230_emtc_emtc_sa205" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 3 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:11790723 Whereas TGFB1 and 2 are proscarring growth factors, TGFB3 is antiscarring TGFB1, 2, and 3 are embryonically expressed in skin and up-regulated at adult wound sites Overlapping expression patterns of HIF1A and TGFB3 in vivo TGFB1 mRNA expression was serum- but not hypoxia-inducible. In contrast, TGFB3 mRNA expression was hypoxia-inducible, but not serum- inducible TGFB3 might be a HIF1A target gene References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB3"/> <bbox w="40.0" h="20.0" x="4854.0" y="5139.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s232_emtc_emtc_sa207" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="42.0" h="40.0" x="6179.0" y="4507.5"/> <glyph class="state variable" id="_20e238bd-e501-492d-9716-d86b1353b8de"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6166.5" y="4504.9023"/> </glyph> <glyph class="unit of information" id="_d270fe97-6d90-49da-adfb-2ecc657c9dfd"> <label text="receptor"/> <bbox w="42.0" h="10.0" x="6179.0" y="4502.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s234_emtc_emtc_sa209" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="52.0" h="45.0" x="6168.344" y="3648.633"/> <glyph class="unit of information" id="_6d5c51d9-cc78-4053-bf33-9f6d7edfc01b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6184.344" y="3643.633"/> </glyph> <glyph class="state variable" id="_1336312a-1ee4-4f82-b6ef-7af27a495ff9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6215.344" y="3643.8748"/> </glyph> <glyph class="state variable" id="_15d8814e-f321-437b-84b7-2124bb9d3d16"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6155.844" y="3644.6797"/> </glyph> <glyph class="unit of information" id="_1ac9005c-a969-4f1c-a5d4-7d085f46096d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6171.844" y="3643.633"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s243_emtc_emtc_sa904" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2 binding component 3 HUGO:BBC3, HGNC:17868, ENTREZ:27113, UNIPROT:Q96PG8, GENECARDS:GC19M047724 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BBC3"/> <bbox w="35.0" h="18.0" x="4308.5" y="1230.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s254_emtc_emtc_sa223" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:8349738 THBS1 cleaves the latent TGFB1 complex, releasing TGFB in its active form PMID:22943793 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: thrombospondin 1 HUGO:THBS1, HGNC:11785, ENTREZ:7057, UNIPROT:P07996,GENECARDS:GC15P039873 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:8349738 THBS1 cleaves the latent TGFB1 complex, releasing TGFB in its active form PMID:22943793 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="THBS1"/> <bbox w="44.0" h="16.0" x="840.969" y="6750.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s261_emtc_emtc_sa228" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1, HGNC:6714, ENTREZ:4052, UNIPROT:Q14766,GENECARDS:GC02P033172, UNIPROT:Q14766 Identifiers_end Maps_Modules_begin: MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LTBPs are microfibril-associated proteins that tether latent TGFB to the ECM There are 4 LTBP proteins (1, 2, 3, 4). Although LTBP1 and 3 bind all three TGFB (1, 2, 3), LTBP4 binds only TGFB1 PMID:9931372 LTBP1 is a member of the fibrillin family An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out PMID:10544215 Extracellular tTgase is located at the basal and apical surfaces of cells and at cell–cell contacts, and that LTBP1 is co-distributed with cell surface tTgase LTPB1 was also found to co-localize with both intracellular and extracellular fibronectin Regulation of tTgase expression is important for controlling matrix storage of latent TGFB1 complexes Fibronectin may be one extracellular component to which LTBP1 is crosslinked when LTBP1 and tTgase interact at the cell surface References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTBP1"/> <bbox w="40.0" h="20.0" x="635.969" y="6526.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s273_emtc_emtc_sa234" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: latency-associated protein* HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, UNIPROT:P10600, GENECARDS:GC14M076424 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP: Latency-associated peptiden encoded by TGFB gene There are 3 LAPs (1, 2, 3) corresponding to 3 TGFB (1, 2, 3) LAP1 contains the RGD motif which is the binding site for integrins aVb1, aVb3, aVb5, aVb6, aVb8, a8b1 PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epitheliaModules_bigin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Latency-associated protein*"/> <bbox w="182.0" h="25.0" x="378.75" y="6466.0"/> <glyph class="unit of information" id="_271b0fff-7d8d-4407-9708-096749e6e172"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="459.75" y="6461.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s337_emtc_emtc_sa295" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA1"/> <bbox w="40.0" h="20.0" x="3503.5" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s338_emtc_emtc_sa296" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2"/> <bbox w="40.0" h="20.0" x="3550.902" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s339_emtc_emtc_sa297" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2B"/> <bbox w="40.0" h="20.0" x="3598.227" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s340_emtc_emtc_sa298" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA3"/> <bbox w="40.0" h="20.0" x="3648.129" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s341_emtc_emtc_sa299" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="40.0" h="20.0" x="3695.332" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s342_emtc_emtc_sa300" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="40.0" h="20.0" x="3743.047" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s343_emtc_emtc_sa301" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="40.0" h="20.0" x="3790.055" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s344_emtc_emtc_sa302" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 7 HUGO:ITGA7 HGNC:6143 ENTREZ:3679 UNIPROT:Q13683 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA7"/> <bbox w="40.0" h="20.0" x="3837.637" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s345_emtc_emtc_sa303" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 8 HUGO:ITGA8 HGNC:6144 ENTREZ:8516 UNIPROT:P53708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA8"/> <bbox w="40.0" h="20.0" x="3884.89" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s346_emtc_emtc_sa304" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" 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References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA10"/> <bbox w="40.0" h="20.0" x="3980.08" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s348_emtc_emtc_sa306" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ 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MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAD"/> <bbox w="40.0" h="20.0" x="4081.885" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s350_emtc_emtc_sa308" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha E (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide) HUGO:ITGAE HGNC:6147 ENTREZ:3682 UNIPROT:P38570 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAE"/> <bbox w="40.0" h="20.0" x="4129.225" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s351_emtc_emtc_sa309" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide) CD11A HUGO:ITGAL HGNC:6148 ENTREZ:3683 UNIPROT:P20701 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAL"/> <bbox w="40.0" h="20.0" x="4177.098" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s352_emtc_emtc_sa310" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha M (complement component 3 receptor 3 subunit) CD11B, CR3A, "integrin, alpha M (complement component receptor 3, alpha; also known as CD11b (p170), macrophage antigen alpha polypeptide)" HUGO:ITGAM HGNC:6149 ENTREZ:3684 UNIPROT:P11215 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAM"/> <bbox w="40.0" h="20.0" x="4224.285" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s353_emtc_emtc_sa311" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha X (complement component 3 receptor 4 subunit) CD11C, "integrin, alpha X (antigen CD11C (p150), alpha polypeptide)" HUGO:ITGAX HGNC:6152 ENTREZ:3687 UNIPROT:P20702 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAX"/> <bbox w="40.0" h="20.0" x="4272.066" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s354_emtc_emtc_sa312" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAV"/> <bbox w="40.0" h="20.0" x="4319.219" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s356_emtc_emtc_sa314" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) synonym CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2, HGNC:6155, ENTREZ:3689, GENECARDS:GC21M046305, UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="40.0" h="20.0" x="4414.805" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s357_emtc_emtc_sa315" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="40.0" h="20.0" x="4461.799" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s358_emtc_emtc_sa316" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB4"/> <bbox w="40.0" h="20.0" x="4509.285" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s359_emtc_emtc_sa317" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB5"/> <bbox w="40.0" h="20.0" x="4557.043" y="5392.5"/> </glyph> 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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 8 HUGO:ITGB8 HGNC:6163 ENTREZ:3696 UNIPROT:P26012 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB8"/> <bbox w="40.0" h="20.0" x="4699.262" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s390_emtc_emtc_sa1943" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Ataxia telangiectasia mutated HUGO:ATM, HGNC:795, ENTREZ:472, UNIPROT:Q13315 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 phosphorylation by ATM inhibits its interaction with p53 PMID:15140942 Phosphorylation at Ser395 PMID:11331603 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ATM"/> <bbox w="40.0" h="19.0" x="3666.0" y="2360.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s407_emtc_emtc_sa2087" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ubiquitin-conjugating enzyme E2D2 HUGO:UBE2D2, HGNC:12475, ENTREZ:7322, UNIPROT:P62837, GENECARDS:GC05P138920 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="UBE2D2"/> <bbox w="55.0" h="18.0" x="896.0" y="1841.667"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s408_emtc_emtc_sa2090" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: deltex homolog 1 HUGO:DTX1, HGNC:3060, ENTREZ:1840, UNIPROT:Q86Y01, GENECARDS:GC12P113495 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DTX1"/> <bbox w="42.0" h="17.0" x="896.0" y="1814.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s421_emtc_emtc_sa1932" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="50.0" h="48.0" x="3764.0" y="2485.5"/> <glyph class="state variable" id="_cab22e5e-19c2-44e0-9767-ede982d25d96"> <state value="P" variable="S395"/> <bbox w="35.0" h="10.0" x="3746.5" y="2483.3826"/> </glyph> <glyph class="state variable" id="_f893623b-b1d6-4325-bb22-26dd9e7a74e5"> <state value="" variable="S186"/> <bbox w="30.0" h="10.0" x="3749.0" y="2525.4822"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s425_emtc_emtc_sa1436" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN HUGO:PTEN, HGNC:9588, ENTREZ:5728, UNIPROT:P60484, GENECARDS:GC10P089613 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTEN"/> <bbox w="44.0" h="16.0" x="4027.75" y="819.272"/> <glyph class="state variable" id="_16a05794-db14-4aea-981b-37f4815119c2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4064.25" y="814.272"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s441_emtc_emtc_sa358" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <clone/> <bbox w="110.0" h="20.0" x="5594.0" y="2945.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s441_sa2186" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actin cytoskeletal* actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <clone/> <bbox w="110.0" h="20.0" x="1375.4" y="3300.6"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s460_emtc_emtc_sa373" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 4 HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9389648 Smad4 has the same overall structure as the receptor-regulated SMADs Smad4 is more divergent and lacks the C-ter phosphorylation motif. Smad4 is not required for nuclear translocation of Smads 1 or 2 Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription. Smad4 contributes 2 functions: N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA; C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription PMID:11074002 In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="60.0" h="20.0" x="4874.0" y="4513.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s463_emtc_emtc_sa376" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 5 "MAD, mothers against decapentaplegic homolog 5 (Drosophila)", MADH5, "SMAD, mothers against DPP homolog 5 (Drosophila)" HUGO:SMAD5 HGNC:6771 ENTREZ:4090 UNIPROT:Q99717 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD5"/> <bbox w="60.0" h="20.0" x="4864.75" y="4086.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s466_emtc_emtc_sa379" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD6"/> <bbox w="60.0" h="20.0" x="4868.0" y="4258.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s469_emtc_emtc_sa382" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD7"/> <bbox w="60.0" h="20.0" x="4868.0" y="4291.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s472_emtc_emtc_sa385" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 9 "MAD, mothers against decapentaplegic homolog 9 (Drosophila)", MADH9, "SMAD, mothers against DPP homolog 9 (Drosophila)" HUGO:SMAD9 HGNC:6774 ENTREZ:4093 UNIPROT:O15198 GENECARDS:GC13M037418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD9"/> <bbox w="60.0" h="20.0" x="4864.75" y="4113.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s473_emtc_emtc_sa386" compartmentRef="emtc_emtc_c33_emtc_emtc_ca33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 The C-ter of SARA interacts TGFBR1 and TGFBR2 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:12154066 Small GTPases such as Rab5 catalyse movement of activated receptor complexes to early endosomal compartments Here, the complex encounter SARA: a phospholipid-bound carrier SARA presents Smads to the TGFBR1 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger, FYVE domain containing 9 HUGO:ZFYVE9, HGNC:6775, ENTREZ:9372, UNIPROT:O95405, GENECARDS:GC01P052608 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:11792802 -SARA contains a FYVE motif which is known to bind phosphatidylinositol 3-phosphate. It might anchor Smad2 to the inner leaflet of the plasma membrane or endosomal vesicles. SARA thus provides a first example of how TGFB signaling centres may be organised at the plasma membrane or endosomal vesicles. -Several other proteins with possible roles in Smad anchoring: PMID:10678166 Microtubules can anchor inactive Smads in the cytoplasm Activation by a ligand results in dissociation of the Smads from the microtubule network It is possible that microtubules serve as tracks for intracellular Smad movement PMID:11278410 Filamin, an actin crosslinking factor and scaffolding protein also associates with Smads and positively regulates transduction of Smad signals. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SARA*"/> <bbox w="60.0" h="20.0" x="5877.0" y="3854.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s480_emtc_emtc_sa391" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="118.0" h="51.0" x="5937.0" y="4373.266"/> <glyph class="state variable" id="_4bb39055-d543-461b-961b-60f6457604dc"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="6037.5" y="4401.743"/> </glyph> <glyph class="state variable" id="_94103949-56bd-4337-86e2-76c45209995e"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5987.039" y="4419.266"/> </glyph> <glyph class="state variable" id="_58401a0e-4b2d-4137-827e-01c5db750608"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="6037.5" y="4414.5215"/> </glyph> <glyph class="state variable" id="_7bd5ce92-fcd8-436e-b030-dfe69e6c5cbe"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="6040.0" y="4391.7217"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s509_emtc_emtc_sa412" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="115.0" h="49.0" x="5763.0" y="4374.5"/> <glyph class="state variable" id="_59218e2e-97ef-4ae4-8702-e06e0830bb2f"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="5748.0" y="4397.663"/> </glyph> <glyph class="state 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class="state variable" id="_7845002c-47d6-469d-b545-5d1a96bb5c35"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5809.2124" y="4418.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s522_emtc_emtc_sa419" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: furin (paired basic amino acid cleaving enzyme) FUR, PACE, "paired basic amino acid cleaving enzyme (furin, membrane associated receptor protein)", PCSK3 HUGO:FURIN HGNC:8568 ENTREZ:5045 UNIPROT:P09958 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FURIN"/> <bbox w="40.0" h="20.0" x="558.0" y="6376.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s581_emtc_emtc_sa442" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19597490 CAR: a tight-junction-associated cell adhesion molecule CAR is downregulated in human cancer and in TGF-b-induced EMT PMID:15820557 CAR: a virus receptor within the tight junction CAR: a transmembrane protein PMID:12727824 CAR: down-stream target of Rag-MEK-ERK pathway PMID:16542650 In epithelial cell, CAR localizes with ZO1 and Occludin References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: coxsackie virus and adenovirus receptor HUGO:CXADR, HGNC:2559, ENTREZ:1525, GENECARDS:GC21P018884, UNIPROT:P78310 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:19597490 CAR: a tight-junction-associated cell adhesion molecule CAR is downregulated in human cancer and in TGF-b-induced EMT PMID:15820557 CAR: a virus receptor within the tight junction CAR: a transmembrane protein PMID:12727824 CAR: down-stream target of Rag-MEK-ERK pathway PMID:16542650 In epithelial cell, CAR localizes with ZO1 and Occludin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CAR*"/> <bbox w="40.0" h="16.0" x="600.0" y="2500.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s586_emtc_emtc_sa448" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15558297 The localization of ZO-1 at gap junctions serves in part to resolve reports of ZO-1 expression in non-epithelial cells such as fibroblasts that lack tight junctions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="46.5" h="18.777779" x="1105.5" y="2562.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s589_emtc_emtc_sa451" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO2*"/> <bbox w="46.5" h="20.0" x="1105.5" y="2602.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s592_emtc_emtc_sa454" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="60.0" h="16.0" x="603.0" y="2845.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s618_emtc_emtc_sa471" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Sp1 transcription factor HUGO:SP1, HGNC:11205, ENTREZ:6667, GENECARDS:GC12P053801, UNIPROT:P08047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SP1"/> <bbox w="40.0" h="20.0" x="3520.5" y="3572.0"/> <glyph class="state variable" id="_ab064a25-b867-4f4f-8ad4-84874e605a15"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3515.5" y="3577.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s621_emtc_emtc_sa474" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4"/> <bbox w="40.0" h="20.0" x="3141.0" y="1700.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s622_emtc_emtc_sa475" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK6"/> <bbox w="40.0" h="20.0" x="3141.0" y="1747.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s633_emtc_emtc_sa500" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455, UNIPROT:P24385 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Only several CDK–cyclin complexes are directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="66.0" h="20.0" x="3114.0" y="1989.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s634_emtc_emtc_sa481" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1B (p27, Kip1) HUGO:CDKN1B, HGNC:1785, ENTREZ:1027, GENECARDS:GC12P012867, UNIPROT:P46527 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:24954210 p27, p16 and p15 inhibits CDK4_6. This induces a G1 cell cycle arrest. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p27KIP1*"/> <bbox w="64.0" h="20.0" x="3336.5" y="1880.5"/> <glyph class="state variable" id="_f6d4502d-9d20-434d-9331-67579edea262"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3331.5" y="1895.3612"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s635_emtc_emtc_sa482" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1A (p21, Cip1) HUGO:CDKN1A, HGNC:1784, ENTREZ:1026, GENECARDS:GC06P036649, UNIPROT:P38936 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:24954210 p27, p16 and p15 inhibits CDK4_6. This induces a G1 cell cycle arrest. PMID:19440234 p21 inhibits CDK2 to induce senescence PMID:10402472 p21 induces metastasis p21 suppresses E2F1-dependent Wnt4 expression, thereby controlling cellular growth. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p21CIP1*"/> <bbox w="64.0" h="20.0" x="3436.584" y="1879.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s636_emtc_emtc_sa483" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2A HUGO:CDKN2A, HGNC:1787, ENTREZ:1029, GENECARDS:GC09M021957, UNIPROT:P42771 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest PMID:26592237 P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p16INK4A*"/> <bbox w="78.0" h="19.0" x="3640.5" y="1879.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s654_emtc_emtc_sa502" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540, UNIPROT:P49841 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. PMID:15020233 MEK1/2 can phosphorylate tyrosine 216, which stimulates GSK3B kinase activity U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK3B, suggesting that MEK1/2 was involved in the phosphorylation of Tyr216 in GSK3B In vitro kinase interaction showed that GSK3B is phosphorylated by recombinant MEK1 at Y216 PMID:16944320 The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones PMID:9832503 GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1 GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. PMID:14663202 GSK3B is highly activated in nuclei and mitochondria. PMID:11967263 Tyr-216 phosphorylation is required for GSK-mediated down-regulation of b-catenin activity. PMID:8524413 Inactiviation of GSK-3 occurs through Akt phosphorylation of serine 9 of GSK-3b. This phosphorylation may be involved in later phases of neuronal apoptosis. Mutation of Ser9 to Ala did not affect GSK-3 -mediated phosphorylation of b-catenin, whereas mutation of Tyr216 to Phe markedly reduced the in vivo phosphorylation of b-catenin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="71.5" h="42.0" x="2899.75" y="2035.5"/> <glyph class="state variable" id="_784a0703-08c8-43d3-9231-de58ff27785d"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="2892.25" y="2033.0223"/> </glyph> <glyph class="state variable" id="_5e01d87e-e84e-4d28-8ef0-174398e6fef6"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="2963.4224" y="2030.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s656_emtc_emtc_sa515" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog (avian) HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748, UNIPROT:P01106 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID :17055429 MYC stimulate P53 and ARF(CDKN2A) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYC"/> <bbox w="40.0" h="20.0" x="3245.0" y="2201.25"/> <glyph class="state variable" id="_86e3f979-98dd-4f12-881b-1aa324f2fedf"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3240.0" y="2206.2341"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s657_emtc_emtc_sa499" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box O1 HUGO:FOXO1, HGNC:3819, ENTREZ:2308, GENECARDS:GC13M041129, UNIPROT:Q12778 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXO1"/> <bbox w="47.0" h="20.0" x="3240.0" y="2171.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s669_emtc_emtc_sa510" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin E1 HUGO:CCNE1, HGNC:1589, ENTREZ:898, GENECARDS:GC19P030302, UNIPROT:P24864 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinE1*"/> <bbox w="60.0" h="20.0" x="3052.5" y="1656.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s674_emtc_emtc_sa513" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase 2 HUGO:CDK2, HGNC:1771, ENTREZ:1017, GENECARDS:GC12P056360, UNIPROT:P24941 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK2"/> <bbox w="40.0" h="20.0" x="3141.0" y="1653.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s675_emtc_emtc_sa514" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger and BTB domain containing 17 HUGO:ZBTB17, HGNC:12936, ENTREZ:7709, GENECARDS:GC01M016268, UNIPROT:Q13105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIZ1*"/> <bbox w="40.0" h="20.0" x="3541.0" y="2580.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s780_emtc_emtc_sa582" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: elastin microfibril interfacer 1 HUGO:EMILIN1, HGNC:19880, ENTREZ:11117, UNIPROT:Q9Y6C2, GENECARDS:GC02P027301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:2190045 Emilin blocks extracellular furin cleavage of pro-TGFB References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EMILIN1"/> <bbox w="55.0" h="20.0" x="435.0" y="6377.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s788_emtc_emtc_sa590" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 13 (membrane-inserted) HUGO:MMP13, HGNC:7159, ENTREZ:4322, GENECARDS:GC11M102847, UNIPROT:P45452 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 MMP13 activates TGFB by cleavage of LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP13"/> <bbox w="40.0" h="20.0" x="2073.0" y="5016.836"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s903_emtc_emtc_sa653" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:11413131 E-cadherin dimerization is essential for adhesion to the integrin aEb7 PMID:17325197 Interaction between E-cadherin and aEb7 integrin plays major role in effective tumor cell lysis, during cytolytic granule polarization and subsequent exocytosis References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="86.0" h="26.0" x="588.0" y="3427.5"/> <glyph class="unit of information" id="_9b33e54e-fee6-498d-90c8-fe8d10f40337"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="621.0" y="3422.5"/> </glyph> <glyph class="state variable" id="_b1e5eaec-2f9a-4004-b10b-0c65ea60c2d9"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="580.5" y="3423.5918"/> </glyph> <glyph class="state variable" id="_b827e34f-2889-4d6c-9256-07d9a781c086"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="666.5" y="3424.0981"/> </glyph> <glyph class="state variable" id="_019f5ccf-2a6e-4728-b4b5-298cb799e253"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="665.83545" y="3448.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s917_emtc_emtc_sa664" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696, UNIPROT:Q9NPB6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="54.0" h="41.0" x="2071.5" y="2336.5"/> <glyph class="state variable" id="_0cf8f48f-cbd2-4eef-aa97-0c079347c458"> <state value="" variable="S345"/> <bbox w="30.0" h="10.0" x="2077.7676" y="2331.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s966_emtc_emtc_sa681" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1, HGNC:16807, ENTREZ:57154, GENECARDS:GC07M098627, UNIPROT:Q9HCE7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:21572392 SMURF1 is an E3 ubiquitin ligase SMURF1 performs a crucial role in the regulation of the BMP signalling pathway in both embryonic development and bone remodelling. PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity Need more reference 34-36 from PMID15761148: RhoA is an important modulator of cell junction formation and stability. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF1"/> <bbox w="60.0" h="20.0" x="1156.0" y="2094.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s987_emtc_emtc_sa685" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:9822605 Members of the Rho/Rac family can be grouped into 3 classes according to amino acid sequence similarities. The first subfamily is composed of four Rac proteins (Rac-1, Rac-2, Rac-3 and RhoG). Some of these proteins promote the activation of protein kinases such as PAK, c-Jun N-terminal kinase (JNK) and p38MAPK. They are also involved in the activation of other independent pathways regulating membrane ruffling and cell proliferation. The second subfamily, Rho, includes RhoA, RhoB, RhoC, RhoD, RhoE and TTF proteins. RhoA has been characterized extensively and shown to be involved in cell transforma- tion, formation of stress fibers and focal adhesions, and in the stimulation of protein kinases such as PKN and p160Rock Finally, the third subfamily is composed of TC10 and the two isoforms of the Cdc42 protein. Cdc42 was shown to be involved in the activation of JNK, PAK and p38MAPK as well as in the formation of filopodia in the plasma membrane PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity RhoA is an important modulator of cell junction formation and stability: PMID:7479854 Rho protein regulates tight junctions and perjunctional actin organization in polarized epithelia PMID:9362522 Rho subfamily is necessary for the formation of both the cadherin-based cell–cell adhesion and the tight junction PMID:9660866 RhoA and Rac1 regulate gate and fence functions of the TJ, and play a role in the spatial organization of TJ proteins at the apex of the lateral membrane PMID:12361600 PMID:11992112 RhoA functions to maintain apical-basal polarity and cell junctions. PMID:11739775 PMID:11729192 RhoA can stabilize tight junctions and increase transepithelial resistance References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHOA"/> <bbox w="52.0" h="18.0" x="4846.0" y="1793.5"/> <glyph class="state variable" id="_da0765f0-8889-4aa6-af21-b57c89194082"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="4836.0" y="1797.4857"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1034_emtc_emtc_sa313" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="40.0" h="20.0" x="4367.025" y="5392.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1332_emtc_emtc_sa697" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) HUGO:ETS1, HGNC:3488, ENTREZ:2113, UNIPROT:P14921, GENECARDS:GC11M128328 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16391805 Ets-1 is a transcription factor Ets-1 involves in inducing MMP2 expression by EMT in human squamous carcinoma cells PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:15111329 The Ets gene family conserves an 85-amino acid DNA-binding ETS domain that binds the consensus sequence 5'-GGA(A/T)-3' in the promoter region of the target genes. Ets has various biological functions, including cellular growth, differentiation, and organ development. Ets-1, first identified among the Ets gene family, has been shown to also be associated with pathological angiogenesis. A number of angiogenesis-related molecules, including MMP-1, MMP-3, MMP-9, integrin 3, vascular endothelial cadherin (VE-cadherin), and neuropilin-1 (NRP1) are reported to be targets of Ets-1 in endothelial cells PMID:21081489 Endogenous Ets-1 is a key mediator of cell migration and Matrigel tube formation in HMECs (human microvascular endothelial cells) PMID:21041997 In cells induced to undergo EMT, TGFB also activates the expresion of ZEB1 and ZEB2 through upregulation of ETS1 expression, which then may cooperate with the bHLH transcription factor E47 (TCF3) PMID:17615296 TGFB induces ETS1 transcriptional expression. TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457) ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1. Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ETS1"/> <bbox w="40.0" h="20.0" x="2323.0" y="4712.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1333_emtc_emtc_sa699" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SIX homeobox 1 HUGO:SIX1, HGNC:10887, ENTREZ:10887, UNIPROT:Q15475, GENECARDS:GC14M061111 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. PMID:19726885 PMID:22286770 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SIX1"/> <bbox w="40.0" h="20.0" x="3040.5" y="4281.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1346_emtc_emtc_sa716" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: E2F transcription factor 1 HUGO:E2F1, HGNC:3113, ENTREZ:1869, UNIPROT:Q01094, GENECARDS:GC20M032263 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E2F1"/> <bbox w="40.0" h="20.0" x="2975.5" y="4282.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1430_emtc_emtc_sa794" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF1"/> <bbox w="40.0" h="20.0" x="4854.0" y="5082.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1435_emtc_emtc_sa427" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="121.0" h="60.0" x="5602.0" y="4468.5"/> <glyph class="unit of information" id="_89ac4bb1-2a58-4b94-80d5-7e573826e888"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5652.5" y="4463.5"/> </glyph> <glyph class="state variable" id="_d8a472cd-07e4-459f-8fa4-83cf98d177ba"> <state value="" variable="S204"/> <bbox w="30.0" h="10.0" x="5587.0" y="4497.9854"/> </glyph> <glyph class="state variable" id="_9063d7bc-8d4d-4b29-a61e-85b4e01053e6"> <state value="" variable="S422"/> <bbox w="30.0" h="10.0" x="5708.0" y="4489.578"/> </glyph> <glyph class="state variable" id="_8e5129b7-efad-4e6c-9e5a-2e22592adef5"> <state value="" variable="T179"/> <bbox w="30.0" h="10.0" x="5587.0" y="4517.681"/> </glyph> <glyph class="state variable" id="_88bd2a8c-ed49-4d55-ab8f-f9326e3ae493"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="5705.5" y="4501.583"/> </glyph> <glyph class="state variable" id="_a41555b7-f057-461c-b165-1c5bd4fdad44"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="5705.5" y="4517.9185"/> </glyph> <glyph class="state variable" id="_3a8462d3-170c-4135-b6a2-acbfad5ad646"> <state value="" variable="S208"/> <bbox w="30.0" h="10.0" x="5587.0" y="4484.1675"/> </glyph> <glyph class="state variable" id="_13d8e30e-2f72-46e7-80c2-21bafe83afef"> <state value="" variable="S213"/> <bbox w="30.0" h="10.0" x="5587.0" y="4467.1035"/> </glyph> <glyph class="state variable" id="_4e837780-0d56-45b3-9551-c898164bf218"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5651.145" y="4523.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1436_emtc_emtc_sa428" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="120.0" h="60.0" x="6039.0" y="4468.5"/> <glyph class="unit of information" id="_839f5607-147e-4cf9-b43e-d884f58008f6"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6089.0" y="4463.5"/> </glyph> <glyph class="state variable" id="_440e697e-8805-440c-9240-83b268e58171"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="6141.5" y="4502.885"/> </glyph> <glyph class="state variable" id="_0b703a16-c784-432e-bf0e-3e63aadf2413"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="6090.0566" y="4523.5"/> </glyph> <glyph class="state variable" id="_3f8c56c7-8213-47a1-8ecd-e749f641d168"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="6141.5" y="4517.9185"/> </glyph> <glyph class="state variable" id="_8fc3995e-ff42-488e-9914-545a71d4bf75"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="6144.0" y="4491.0947"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1442_emtc_emtc_sa236" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="50.625" h="48.5" x="6177.688" y="4411.25"/> <glyph class="unit of information" id="_1c82b174-8bb7-4e1b-8906-49460892f990"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6193.0005" y="4406.25"/> </glyph> <glyph class="state variable" id="_44341602-64b2-45b1-b5db-42038bc2a57f"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6165.188" y="4409.1626"/> </glyph> <glyph class="unit of information" id="_98c0ff80-fc51-49a1-8b81-37bf35891744"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6180.5005" y="4406.25"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1445_emtc_emtc_sa798" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1C (p57, Kip2) HUGO:CDKN1C, HGNC:1786, ENTREZ:1028, UNIPROT:P49918, GENECARDS:GC11M002904 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:20428755 p57 is a cyclin-dependent kinase (CDK) inhibitor p57 was initially considered to be a tumor suppressor based on its ability to regulate cell cycle progression p57 is also involved in the regulation of other cellular processes including transcription, apoptosis, differentiation, development, and migration The multifunction of p57 participate in many processes in tumorigenesis involving in different mechanisms including regulation of microRNAs The presence of a nuclear localization signal in p57 is intriguing because it may affect the subcellular localization of p57, which can result in abnormal proliferation and motility of cells, and may be oncogenic under certain circumstances, as observed for p21 and p27 PMID:17464323 Translocation of p57Kip2 to mitochondria occurs within 20 min after staurosporine (apoptotic agent) application. In fact, p57Kip2 primarily promotes the intrinsic apoptotic pathways, favoring Bax activation and loss of mitochondrial transmembrane potential, consequent release of cytochrome-c into cytosol, caspase-9 and caspase-3 activation. In accordance, Bcl2 overexpression is able to inhibit p57Kip2 cell death promoting effect. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57Kip2 influences the mitochondrial apoptotic cell death pathway in cancer cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p57KIP2*"/> <bbox w="66.0" h="20.0" x="3742.0" y="2120.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1541_emtc_emtc_sa811" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-raf-1 murine leukemia viral oncogene homolog 1 HUGO:RAF1, HGNC:9829, ENTREZ:5894 , GENECARDS:GC03M012625, UNIPROT:P04049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). 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YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAF1"/> <bbox w="102.0" h="45.0" x="6066.0" y="1173.5"/> <glyph class="state variable" id="_6c97cffe-4824-45d0-81ea-5503f11e1944"> <state value="closed" variable=""/> <bbox w="40.0" h="10.0" x="6097.0" y="1168.5"/> </glyph> <glyph class="state variable" id="_7f266d08-8c77-4d7a-b80a-26cf92e4b117"> <state value="" variable="Y340"/> <bbox w="30.0" h="10.0" x="6152.4487" y="1168.5"/> </glyph> <glyph class="state variable" id="_8e88226f-4bfe-4d2f-813a-a1a85b77ad74"> <state value="" variable="Y341"/> <bbox w="30.0" h="10.0" x="6151.896" y="1213.5"/> </glyph> <glyph class="state variable" id="_32920617-aa87-4c32-83b5-c7848facfa9d"> <state value="P" variable="S259"/> <bbox w="35.0" h="10.0" x="6048.5" y="1168.6061"/> </glyph> <glyph class="state variable" id="_c7e21203-afa7-4b08-bd2f-549887ec9703"> <state value="P" variable="S621"/> <bbox w="35.0" h="10.0" x="6048.5" y="1212.317"/> </glyph> <glyph class="state variable" id="_3f46af5b-2288-455f-802b-549ac5814c2b"> <state value="" variable="S338"/> <bbox w="30.0" h="10.0" x="6051.0" y="1190.9641"/> </glyph> <glyph class="state variable" id="_ce75ceee-5d2e-44dc-a622-8ef738f7f2f9"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="6158.0" y="1191.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1578_emtc_emtc_sa825" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-raf-1 murine leukemia viral oncogene homolog 1 HUGO:RAF1, HGNC:9829, ENTREZ:5894 , GENECARDS:GC03M012625, UNIPROT:P04049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAF1"/> <bbox w="99.0" h="42.0" x="5626.0" y="814.5"/> <glyph class="state variable" id="_dd3c6935-8360-4e76-b240-41e7abb76d8a"> <state value="open" variable=""/> <bbox w="30.0" h="10.0" x="5660.5" y="809.5"/> </glyph> <glyph class="state variable" id="_2c88097e-0819-49fa-b84e-582afde9361d"> <state value="P" variable="Y340"/> <bbox w="35.0" h="10.0" x="5706.965" y="809.5"/> </glyph> <glyph class="state variable" id="_58beff8b-bd80-446c-8a98-2cced998b974"> <state value="P" variable="Y341"/> <bbox w="35.0" h="10.0" x="5706.428" y="851.5"/> </glyph> <glyph class="state variable" id="_43db9198-980f-4ad4-8bf7-e06d7e9cbfe2"> <state value="P" variable="S259"/> <bbox w="35.0" h="10.0" x="5608.5" y="809.599"/> </glyph> <glyph class="state variable" id="_8881dde2-30cd-406a-a499-2e6c28583a2c"> <state value="P" variable="S621"/> <bbox w="35.0" h="10.0" x="5608.5" y="850.39594"/> </glyph> <glyph class="state variable" id="_160928c6-5abf-4ee1-83b1-602614cdcff4"> <state value="" variable="S338"/> <bbox w="30.0" h="10.0" x="5611.0" y="830.46655"/> </glyph> <glyph class="state variable" id="_d2ed7249-616e-4565-bc72-b6738464c75f"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="5717.5" y="830.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1579_emtc_emtc_sa829" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase 1 HUGO:MAP2K1, HGNC:6840, ENTREZ:5604, GENECARDS:GC15P066679, UNIPROT:Q02750 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:7565670 MEK-1/2 have a proline rich domain and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells. MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. PMID:7731720 B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine residues 218 and 222. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MEK1*"/> <bbox w="60.0" h="50.0" x="5663.0" y="917.0"/> <glyph class="state variable" id="_c797f073-37aa-49cd-8410-76a38a18a5d7"> <state value="" variable="S218"/> <bbox w="30.0" h="10.0" x="5648.0" y="915.96936"/> </glyph> <glyph class="state variable" id="_94d81eb6-496f-48ba-a566-87a86463684a"> <state value="" variable="S222"/> <bbox w="30.0" h="10.0" x="5708.0" y="914.6049"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1580_emtc_emtc_sa830" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase 2 HUGO:MAP2K2, HGNC:6842, ENTREZ:5605, GENECARDS:GC19M004090, UNIPROT:P36507 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:7565670 MEK-1/2 have a proline rich domain and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells. MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MEK2*"/> <bbox w="60.0" h="40.0" x="5783.0" y="922.0"/> <glyph class="state variable" id="_5ce20782-1700-4ee0-ab0a-5707a80641c8"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="5775.5" y="920.83844"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1581_emtc_emtc_sa831" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 3 HUGO:MAPK3, HGNC:6877, ENTREZ:5595, GENECARDS:GC16M030125, UNIPROT:P27361 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK1 phosphorylates the critical Tyr and Thr on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK1*"/> <bbox w="48.0" h="43.5" x="5689.0" y="1140.25"/> <glyph class="state variable" id="_bdbff420-3bb0-4ed1-94e5-7c05294b114a"> <state value="" variable="T"/> <bbox w="15.0" h="10.0" x="5681.5" y="1137.4607"/> </glyph> <glyph class="state variable" id="_29bcb92b-c721-41b3-8d82-2b81562bbb1d"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5729.5" y="1135.4707"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1582_emtc_emtc_sa832" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 1 HUGO:MAPK1, HGNC:6871, ENTREZ:5594, GENECARDS:GC22M022108, UNIPROT:P28482 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK2 (phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK2 phosphorylates the critical Tyr and Thr on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK2*"/> <bbox w="48.0" h="43.5" x="5769.0" y="1140.25"/> <glyph class="state variable" id="_b99fe5c6-6b4b-44e6-929a-22de3e8fb9c8"> <state value="" variable="T"/> <bbox w="15.0" h="10.0" x="5761.5" y="1136.9231"/> </glyph> <glyph class="state variable" id="_b73fb8e8-7b63-4602-b2fe-a501f967c7a9"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5809.5" y="1135.5328"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1583_emtc_emtc_sa833" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase 1 HUGO:MAP2K1, HGNC:6840, ENTREZ:5604, GENECARDS:GC15P066679, UNIPROT:Q02750 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:7565670 MEK-1/2 have a proline rich domain and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells. MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. PMID:7731720 B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine residues 218 and 222. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MEK1*"/> <bbox w="60.0" h="50.0" x="5663.0" y="1037.0"/> <glyph class="state variable" id="_cbd50b77-55ec-47b9-ba9d-60b50fa11db7"> <state value="P" variable="S218"/> <bbox w="35.0" h="10.0" x="5645.5" y="1035.9694"/> </glyph> <glyph class="state variable" id="_4a481899-f10e-471d-9a19-64e3eaa919b8"> <state value="P" variable="S222"/> <bbox w="35.0" h="10.0" x="5705.5" y="1034.6049"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1585_emtc_emtc_sa836" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase 2 HUGO:MAP2K2, HGNC:6842, ENTREZ:5605, GENECARDS:GC19M004090, UNIPROT:P36507 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:7565670 MEK-1/2 have a proline rich domain and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells. MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MEK2*"/> <bbox w="60.0" h="40.0" x="5783.0" y="1042.0"/> <glyph class="state variable" id="_14af285a-b3c9-4e07-9b7f-49a77e555c3b"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="5773.0" y="1040.8385"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1586_emtc_emtc_sa839" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 3 HUGO:MAPK3, HGNC:6877, ENTREZ:5595, GENECARDS:GC16M030125, UNIPROT:P27361 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK1 phosphorylates the critical Tyr and Thr on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK1*"/> <bbox w="48.0" h="43.5" x="5558.0" y="1140.25"/> <glyph class="state variable" id="_c8a6a8f6-96d5-402d-a90a-a08f0e50593e"> <state value="P" variable="T"/> <bbox w="20.0" h="10.0" x="5548.0" y="1137.4607"/> </glyph> <glyph class="state variable" id="_4e7b5462-eeca-4243-a81e-35732d7f4072"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5596.0" y="1135.4707"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1587_emtc_emtc_sa840" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 1 HUGO:MAPK1, HGNC:6871, ENTREZ:5594, GENECARDS:GC22M022108, UNIPROT:P28482 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK2 (phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK2 phosphorylates the critical Tyr and Thr on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK2*"/> <bbox w="48.0" h="43.5" x="5900.0" y="1140.25"/> <glyph class="state variable" id="_0b67e744-7f1a-4c1f-a57a-bf3e0996e48a"> <state value="P" variable="T"/> <bbox w="20.0" h="10.0" x="5890.0" y="1136.9231"/> </glyph> <glyph class="state variable" id="_1d3a1c66-fb7d-492d-9fa8-2a6f043b58d8"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5938.0" y="1135.5328"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1590_emtc_emtc_sa843" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 3 HUGO:MAPK3, HGNC:6877, ENTREZ:5595, GENECARDS:GC16M030125, UNIPROT:P27361 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK1 phosphorylates the critical Tyr and Thr on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK1*"/> <bbox w="54.0" h="49.5" x="5555.0" y="1237.25"/> <glyph class="unit of information" id="_f2d14985-9c0b-487a-afb4-393b7d68e1ae"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5572.0" y="1232.25"/> </glyph> <glyph class="state variable" id="_f5bd5ccf-6a2d-4735-9712-2cf24a69a16d"> <state value="P" variable="T"/> <bbox w="20.0" h="10.0" x="5545.0" y="1234.7656"/> </glyph> <glyph class="state variable" id="_b17289b6-2686-431e-ad9d-fc7170d15428"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5599.0" y="1232.5012"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s1591_emtc_emtc_sa844" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 1 HUGO:MAPK1, HGNC:6871, ENTREZ:5594, GENECARDS:GC22M022108, UNIPROT:P28482 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK2 (phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK2 phosphorylates the critical Tyr and Thr on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK2*"/> <bbox w="54.0" h="49.5" x="5897.0" y="1237.25"/> <glyph class="unit of information" id="_c0d59061-2b9e-41eb-86bf-77b5fbde85b5"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5914.0" y="1232.25"/> </glyph> <glyph class="state variable" id="_2fc03443-9a0b-4364-a085-4c71c2cef145"> <state value="P" variable="T"/> <bbox w="20.0" h="10.0" x="5887.0" y="1234.1538"/> </glyph> <glyph class="state variable" id="_cd412a0d-2084-48ed-97e0-3a7014925442"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5941.0" y="1232.5719"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1592_emtc_emtc_sa845" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MAP kinase interacting serine/threonine kinase 1 HUGO:MKNK1, HGNC:7110, ENTREZ:8569, GENECARDS:GC01M047023, UNIPROT:Q9BUB5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9155017 Mnk1 and Mnk2 bind to Erk1, Erk2 and p38 but not JNK Mnk1 and Mnk2 are in vitro substrates of Erk2 and p38 Mnk1 is a MAP kinase-activated eIF-4E kinase. In vitro, Mnk1 rapidly phosphorylates eIF-4E at the physiologically relevant site, Ser209 PMID:9878069 Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. Phosphorylation of eIF-4E is believed to enhance its affinity for the 5'-cap References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MKNK1"/> <bbox w="60.0" h="20.0" x="5683.0" y="1192.0"/> <glyph class="state variable" id="_471e4437-500b-4462-86c9-14f80c97888c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5678.0" y="1187.6821"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1593_emtc_emtc_sa846" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MAP kinase interacting serine/threonine kinase 2 HUGO:MKNK2, HGNC:7111, ENTREZ:2872, GENECARDS:GC19M002037, UNIPROT:Q9HBH9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9155017 Mnk1 and Mnk2 bind to Erk1, Erk2 and p38 but not JNK Mnk1 and Mnk2 are in vitro substrates of Erk2 and p38 Mnk1 is a MAP kinase-activated eIF-4E kinase References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MKNK2"/> <bbox w="60.0" h="20.0" x="5763.0" y="1192.0"/> <glyph class="state variable" id="_97227d37-d99d-4b35-82e9-264a545fe00b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5758.0" y="1188.1115"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1594_emtc_emtc_sa847" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MAP kinase interacting serine/threonine kinase 1 HUGO:MKNK1, HGNC:7110, ENTREZ:8569, GENECARDS:GC01M047023, UNIPROT:Q9BUB5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9155017 Mnk1 and Mnk2 bind to Erk1, Erk2 and p38 but not JNK Mnk1 and Mnk2 are in vitro substrates of Erk2 and p38 Mnk1 is a MAP kinase-activated eIF-4E kinase. In vitro, Mnk1 rapidly phosphorylates eIF-4E at the physiologically relevant site, Ser209 PMID:9878069 Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. Phosphorylation of eIF-4E is believed to enhance its affinity for the 5'-cap References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MKNK1"/> <bbox w="60.0" h="20.0" x="5683.0" y="1292.0"/> <glyph class="state variable" id="_ab1c1d0c-9dcb-482f-b168-3f755342df93"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5675.5" y="1287.6821"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1595_emtc_emtc_sa848" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MAP kinase interacting serine/threonine kinase 2 HUGO:MKNK2, HGNC:7111, ENTREZ:2872, GENECARDS:GC19M002037, UNIPROT:Q9HBH9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9155017 Mnk1 and Mnk2 bind to Erk1, Erk2 and p38 but not JNK Mnk1 and Mnk2 are in vitro substrates of Erk2 and p38 Mnk1 is a MAP kinase-activated eIF-4E kinase References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MKNK2"/> <bbox w="60.0" h="20.0" x="5763.0" y="1292.0"/> <glyph class="state variable" id="_d72d9d6b-99b6-4cd1-83c8-fe1e96e463a5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5755.5" y="1288.1115"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1596_emtc_emtc_sa849" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: eukaryotic translation initiation factor 4E HUGO:EIF4E, HGNC:3287, ENTREZ:1977, GENECARDS:GC04M099799, UNIPROT:P06730 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9878069 Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. PMID:9155017 In vitro, Mnk1 rapidly phosphorylates eIF-4E at the physiologically relevant site, Ser209 Phosphorylation of eIF-4E is believed to enhance its affinity for the 5'-cap References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EIF4E"/> <bbox w="60.0" h="20.0" x="5551.0" y="1305.0"/> <glyph class="state variable" id="_5a7c457c-1220-492e-9777-41609548ea33"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5546.0" y="1300.439"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1597_emtc_emtc_sa850" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: eukaryotic translation initiation factor 4E HUGO:EIF4E, HGNC:3287, ENTREZ:1977, GENECARDS:GC04M099799, UNIPROT:P06730 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9878069 Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. PMID:9155017 In vitro, Mnk1 rapidly phosphorylates eIF-4E at the physiologically relevant site, Ser209 Phosphorylation of eIF-4E is believed to enhance its affinity for the 5'-cap References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EIF4E"/> <bbox w="60.0" h="20.0" x="5551.0" y="1373.0"/> <glyph class="state variable" id="_e6d0e34c-ce8b-4e08-b6d6-6ef483742018"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5543.5" y="1368.439"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1598_emtc_emtc_sa853" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162, UNIPROT:Q16665 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: http://www.omicsonline.org/1948-5956/JCST-03-035.php HIF-1 is the Commander of Gateways to Cancer PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIFα*"/> <bbox w="40.0" h="20.0" x="3844.0" y="1856.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1602_emtc_emtc_sa857" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 14 HUGO:KRT14, HGNC:6416, ENTREZ:3861, GENECARDS:GC17M039738, UNIPROT:P02533 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT14"/> <bbox w="60.0" h="20.0" x="4833.5" y="3115.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1605_emtc_emtc_sa860" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343, UNIPROT:P05783 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT18"/> <bbox w="60.0" h="20.0" x="4833.5" y="3086.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1608_emtc_emtc_sa863" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 19 HUGO:KRT19, HGNC:6436, ENTREZ:3880, GENECARDS:GC17M039679, UNIPROT:P08727 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT19"/> <bbox w="60.0" h="20.0" x="4833.5" y="3046.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1610_emtc_emtc_sa865" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: aryl hydrocarbon receptor nuclear translocator HUGO:ARNT, HGNC:700, ENTREZ:405, GENECARDS:GC01M150782, UNIPROT:P27540 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: http://www.omicsonline.org/1948-5956/JCST-03-035.php HIF-1 is the Commander of Gateways to Cancer PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF1B*"/> <bbox w="46.0" h="20.0" x="3943.0" y="1855.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1619_emtc_emtc_sa873" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: L1 cell adhesion molecule HUGO:L1CAM, HGNC:6470, ENTREZ:3897, GENECARDS:GC0XM153126, UNIPROT:P32004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: ISBN:978-953-51-0410-0 PMID:8893017 PMID:20044598 The adhesion molecule L1CAM (CD171) is a 220 kD transmembrane glyocoprotein and belongs to the immunoglobulin superfamily. The extracellular part of the molecule comprises six Ig-like domains followed by 5 fibronectin type III repeats. The transmembrane domain is followed by a short cytoplasmic tail of 32kD PMID:10413675 L1CAM can be expressed and mediate its effects as a membrane-bound form. L1CAM can also be proteolytically cleaved by different proteases releasing a soluble ectodomain that is likewise functionally active. PMID:16199880 PMID:11706054 The metalloproteases ADAM 10 and 17 as well as plasmin have been described to cleave L1CAM generating a soluble 200 kD and 150 kD form, respectively After ADAM-mediated cleavage, the membrane-bound intracellular C-terminal fragment of L1CAM can be further processed by the presenilin/gamma-secretase complex giving rise of a 28 kD fragment. PMID:19260824 This small intracellular fragment translocates into the nucleus where it is thought to contribute to L1CAM-dependent gene regulation. L1CAM can bind to different substrates/molecules in a cell and context dependent manner. PMID:10469653 LACAM can undergo homophilic binding to itself as a membrane-bound or shedded form. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. PMID:8898967 PMID:8636223 PMID:11553709 PMID:10455125 PMID:16377081 PMID:7613634 PMID:1720120 L1CAM can interact with a plethora of other proteins, e.g. integrins aVb1, aVb3, aVb5, a5b1, neuropilin-1, CD24, neurocan, and axonin-1/TAX-1. PMID:6368220 L1CAM was originally identified in cells of the nervous system PMID:9127006 L1CAM expression has been also found in certain populations of hematopoietic cells. PMID:19273627 Potential role for L1CAM in transendothelial migration and trafficking of murine dendritic cells. PMID:9864376 Furthermore, L1CAM is expressed by renal tubular epithelial cells under physiological conditions being involved in branching of renal tubes in the kidney However, distribution of L1CAM in adults is quite restricted so that its elevated expression in cancerous tissues which is discussed in the next paragraph favours its suitability as therapeutic target in anti-cancer therapy. PMID:19356150 PMID:21195665 L1CAM expression in tumors can be associated with the activation of several signalling pathways that are known to play a pivotal role in tumor progression e.g. the MAPK/ERK and AKT pathway or FAK-mediated signalling PMID:15716380 PMID:17699774 PMID:20501702 L1CAM is a target gene of b-catenin-TCF signaling in colorectal cancer cells. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis The transmembrane localization and shedding of L1CAM by metalloproteases, including ADAM10 could be useful for detection and as target for colon cancer therapy. Expression of L1CAM and ADAM10 in human colon cancer cells induces metastasis. NFkB signaling and ezrin are essential for L1CAM-mediated metastasis of colon cancer cells. PMID:21123622 Gavert and al. showed that L1CAM-mediated colon cancer cell metastasis does not require changes in EMT and cancer stem cell markers. BUT in other context, PMID:19435915 PMID:21109948 Geismann and al. showed that upregulation of L1CAM in pancreatic duct cells is TGFB1- and SNAI2-dependent. Binding of SNAI2 to the L1CAM promoter is essential for TGFB1-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. TGFB1–mediated L1CAM expression is SMAD independent but requires JNK activation. In the context of the human PDAC (pancreatic ductal epithelial cell) line H6c7 which mimics the early steps in PDAC tumorigenesis,TGFB1 induces SNAI2 expression in H6c7 cells through JNK activation. THUS, the impact of L1CAM on EMT might be either tumor specific and/or tumor stage dependent. Further studies are required to elaborate whether upregulation of L1CAM is part of the EMT or even the inducing event. If it is the case, elevated cell migration and apoptosis resistance could be abolished by interfering wih TGFB1 signaling or by supression of SNAI2 or L1CAM. PMID:16506207 PMID:17952127 PMID:21373966 Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated. A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes. Besides its ability to induce Erk1/2 and FAK signalling pathways, L1CAM can also lead to the activation of NF-kB, so that inhibition of NF-kB reduced L1CAM-mediated metastasis of colon cancer cells. PMID:17145883 Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases B-catenin transcriptional activity, thus increases scattering and motility of MCF7 breast carcinoma cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="L1CAM"/> <bbox w="60.0" h="20.0" x="593.5" y="3648.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1622_emtc_emtc_sa876" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: prokineticin 1 HUGO:PROK1, HGNC:18454, ENTREZ:84432, GENECARDS:GC01P110994, UNIPROT:P58294 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11528470 EG-VEGF (Prokinecticin 1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, VEGFR1, and Erythoproietin PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EG-VEGF*"/> <bbox w="60.0" h="20.0" x="4870.0" y="4892.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1625_emtc_emtc_sa880" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fms-related tyrosine kinase 1 HUGO:FLT1, HGNC:3763, ENTREZ:2321, GENECARDS:GC13M028874, UNIPROT:P17948 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11528470 VEGFR1 (FLT1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, EG-VEGF, and Erythoproietin PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 PMID:1312256 PMID:7929268 PMID:9751730 VEGFR1 is a hight-affinnity receptor for VEGF-A, B and PLGF PMID:11166270 PMID:11312109 VEGFR1 is expressed in vascular endothelial and some non-endothelial cells including harmatopoietic stem cells, macrophages and monocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR1*"/> <bbox w="60.0" h="24.0" x="4870.0" y="4930.5"/> <glyph class="unit of information" id="_1f0548d7-78d5-400a-b092-167558181530"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4877.5" y="4925.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1626_emtc_emtc_sa881" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: kinase insert domain receptor (a type III receptor tyrosine kinase) HUGO:KDR, HGNC:6307, ENTREZ:3791, GENECARDS:GC04M055944, UNIPROT:P35968 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:11166270 VEGFR2 is highly specific towards VEGFA. PMID:11741095 PMID:13678960 However VEGFR2 also binds to processed forms of VEGF-C, D, E. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. PMID:15501236 PMID:14739162 Although Endothelial cells express both receptors VEGFR1 and VEGFR2, only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR2*"/> <bbox w="61.0" h="29.0" x="4871.0" y="4984.996"/> <glyph class="state variable" id="_f2f9ded8-614f-451b-9917-24921ba82ce0"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="4863.5" y="4980.391"/> </glyph> <glyph class="unit of information" id="_abec6b03-79f7-450c-9e90-76b7d0192a0c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4879.0" y="4979.996"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1635_emtc_emtc_sa888" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: L1 cell adhesion molecule HUGO:L1CAM, HGNC:6470, ENTREZ:3897, GENECARDS:GC0XM153126, UNIPROT:P32004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: ISBN:978-953-51-0410-0 PMID:8893017 PMID:20044598 The adhesion molecule L1CAM (CD171) is a 220 kD transmembrane glyocoprotein and belongs to the immunoglobulin superfamily. The extracellular part of the molecule comprises six Ig-like domains followed by 5 fibronectin type III repeats. The transmembrane domain is followed by a short cytoplasmic tail of 32kD PMID:10413675 L1CAM can be expressed and mediate its effects as a membrane-bound form. L1CAM can also be proteolytically cleaved by different proteases releasing a soluble ectodomain that is likewise functionally active. PMID:16199880 PMID:11706054 The metalloproteases ADAM 10 and 17 as well as plasmin have been described to cleave L1CAM generating a soluble 200 kD and 150 kD form, respectively After ADAM-mediated cleavage, the membrane-bound intracellular C-terminal fragment of L1CAM can be further processed by the presenilin/gamma-secretase complex giving rise of a 28 kD fragment. PMID:19260824 This small intracellular fragment translocates into the nucleus where it is thought to contribute to L1CAM-dependent gene regulation. L1CAM can bind to different substrates/molecules in a cell and context dependent manner. PMID:10469653 LACAM can undergo homophilic binding to itself as a membrane-bound or shedded form. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. PMID:8898967 PMID:8636223 PMID:11553709 PMID:10455125 PMID:16377081 PMID:7613634 PMID:1720120 L1CAM can interact with a plethora of other proteins, e.g. integrins aVb1, aVb3, aVb5, a5b1, neuropilin-1, CD24, neurocan, and axonin-1/TAX-1. PMID:6368220 L1CAM was originally identified in cells of the nervous system PMID:9127006 L1CAM expression has been also found in certain populations of hematopoietic cells. PMID:19273627 Potential role for L1CAM in transendothelial migration and trafficking of murine dendritic cells. PMID:9864376 Furthermore, L1CAM is expressed by renal tubular epithelial cells under physiological conditions being involved in branching of renal tubes in the kidney However, distribution of L1CAM in adults is quite restricted so that its elevated expression in cancerous tissues which is discussed in the next paragraph favours its suitability as therapeutic target in anti-cancer therapy. PMID:19356150 PMID:21195665 L1CAM expression in tumors can be associated with the activation of several signalling pathways that are known to play a pivotal role in tumor progression e.g. the MAPK/ERK and AKT pathway or FAK-mediated signalling PMID:15716380 PMID:17699774 PMID:20501702 L1CAM is a target gene of b-catenin-TCF signaling in colorectal cancer cells. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis The transmembrane localization and shedding of L1CAM by metalloproteases, including ADAM10 could be useful for detection and as target for colon cancer therapy. Expression of L1CAM and ADAM10 in human colon cancer cells induces metastasis. NFkB signaling and ezrin are essential for L1CAM-mediated metastasis of colon cancer cells. PMID:21123622 Gavert and al. showed that L1CAM-mediated colon cancer cell metastasis does not require changes in EMT and cancer stem cell markers. BUT in other context, PMID:19435915 PMID:21109948 Geismann and al. showed that upregulation of L1CAM in pancreatic duct cells is TGFB1- and SNAI2-dependent. Binding of SNAI2 to the L1CAM promoter is essential for TGFB1-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. TGFB1–mediated L1CAM expression is SMAD independent but requires JNK activation. In the context of the human PDAC (pancreatic ductal epithelial cell) line H6c7 which mimics the early steps in PDAC tumorigenesis,TGFB1 induces SNAI2 expression in H6c7 cells through JNK activation. THUS, the impact of L1CAM on EMT might be either tumor specific and/or tumor stage dependent. Further studies are required to elaborate whether upregulation of L1CAM is part of the EMT or even the inducing event. If it is the case, elevated cell migration and apoptosis resistance could be abolished by interfering wih TGFB1 signaling or by supression of SNAI2 or L1CAM. PMID:16506207 PMID:17952127 PMID:21373966 Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated. A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes. Besides its ability to induce Erk1/2 and FAK signalling pathways, L1CAM can also lead to the activation of NF-kB, so that inhibition of NF-kB reduced L1CAM-mediated metastasis of colon cancer cells. PMID:17145883 Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases B-catenin transcriptional activity, thus increases scattering and motility of MCF7 breast carcinoma cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="L1CAM"/> <bbox w="60.0" h="20.0" x="499.0" y="3651.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1733_emtc_emtc_sa895" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="39.0" h="19.0" x="3971.5" y="2010.5"/> <glyph class="state variable" id="_39be73cb-413f-41b9-9f17-a67ded3c83e8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4005.5" y="2011.065"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1806_emtc_emtc_sa905" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:12667443 PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:22836101 BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro-survival family members such as BCL2L1 act to inhibit BAX activation PMID:23064052 PMID:11085534 BCL2 and BCL2L1 are known to be overexpressed in several cancers. In particular, BCL2L1 overexpression has been correlated with cancer cells resistance to chemotherapeutic agents References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2-XL*"/> <bbox w="64.0" h="21.0" x="4519.0" y="1342.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1807_emtc_emtc_sa907" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="34.5" h="20.0" x="4358.75" y="1344.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1811_emtc_emtc_sa906" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="49.0" h="19.0" x="4457.5" y="1269.0"/> <glyph class="state variable" id="_0aa2f368-ca0a-42c2-9cb9-71952dadf0db"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4501.5" y="1269.565"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1841_emtc_emtc_sa909" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2-antagonist/killer 1 HUGO:BAK1, HGNC:949, ENTREZ:578, UNIPROT:Q16611, GENECARDS:GC06M033489 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAK1"/> <bbox w="39.0" h="19.0" x="4118.5" y="1251.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1857_emtc_emtc_sa935" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="N-Cadherin*"/> <bbox w="80.0" h="20.0" x="596.0" y="3838.5"/> <glyph class="state variable" id="_9fc7009f-d1ef-41e4-a636-b4452fcf651f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="671.0" y="3853.0654"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1858_emtc_emtc_sa936" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="P-Cadherin*"/> <bbox w="80.0" h="20.0" x="596.0" y="3930.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1859_emtc_emtc_sa937" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="R-Cadherin*"/> <bbox w="80.0" h="20.0" x="598.0" y="4029.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1860_emtc_emtc_sa938" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by 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MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="P-Cadherin*"/> <bbox w="80.0" h="20.0" x="470.0" y="3929.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1862_emtc_emtc_sa940" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="R-Cadherin*"/> <bbox w="80.0" h="20.0" x="469.0" y="4028.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1863_emtc_emtc_sa941" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VE-Cadherin*"/> <bbox w="80.0" h="20.0" x="592.0" y="4137.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1864_emtc_emtc_sa942" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VE-Cadherin*"/> <bbox w="80.0" h="20.0" x="476.0" y="4141.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1869_emtc_emtc_sa947" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="20.0" x="468.0" y="3385.0"/> <glyph class="state variable" id="_faf1b5fd-a981-4121-a33b-6f371abcc933"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="460.5" y="3380.8398"/> </glyph> <glyph class="state variable" id="_f96c512b-d874-4d8e-8536-0d30c8d5b0c7"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="540.5" y="3381.2292"/> </glyph> <glyph class="state variable" id="_da83f362-d501-4485-8e69-8508fe9a40cd"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="539.8818" y="3400.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1872_emtc_emtc_sa979" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="75.0" h="29.0" x="1060.0" y="3894.5"/> <glyph class="state variable" id="_a5c0a963-45cd-4adf-b873-d8f64879ab2e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1055.0" y="3891.2417"/> </glyph> <glyph class="state variable" id="_a7f20abc-5efb-4526-ae85-99c5adc41b38"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1092.5299" y="3889.5"/> </glyph> <glyph class="state variable" id="_bcf2dff7-b490-40e2-b2b1-b4477ab163e1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1130.0" y="3889.5"/> </glyph> <glyph class="state variable" id="_6d79870f-07a4-4228-a691-e64b29cdba37"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1107.5126" y="3889.5"/> </glyph> <glyph class="state variable" id="_88e5861c-6862-48c2-b03b-bd9ac6b7d23b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1076.6804" y="3889.5"/> </glyph> <glyph class="state variable" id="_a05daba8-75ef-4d0f-a693-1c2a64a20ae9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1130.0" y="3916.7993"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1876_emtc_emtc_sa953" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="50.0" h="16.0" x="2837.0" y="3570.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1877_emtc_emtc_sa954" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 2 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC2"/> <bbox w="53.0" h="17.0" x="2705.0" y="3511.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1878_emtc_emtc_sa955" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1 polycomb ring finger oncogene "B lymphoma Mo-MLV insertion region 1 homolog (mouse)", PCGF4, "polycomb group ring finger 4" HUGO:BMI1 HGNC:1066 ENTREZ:648 UNIPROT:P35226 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1"/> <bbox w="42.0" h="16.0" x="2310.0" y="4078.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1879_emtc_emtc_sa956" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 2 (Drosophila) "enhancer of zeste (Drosophila) homolog 2" HUGO:EZH2 HGNC:3527 ENTREZ:2146 UNIPROT:Q15910 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH2"/> <bbox w="41.0" h="16.0" x="2964.0" y="3331.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1953_emtc_emtc_sa958" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: Feedback loops PMID:22514743 PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="50.0" h="20.0" x="2690.5" y="2114.0"/> <glyph class="state variable" id="_955cc0e0-580a-4daf-a1e8-54f0b0bfa5d2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2683.0" y="2110.0222"/> </glyph> <glyph class="state variable" id="_2806cd2d-5693-45fe-af6e-8fcb4165a315"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2735.5" y="2110.0508"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1954_emtc_emtc_sa959" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: Feedback loops PMID:22514743 PMID:17018611 Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="50.0" h="20.0" x="2690.0" y="1721.5"/> <glyph class="state variable" id="_f10e85ad-ce7a-4b0b-b944-83069b911f2c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2682.5" y="1717.5221"/> </glyph> <glyph class="state variable" id="_ca2fdefb-5abf-4933-bda9-be3860fe119c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2732.5" y="1717.5508"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1957_emtc_emtc_sa501" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) HUGO:CDKN2B, HGNC:1788, ENTREZ:1030, GENECARDS:GC09M021992, UNIPROT:P42772 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p15INK4B*"/> <bbox w="80.0" h="20.0" x="3531.666" y="1879.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1958_emtc_emtc_sa480" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455, UNIPROT:P24385 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Only several CDK–cyclin complexes are directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="59.0" h="20.0" x="2809.0" y="1633.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1959_emtc_emtc_sa496" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540, UNIPROT:P49841 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. PMID:15020233 MEK1/2 can phosphorylate tyrosine 216, which stimulates GSK3B kinase activity U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK3B, suggesting that MEK1/2 was involved in the phosphorylation of Tyr216 in GSK3B In vitro kinase interaction showed that GSK3B is phosphorylated by recombinant MEK1 at Y216 PMID:16944320 The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones PMID:9832503 GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1 GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. PMID:14663202 GSK3B is highly activated in nuclei and mitochondria. PMID:11967263 Tyr-216 phosphorylation is required for GSK-mediated down-regulation of b-catenin activity. PMID:8524413 Inactiviation of GSK-3 occurs through Akt phosphorylation of serine 9 of GSK-3b. This phosphorylation may be involved in later phases of neuronal apoptosis. Mutation of Ser9 to Ala did not affect GSK-3 -mediated phosphorylation of b-catenin, whereas mutation of Tyr216 to Phe markedly reduced the in vivo phosphorylation of b-catenin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="63.0" h="40.0" x="2778.0" y="1840.5"/> <glyph class="state variable" id="_0cb26f89-6051-4c3b-b167-7f724ba4445a"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="2770.5" y="1837.9022"/> </glyph> <glyph class="state variable" id="_ea6d8f2c-749e-4ebe-a870-2a07682a6160"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="2833.2114" y="1835.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1963_emtc_emtc_sa967" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540, UNIPROT:P49841 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. PMID:15020233 MEK1/2 can phosphorylate tyrosine 216, which stimulates GSK3B kinase activity U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK3B, suggesting that MEK1/2 was involved in the phosphorylation of Tyr216 in GSK3B In vitro kinase interaction showed that GSK3B is phosphorylated by recombinant MEK1 at Y216 PMID:16944320 The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones PMID:9832503 GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1 GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. PMID:14663202 GSK3B is highly activated in nuclei and mitochondria. PMID:11967263 Tyr-216 phosphorylation is required for GSK-mediated down-regulation of b-catenin activity. PMID:8524413 Inactiviation of GSK-3 occurs through Akt phosphorylation of serine 9 of GSK-3b. This phosphorylation may be involved in later phases of neuronal apoptosis. Mutation of Ser9 to Ala did not affect GSK-3 -mediated phosphorylation of b-catenin, whereas mutation of Tyr216 to Phe markedly reduced the in vivo phosphorylation of b-catenin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="56.0" h="40.0" x="2090.0" y="1839.5"/> <glyph class="state variable" id="_eb961989-884e-441e-ace7-6838ed7265fa"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="2080.0" y="1836.9022"/> </glyph> <glyph class="state variable" id="_f6aaa8ce-da93-40ec-95f6-fadf3deebcc2"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="2138.2434" y="1834.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1964_emtc_emtc_sa968" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540, UNIPROT:P49841 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. PMID:15020233 MEK1/2 can phosphorylate tyrosine 216, which stimulates GSK3B kinase activity U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK3B, suggesting that MEK1/2 was involved in the phosphorylation of Tyr216 in GSK3B In vitro kinase interaction showed that GSK3B is phosphorylated by recombinant MEK1 at Y216 PMID:16944320 The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones PMID:9832503 GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1 GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. PMID:14663202 GSK3B is highly activated in nuclei and mitochondria. PMID:11967263 Tyr-216 phosphorylation is required for GSK-mediated down-regulation of b-catenin activity. PMID:8524413 Inactiviation of GSK-3 occurs through Akt phosphorylation of serine 9 of GSK-3b. This phosphorylation may be involved in later phases of neuronal apoptosis. Mutation of Ser9 to Ala did not affect GSK-3 -mediated phosphorylation of b-catenin, whereas mutation of Tyr216 to Phe markedly reduced the in vivo phosphorylation of b-catenin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="64.0" h="40.0" x="2899.0" y="1840.5"/> <glyph class="state variable" id="_a3e2f121-70ca-4314-857f-924049648578"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="2891.5" y="1837.9022"/> </glyph> <glyph class="state variable" id="_6ddd8eab-f690-4b69-a5c2-ce235089ae07"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="2952.7068" y="1835.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s1970_emtc_emtc_sa973" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin E1 HUGO:CCNE1, HGNC:1589, ENTREZ:898, GENECARDS:GC19P030302, UNIPROT:P24864 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinE1*"/> <bbox w="60.0" h="20.0" x="3116.0" y="1944.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2044_emtc_emtc_sa982" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: casein kinase 1, alpha 1 HUGO:CSNK1A1, HGNC:2451, ENTREZ:1452, UNIPROT:P48729, GENECARDS:GC05M148854 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has recently been shown that the GSK-3 dependent phosphorylation of b-catenin requiresprior priming through phosphorylation of Ser45 GSK-3b wasfound to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CK1α*"/> <bbox w="60.0" h="20.0" x="1148.0" y="3564.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2045_emtc_emtc_sa983" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN1"/> <bbox w="40.0" h="20.0" x="800.0" y="3629.5"/> <glyph class="state variable" id="_3896bda8-621e-41e5-ba58-135f77e08deb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="815.416" y="3624.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2046_emtc_emtc_sa2230" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dishevelled, dsh homolog 1 (Drosophila) HUGO:DVL1, HGNC:3084, ENTREZ:1855, UNIPROT:O14640 , GENECARDS:GC01M001262 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding, DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DVL1"/> <bbox w="40.0" h="20.0" x="830.5" y="5944.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2047_emtc_emtc_sa985" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="APC"/> <bbox w="40.0" h="20.0" x="911.0" y="3681.5"/> <glyph class="state variable" id="_b83d1608-713d-43ab-9e5a-9a072a13ec07"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="926.416" y="3676.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2072_emtc_emtc_sa1009" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, alpha HUGO:TGFA HGNC:11765 ENTREZ:7039 UNIPROT:P01135 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFA"/> <bbox w="42.0" h="17.0" x="2320.0" y="6622.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2073_emtc_emtc_sa1010" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor necrosis factor TNFA, "tumor necrosis factor (TNF superfamily, member 2)" HUGO:TNF HGNC:11892 ENTREZ:7124 UNIPROT:P01375 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19411070 TNFa dramatically enhanced the protein stabilization of Snail1 through NF-kB mediated CSN2 induction. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TNF"/> <bbox w="36.0" h="17.0" x="2977.0" y="115.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2075_emtc_emtc_sa1012" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF2"/> <bbox w="40.0" h="19.0" x="2930.0" y="6507.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2076_emtc_emtc_sa1013" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: epidermal growth factor "epidermal growth factor (beta-urogastrone)" HUGO:EGF HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGF"/> <bbox w="33.0" h="19.0" x="2238.125" y="6621.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2152_emtc_emtc_sa1017" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-3 partitioning defective 3 homolog (C. elegans) HUGO:PARD3, HGNC:16051, ENTREZ:56288, GENECARDS:GC10M034438, UNIPROT:Q8TEW0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR3*"/> <bbox w="51.0" h="24.0" x="2077.0" y="2390.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2162_emtc_emtc_sa1024" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-3 partitioning defective 3 homolog (C. elegans) HUGO:PARD3, HGNC:16051, ENTREZ:56288, GENECARDS:GC10M034438, UNIPROT:Q8TEW0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR3*"/> <bbox w="38.0" h="19.0" x="604.0" y="2393.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2167_emtc_emtc_sa1517" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 1 "p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)", "p21/Cdc42/Rac1-activated kinase 1 (yeast Ste20-related)" HUGO:PAK1 HGNC:8590 ENTREZ:5058 UNIPROT:Q13153 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="35.0" h="20.0" x="5545.5" y="2266.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2167_emtc_emtc_sa1032" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 1 "p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)", "p21/Cdc42/Rac1-activated kinase 1 (yeast Ste20-related)" HUGO:PAK1 HGNC:8590 ENTREZ:5058 UNIPROT:Q13153 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="35.0" h="20.0" x="5688.5" y="2266.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2168_emtc_emtc_sa1518" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 2 "p21 (CDKN1A)-activated kinase 2" HUGO:PAK2 HGNC:8591 ENTREZ:5062 UNIPROT:Q13177 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK2"/> <clone/> <bbox w="35.0" h="19.0" x="5545.5" y="2293.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2168_emtc_emtc_sa1033" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 2 "p21 (CDKN1A)-activated kinase 2" HUGO:PAK2 HGNC:8591 ENTREZ:5062 UNIPROT:Q13177 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK2"/> <clone/> <bbox w="35.0" h="19.0" x="5688.5" y="2293.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2169_emtc_emtc_sa1034" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 3 "mental retardation, X-linked 47", MRX30, MRX47, "p21 (CDKN1A)-activated kinase 3" HUGO:PAK3 HGNC:8592 ENTREZ:5063 UNIPROT:O75914 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK3"/> <clone/> <bbox w="35.0" h="20.0" x="5688.5" y="2236.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2169_emtc_emtc_sa1519" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 3 "mental retardation, X-linked 47", MRX30, MRX47, "p21 (CDKN1A)-activated kinase 3" HUGO:PAK3 HGNC:8592 ENTREZ:5063 UNIPROT:O75914 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK3"/> <clone/> <bbox w="35.0" h="20.0" x="5545.5" y="2236.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2173_emtc_emtc_sa1038" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: WAS protein family, member 1 HUGO:WASF1 HGNC:12732 ENTREZ:8936 UNIPROT:Q92558 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASF1"/> <clone/> <bbox w="45.0" h="22.0" x="5871.5" y="2750.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2173_emtc_emtc_sa1501" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: WAS protein family, member 1 HUGO:WASF1 HGNC:12732 ENTREZ:8936 UNIPROT:Q92558 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASF1"/> <clone/> <bbox w="45.0" h="22.0" x="5971.5" y="2750.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2174_emtc_emtc_sa1039" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: WAS protein family, member 2 HUGO:WASF2 HGNC:12733 ENTREZ:10163 UNIPROT:Q9Y6W5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASF2"/> <clone/> <bbox w="47.0" h="21.0" x="5692.5" y="2752.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2174_emtc_emtc_sa1490" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: WAS protein family, member 2 HUGO:WASF2 HGNC:12733 ENTREZ:10163 UNIPROT:Q9Y6W5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASF2"/> <clone/> <bbox w="47.0" h="21.0" x="5808.5" y="2752.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2175_emtc_emtc_sa1040" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Wiskott-Aldrich syndrome IMD2, THC, "thrombocytopenia 1 (X-linked)", "Wiskott-Aldrich syndrome (eczema-thrombocytopenia)" HUGO:WAS HGNC:12731 ENTREZ:7454 UNIPROT:P42768 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 induces actin cytoskeleton changes by activating WASP and N-WASP. WASP and N-WASP binds to ARP2/3 and this lieads to actin cytoskeletal polymerization and filopodia formation. PMID:8625410 PMID:16293614 PMID:10467124 PMID:10511705 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASP*"/> <bbox w="49.0" h="18.0" x="6018.0" y="2613.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2176_emtc_emtc_sa1041" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Wiskott-Aldrich syndrome-like HUGO:WASL HGNC:12735 ENTREZ:8976 UNIPROT:O00401 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 induces actin cytoskeleton changes by activating WASP and N-WASP. WASP and N-WASP binds to ARP2/3 and this lieads to actin cytoskeletal polymerization and filopodia formation. PMID:8625410 PMID:16293614 PMID:10467124 PMID:10511705 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="N-WASP*"/> <bbox w="64.0" h="20.0" x="5944.0" y="2613.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2177_emtc_emtc_sa1042" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ARP2 actin-related protein 2 homolog (yeast) "ARP2 (actin-related protein 2, yeast) homolog" HUGO:ACTR2 HGNC:169 ENTREZ:10097 UNIPROT:P61160 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ACTR2"/> <bbox w="47.0" h="18.0" x="5988.5" y="2908.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2178_emtc_emtc_sa1043" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ARP3 actin-related protein 3 homolog (yeast) "ARP3 (actin-related protein 3, yeast) homolog" HUGO:ACTR3 HGNC:170 ENTREZ:10096 UNIPROT:P61158 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ACTR3"/> <bbox w="46.0" h="19.0" x="5914.0" y="2908.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2179_emtc_emtc_sa1044" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42 binding protein kinase alpha (DMPK-like) HUGO:CDC42BPA HGNC:1737 ENTREZ:8476 UNIPROT:Q5VT25 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42BPA"/> <clone/> <bbox w="71.0" h="20.0" x="5030.5" y="2711.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2179_emtc_emtc_sa1524" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42 binding protein kinase alpha (DMPK-like) HUGO:CDC42BPA HGNC:1737 ENTREZ:8476 UNIPROT:Q5VT25 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42BPA"/> <clone/> <bbox w="71.0" h="20.0" x="5166.0" y="2711.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2180_emtc_emtc_sa1045" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 11 MLK3, PTK1 HUGO:MAP3K11 HGNC:6850 ENTREZ:4296 UNIPROT:Q16584 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17161586 CDC42 can activate JNL pathway aslo by binding and stimulation of MAP3K11 (MLK3). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K11"/> <clone/> <bbox w="63.203125" h="22.0" x="5500.898" y="2384.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2180_emtc_emtc_sa1547" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 11 MLK3, PTK1 HUGO:MAP3K11 HGNC:6850 ENTREZ:4296 UNIPROT:Q16584 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17161586 CDC42 can activate JNL pathway aslo by binding and stimulation of MAP3K11 (MLK3). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K11"/> <clone/> <bbox w="63.203125" h="22.0" x="5665.334" y="2384.166"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2181_emtc_emtc_sa1046" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 4 "p21(CDKN1A)-activated kinase 4" HUGO:PAK4 HGNC:16059 ENTREZ:10298 UNIPROT:O96013 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK4"/> <clone/> <bbox w="35.0" h="21.0" x="5688.5" y="2318.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2181_emtc_emtc_sa1520" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: p21 protein (Cdc42/Rac)-activated kinase 4 "p21(CDKN1A)-activated kinase 4" HUGO:PAK4 HGNC:16059 ENTREZ:10298 UNIPROT:O96013 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK4"/> <clone/> <bbox w="35.0" h="21.0" x="5545.5" y="2318.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2182_emtc_emtc_sa1047" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LIM domain kinase 2 HUGO:LIMK2 HGNC:6614 ENTREZ:3985 UNIPROT:P53671 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIMK2"/> <bbox w="42.0" h="19.0" x="4825.75" y="2752.75"/> <glyph class="state variable" id="_d2d0b85d-0594-4e28-b182-16a7586bded3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" 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compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, zeta HUGO:PRKCZ HGNC:9412 ENTREZ:5590 UNIPROT:Q05513 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCZ"/> <clone/> <bbox w="53.0" h="19.0" x="5805.5" y="2487.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2184_emtc_emtc_sa1049" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42 effector protein (Rho GTPase binding) 2 HUGO:CDC42EP2 HGNC:16263 ENTREZ:10435 UNIPROT:O14613 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 promotes cytoskeleton remodeling by binding to CDC42EPs (CDC42EP2 and CDC42EP3) PMID:10490598 PMID:11035016 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42EP2"/> <bbox w="69.0" h="19.0" x="6108.5" y="2274.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2185_emtc_emtc_sa1050" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42 effector protein (Rho GTPase binding) 3 HUGO:CDC42EP3 HGNC:16943 ENTREZ:10602 UNIPROT:Q9UKI2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42EP3"/> <bbox w="70.0" h="17.0" x="6109.0" y="2307.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2186_emtc_emtc_sa1051" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42 small effector 1 HUGO:CDC42SE1 HGNC:17719 ENTREZ:56882 UNIPROT:Q9NRR8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10816584 PMID:17045588 CDC42SE1 (SPEC1) binds to CDC42 and supresses CDC42-induced JNK activation and cytoskeleton remodeling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42SE1"/> <bbox w="66.0" h="18.0" x="6114.0" y="2096.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2188_emtc_emtc_sa1053" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cytoplasmic FMR1 interacting protein 2 HUGO:CYFIP2 HGNC:13760 ENTREZ:26999 UNIPROT:Q96F07 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CYFIP2"/> <bbox w="50.0" h="16.0" x="5864.0" y="2355.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2189_emtc_emtc_sa1054" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BAI1-associated protein 2 HUGO:BAIAP2 HGNC:947 ENTREZ:10458 UNIPROT:Q9UQB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAIAP2"/> <clone/> <bbox w="45.0" h="16.0" x="5649.5" y="2694.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2189_emtc_emtc_sa1489" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BAI1-associated protein 2 HUGO:BAIAP2 HGNC:947 ENTREZ:10458 UNIPROT:Q9UQB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAIAP2"/> <clone/> <bbox w="45.0" h="16.0" x="5749.5" y="2694.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2190_emtc_emtc_sa1055" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ADP-ribosylation factor interacting protein 2 HUGO:ARFIP2 HGNC:17160 ENTREZ:23647 UNIPROT:P53365 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARFIP2"/> <clone/> <bbox w="45.0" h="18.0" x="5609.5" y="2573.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2190_emtc_emtc_sa1482" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ADP-ribosylation factor interacting protein 2 HUGO:ARFIP2 HGNC:17160 ENTREZ:23647 UNIPROT:P53365 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARFIP2"/> <clone/> <bbox w="45.0" h="18.0" x="5747.0" y="2573.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2191_emtc_emtc_sa1056" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-4-phosphate 5-kinase, type I, alpha HUGO:PIP5K1A HGNC:8994 ENTREZ:8394 UNIPROT:Q99755 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PIP5K1A"/> <bbox w="57.0" h="18.0" x="5523.5" y="2613.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2192_emtc_emtc_sa1057" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MCF.2 cell line derived transforming sequence-like HUGO:MCF2L, HGNC:14576, ENTREZ:23263, GENECARDS:GC13P113548, UNIPROT:O15068 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:7957046 OST (so-called DBS, MCF2L, ARHGEF14) encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways PMID:14701795 Co-expression of DBS with activated Rac1 causes enhanced focus forming activity and elevated levels of GTPRhoA in NIH3T3 cells Interaction between activated Rac1 and DBS is specific for Rac1 and is not observed between Rac1 and several other members of the Rho-specific guanine nucleotide exchange factor family. These results showed that activated Rac1 bt stimulation of DBS activity promotes RhoA activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF14*"/> <bbox w="73.0" h="17.0" x="5255.5" y="2128.214"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2193_emtc_emtc_sa1058" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: NCK adaptor protein 1 HUGO:NCK1 HGNC:7664 ENTREZ:4690 UNIPROT:P16333 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCK1"/> <bbox w="37.0" h="18.0" x="5865.5" y="2275.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2194_emtc_emtc_sa1059" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: NCK-associated protein 1 HUGO:NCKAP1 HGNC:7666 ENTREZ:10787 UNIPROT:Q9Y2A7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCKAP1"/> <bbox w="52.0" h="18.0" x="5923.0" y="2354.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2196_emtc_emtc_sa1061" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ralA binding protein 1 HUGO:RALBP1 HGNC:9841 ENTREZ:10928 UNIPROT:Q15311 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:7673236 RalBP1 as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RALBP1"/> <bbox w="50.0" h="19.0" x="6021.1" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2197_emtc_emtc_sa1062" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: active BCR-related HUGO:ABR HGNC:81 ENTREZ:29 UNIPROT:Q12979 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:7479768 PMID:8262969 ABR and BCR as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ABR"/> <bbox w="36.0" h="19.0" x="6075.3" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2198_emtc_emtc_sa1063" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 1 HUGO:ARHGAP1, HGNC:673, ENTREZ:392, GENECARDS:GC11M046698, UNIPROT:Q07960 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9548756 RhoGAP1 (so-called ARHGAP1 or p50RhoGAP) is an RhoGTPase activiating protein. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP1"/> <bbox w="64.0" h="19.0" x="5105.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2199_emtc_emtc_sa1064" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 9 HUGO:ARHGAP9 HGNC:14130 ENTREZ:64333 UNIPROT:Q9BRR9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP9"/> <bbox w="67.0" h="18.0" x="5245.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2200_emtc_emtc_sa1065" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 12 HUGO:ARHGAP12 HGNC:16348 ENTREZ:94134 UNIPROT:Q8IWW6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP12"/> <bbox w="70.0" h="18.0" x="5317.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2201_emtc_emtc_sa1066" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 24 HUGO:ARHGAP24 HGNC:25361 ENTREZ:83478 UNIPROT:Q8N264 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP24"/> <bbox w="75.0" h="17.0" x="5542.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2202_emtc_emtc_sa1067" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SLIT-ROBO Rho GTPase activating protein 3 "SLIT-ROBO Rho GTPase activating protein 2", SRGAP2 HUGO:SRGAP3 HGNC:19744 ENTREZ:9901 UNIPROT:O43295 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP14*"/> <bbox w="75.0" h="16.0" x="5391.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2203_emtc_emtc_sa1068" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: breakpoint cluster region BCR1, D22S11 HUGO:BCR HGNC:1014 ENTREZ:613 UNIPROT:P11274 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:7479768 ABR and BCR as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCR"/> <bbox w="36.0" h="20.0" x="5980.9" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2204_emtc_emtc_sa1069" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rac GTPase activating protein 1 HUGO:RACGAP1 HGNC:9804 ENTREZ:29127 UNIPROT:Q9H0H5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: Cross-talk between small GTPase signaling pathways. PMID:12134164 PMID:7673236 HRAS activates TIAM1 which is a GEF for Rac1. RalBP1 (which is an effector for RalA and RalB) inactivates Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RACGAP1"/> <bbox w="56.0" h="18.0" x="5920.7" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2205_emtc_emtc_sa1424" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 32 HUGO:ARHGAP32, HGNC:17399, ENTREZ:9743, GENECARDS:GC11M128834, UNIPROT:A7KAX9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12788081 p250GAP (so-called ARHGAP32 or p200RhoGAP) is a RhoGAP protein that is expressed predominantly in brain. ARHGAP32 is associated with and phosphorylated by Fyn, a member of Src-family protein tyrosine kinase. PMID:12857875 ARHGAP32 as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP32"/> <bbox w="75.0" h="17.0" x="5766.5" y="1726.5"/> <glyph class="state variable" id="_309145b2-c0f7-4e1b-8eca-9ac149f9fecb"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5834.0" y="1729.5554"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2206_emtc_emtc_sa1071" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: chimerin 2 HUGO:CHN2 HGNC:1944 ENTREZ:1124 UNIPROT:P52757 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17346241 CHN2 as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CHN2"/> <bbox w="43.0" h="16.0" x="6115.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2207_emtc_emtc_sa1072" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GDP dissociation inhibitor (GDI) alpha HUGO:ARHGDIA, HGNC:678, ENTREZ:396, GENECARDS:GC17M079825, UNIPROT:P52565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGDIA"/> <bbox w="55.0" h="17.0" x="4922.5" y="1846.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2208_emtc_emtc_sa1073" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GDP dissociation inhibitor (GDI) beta HUGO:ARHGDIB, HGNC:679, ENTREZ:397, GENECARDS:GC12M015094, UNIPROT:P52566 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGDIB"/> <bbox w="60.0" h="17.0" x="4922.5" y="1881.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2209_emtc_emtc_sa1074" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: caspase 1, apoptosis-related cysteine peptidase "caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)", "caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase)", IL1BC HUGO:CASP1 HGNC:1499 ENTREZ:834 UNIPROT:P29466 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11989976 PMID:17959595 Caspase1,3 promote proteosomal degradation of ARHGDIB References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caspase1*"/> <bbox w="71.0" h="19.0" x="4652.0" y="1785.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2210_emtc_emtc_sa1075" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: caspase 3, apoptosis-related cysteine peptidase "caspase 3, apoptosis-related cysteine protease" HUGO:CASP3 HGNC:1504 ENTREZ:836 UNIPROT:P42574 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11989976 PMID:17959595 Caspase1,3 promote proteosomal degradation of ARHGDIB References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caspase3*"/> <bbox w="70.0" h="19.0" x="4552.5" y="1850.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2211_emtc_emtc_sa1076" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Ezrin HUGO:EZR, HGNC:12691, ENTREZ:7430, GENECARDS:GC06M159186, UNIPROT:P15311 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9287351 ERM family (ezrin/radixin/moesin) Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein. PMID:10047517 Regulation of cortical structure by the ERM protein family. PMID:12045227 Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo. ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type. The Rho-independent activation mechanism of ERM proteins therefore exists. Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZR"/> <bbox w="32.0" h="17.0" x="5238.0" y="1875.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2212_emtc_emtc_sa1077" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vav 1 guanine nucleotide exchange factor HUGO:VAV1, HGNC:12657, ENTREZ:7409, GENECARDS:GC19P006772, UNIPROT:P15498 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: VAV1,2 are GEFs for Rac1. PMID:11080163 VAV2 is recruited by the CD19 co-receptor of the B cells and participates in the B cell receptor signaling. PMID:12165654 in the T cell, VAV1 forms complex with LCP2. This complex is involved in the T cell receptor and CD28 signaling cascades. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VAV1"/> <clone/> <bbox w="34.0" h="19.0" x="5295.0" y="2257.143"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2212_emtc_emtc_sa1666" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vav 1 guanine nucleotide exchange factor HUGO:VAV1, HGNC:12657, ENTREZ:7409, GENECARDS:GC19P006772, UNIPROT:P15498 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: VAV1,2 are GEFs for Rac1. PMID:11080163 VAV2 is recruited by the CD19 co-receptor of the B cells and participates in the B cell receptor signaling. PMID:12165654 in the T cell, VAV1 forms complex with LCP2. This complex is involved in the T cell receptor and CD28 signaling cascades. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VAV1"/> <clone/> <bbox w="34.0" h="19.0" x="5505.5" y="2255.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2213_emtc_emtc_sa1452" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vav 2 guanine nucleotide exchange factor HUGO:VAV2, HGNC:12658, ENTREZ:7410, GENECARDS:GC09M136627, UNIPROT:P52735 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9822605 Phosphorylated Vav-2 was found to be active on RhoA, RhoB and the more distantly related RhoG protein VAV1,2 are GEFs for Rac1. PMID:11080163 VAV2 is recruited by the CD19 co-receptor of the B cells and participates in the B cell receptor signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VAV2"/> <clone/> <bbox w="40.0" h="20.0" x="5292.0" y="2231.357"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2213_emtc_emtc_sa1516" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vav 2 guanine nucleotide exchange factor HUGO:VAV2, HGNC:12658, ENTREZ:7410, GENECARDS:GC09M136627, UNIPROT:P52735 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9822605 Phosphorylated Vav-2 was found to be active on RhoA, RhoB and the more distantly related RhoG protein VAV1,2 are GEFs for Rac1. PMID:11080163 VAV2 is recruited by the CD19 co-receptor of the B cells and participates in the B cell receptor signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VAV2"/> <clone/> <bbox w="40.0" h="20.0" x="5132.0" y="2232.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2214_emtc_emtc_sa1079" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho/Rac guanine nucleotide exchange factor (GEF) 2 HUGO:ARHGEF2, HGNC:682, ENTREZ:9181, GENECARDS:GC01M155916, UNIPROT:Q92974 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:18287519 GEF-H1(so-called ARHGEF2) is a microtubule-associated guanine nucleotide exchange factor that activates RhoA upon release from microtubules. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF2"/> <bbox w="58.0" h="18.0" x="5263.0" y="1999.286"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2215_emtc_emtc_sa1080" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho guanine nucleotide exchange factor (GEF) 4 HUGO:ARHGEF4, HGNC:684, ENTREZ:50649, GENECARDS:GC02P131595, UNIPROT:Q9NR80 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF4"/> <bbox w="64.0" h="18.0" x="5260.0" y="2050.857"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2216_emtc_emtc_sa1081" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa) "lymphocyte cytosolic protein 2 (SH2 domain-containing leukocyte protein of 76kD)", SLP76 HUGO:LCP2 HGNC:6529 ENTREZ:3937 UNIPROT:Q13094 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LCP2"/> <bbox w="36.0" h="18.0" x="5094.0" y="2073.5"/> <glyph class="state variable" id="_c0b14a24-1ef6-45bf-8a5f-96fcdd7abe36"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5089.0" y="2077.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2217_emtc_emtc_sa1082" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zeta-chain (TCR) associated protein kinase 70kDa SRK, "zeta-chain (TCR) associated protein kinase (70 kD)" HUGO:ZAP70 HGNC:12858 ENTREZ:7535 UNIPROT:P43403 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZAP70"/> <clone/> <bbox w="44.0" h="18.0" x="4950.0" y="2233.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2217_emtc_emtc_sa1512" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zeta-chain (TCR) associated protein kinase 70kDa SRK, "zeta-chain (TCR) associated protein kinase (70 kD)" HUGO:ZAP70 HGNC:12858 ENTREZ:7535 UNIPROT:P43403 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZAP70"/> <clone/> <bbox w="44.0" h="18.0" x="4950.0" y="2033.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2218_emtc_emtc_sa1083" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CD3d molecule, delta (CD3-TCR complex) "CD3d antigen, delta polypeptide (TiT3 complex)", T3D HUGO:CD3D HGNC:1673 ENTREZ:915 UNIPROT:P04234 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CD3"/> <bbox w="31.0" h="22.0" x="5911.0" y="171.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2219_emtc_emtc_sa1084" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CD19 molecule "CD19 antigen" HUGO:CD19 HGNC:1633 ENTREZ:930 UNIPROT:P15391 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CD19"/> <bbox w="32.0" h="25.0" x="5990.5" y="170.0"/> <glyph class="unit of information" id="_5a30bb47-de32-4c00-a6d5-8ef1c9b35b07"> <label text="receptor"/> <bbox w="32.0" h="10.0" x="5990.5" y="165.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2220_emtc_emtc_sa1085" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: T-cell lymphoma invasion and metastasis 1 HUGO:TIAM1 HGNC:11805 ENTREZ:7074 UNIPROT:Q13009 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12447393 PMID:20841469 Nm23-H1 has been shown to decrease cellular levels of active Rac1 in vivo by sequestering the Rac1 guanine nucleotide-exchange factor Tiam1 This effect of Nm23-H1 on activation of Rac1 seems to be independent of its effect on dynamin-dependent fission and does not require kinase activity References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIAM1"/> <clone/> <bbox w="38.0" h="16.0" x="5293.0" y="2334.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2220_emtc_emtc_sa1513" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: T-cell lymphoma invasion and metastasis 1 HUGO:TIAM1 HGNC:11805 ENTREZ:7074 UNIPROT:Q13009 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12447393 PMID:20841469 Nm23-H1 has been shown to decrease cellular levels of active Rac1 in vivo by sequestering the Rac1 guanine nucleotide-exchange factor Tiam1 This effect of Nm23-H1 on activation of Rac1 seems to be independent of its effect on dynamin-dependent fission and does not require kinase activity References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIAM1"/> <clone/> <bbox w="38.0" h="16.0" x="5393.0" y="2334.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2221_emtc_emtc_sa1515" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MCF.2 cell line derived transforming sequence HUGO:MCF2 HGNC:6940 ENTREZ:4168 UNIPROT:P10911 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11394904 PMID:10652228 GEF activity of MCF2 (DBL) towards CDC42 or Rac1 is enhanced upon TNK2 (ACK1) phosphorylation. PMID:18470881 Nm23-H1 binds Dbl-1 and thus interferes with the ability of Dbl-1 to load GTP onto CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MCF2"/> <bbox w="35.0" h="16.0" x="5194.5" y="2282.928"/> <glyph class="state variable" id="_5e937b17-d43a-4375-93af-a15cef199d78"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5224.2295" y="2293.928"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2222_emtc_emtc_sa1411" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: epithelial cell transforming sequence 2 oncogene HUGO:ECT2, HGNC:3155, ENTREZ:1894, GENECARDS:GC03P172468, UNIPROT:Q9H8V3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10579713 Human ECT2 (so-called ARHGEF31)is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. PMID:10837491 The level of GTP-Rho did not change significantly from the S phase to the prometaphase, but increased thereafter, peaking in the telophase, and returned to the original level in the G1 phase. Expression of the dominant negative form of ECT2 completely suppressed both the rise of GTP-Rho in the telophase and the increased GDP-GTP exchange activity in the mitotic cell extracts. These results suggest a critical role of ECT2 in Rho activation during cytokinesis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF31*"/> <bbox w="71.0" h="16.0" x="5256.5" y="2179.786"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2223_emtc_emtc_sa1088" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tyrosine kinase, non-receptor, 2 HUGO:TNK2 HGNC:19297 ENTREZ:10188 UNIPROT:Q07912 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11394904 PMID:10652228 GEF activity of MCF2 (DBL) towards CDC42 or Rac1 is enhanced upon TNK2 (ACK1) phosphorylation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TNK2"/> <bbox w="42.0" h="16.0" x="5231.0" y="2334.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2224_emtc_emtc_sa1089" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein geranylgeranyltransferase type I, beta subunit HUGO:PGGT1B HGNC:8895 ENTREZ:5229 UNIPROT:P53609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PGGT1B"/> <bbox w="53.0" h="19.0" x="5250.5" y="2724.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2225_emtc_emtc_sa1090" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GDP dissociation inhibitor (GDI) gamma HUGO:ARHGDIG, HGNC:680, ENTREZ:398, GENECARDS:GC16P000318, UNIPROT:Q99819 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. ARHGDIG is about 50 percent identical to ARHGDIA and ARHGDIB. ARHGFIG binds to CDC42 and RhoA with less affinity compared with ARHGDIA and does not bind with Rac1, Rac2, or Ras. ARHGDIG functions as a GDI for CDC42 but with about 20 times less efficiency than ARHGDIA. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGDIG"/> <bbox w="63.0" h="16.0" x="4922.5" y="1916.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2226_emtc_emtc_sa1091" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2/adenovirus E1B 19kDa interacting protein 2 "BCL2/adenovirus E1B 19kD-interacting protein 2" HUGO:BNIP2 HGNC:1083 ENTREZ:663 UNIPROT:Q12982 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10551883 FGFR1 regulates activity of CDC42 by binding and phosphorylating thus inactivating BCL2. Phosphorylated BCL2 binds to another CDC42_GAP, ARHGAP1 and neutralize the GAP activity of ARHGAP1 as well. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BNIP2"/> <bbox w="39.0" h="17.0" x="5900.5" y="2430.0"/> <glyph class="state variable" id="_6a405c50-fc86-47d4-b76b-439c55addcfd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5895.5" y="2425.3953"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2227_emtc_emtc_sa2357" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Fibroblas growth factors FGF fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR1"/> <bbox w="80.0" h="50.0" x="1540.5" y="159.5"/> <glyph class="unit of information" id="_7242e75d-b736-4cf8-945c-3f9bb356cc07"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1558.0" y="154.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2228_emtc_emtc_sa1093" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: deleted in liver cancer 1 HUGO:DLC1 HGNC:2897 ENTREZ:10395 UNIPROT:Q96QB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DLC1"/> <bbox w="41.0" h="16.0" x="6115.5" y="1815.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2229_emtc_emtc_sa1094" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 5 GFI2, "growth factor independent 2" HUGO:ARHGAP5 HGNC:675 ENTREZ:394 UNIPROT:Q13017 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 ARHGAP5 as a GAP of CDC42 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP5"/> <bbox w="66.0" h="16.0" x="5175.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2230_emtc_emtc_sa1095" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RAS p21 protein activator (GTPase activating protein) 1 RASA HUGO:RASA1 HGNC:9871 ENTREZ:5921 UNIPROT:P20936 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RASA1"/> <bbox w="42.0" h="16.0" x="5186.0" y="1725.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2231_emtc_emtc_sa1096" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: FYN oncogene related to SRC, FGR, YES HUGO:FYN HGNC:4037 ENTREZ:2534 UNIPROT:P06241 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FYN"/> <bbox w="36.0" h="17.0" x="5400.5" y="2303.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2232_emtc_emtc_sa1097" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 31 HUGO:ARHGAP31 HGNC:29216 ENTREZ:57514 UNIPROT:Q2M1Z3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP31"/> <bbox w="65.0" h="17.0" x="5696.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2233_emtc_emtc_sa1098" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 17 HUGO:ARHGAP17 HGNC:18239 ENTREZ:55114 UNIPROT:Q68EM7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP17"/> <bbox w="66.0" h="16.0" x="5470.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2234_emtc_emtc_sa1099" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: FYVE, RhoGEF and PH domain containing 1 "faciogenital dysplasia (Aarskog-Scott syndrome)", FGDY HUGO:FGD1 HGNC:3663 ENTREZ:2245 UNIPROT:P98174 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGD1"/> <bbox w="39.0" h="16.0" x="6018.5" y="1854.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2235_emtc_emtc_sa1100" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dedicator of cytokinesis 6 HUGO:DOCK6 HGNC:19189 ENTREZ:57572 UNIPROT:Q96HP0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DOCK6"/> <bbox w="48.0" h="18.0" x="6104.5" y="1904.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2236_emtc_emtc_sa1101" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dedicator of cytokinesis 9 HUGO:DOCK9 HGNC:14132 ENTREZ:23348 UNIPROT:Q9BZ29 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DOCK9"/> <bbox w="47.0" h="16.0" x="6131.5" y="1945.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2237_emtc_emtc_sa1102" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dedicator of cytokinesis 11 HUGO:DOCK11 HGNC:23483 ENTREZ:139818 UNIPROT:Q5JSL3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DOCK11"/> <bbox w="54.0" h="17.0" x="6063.5" y="1958.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2238_emtc_emtc_sa1103" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: FYVE, RhoGEF and PH domain containing 4 "FGD1 family, member 4" HUGO:FGD4 HGNC:19125 ENTREZ:121512 UNIPROT:Q96M96 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGD4"/> <bbox w="36.0" h="18.0" x="6063.5" y="1854.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2239_emtc_emtc_sa1104" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: spermatogenesis associated 13 HUGO:SPATA13 HGNC:23222 ENTREZ:221178 UNIPROT:Q96N96 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SPATA13"/> <bbox w="56.0" h="17.0" x="5994.5" y="1975.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2240_emtc_emtc_sa1105" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: differentially expressed in FDCP 6 homolog (mouse) HUGO:DEF6 HGNC:2760 ENTREZ:50619 UNIPROT:Q9H4E7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DEF6"/> <bbox w="35.0" h="16.0" x="5294.5" y="2308.715"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2242_emtc_emtc_sa1107" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho guanine nucleotide exchange factor (GEF) 3 HUGO:ARHGEF3, HGNC:683, ENTREZ:50650, GENECARDS:GC03M056736, UNIPROT:Q9NR81 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15331592 XPLN(so-called ARHGEF3) is a Rho guanine nucleotide exchange factor References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF3"/> <bbox w="66.0" h="18.0" x="5259.0" y="2025.071"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2243_emtc_emtc_sa1108" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho guanine nucleotide exchange factor (GEF) 10-like HUGO:ARHGEF10L, HGNC:25540, ENTREZ:55160, GENECARDS:GC01P017866, UNIPROT:Q9HCE6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:16112081 In vitro, GrinchGEF (ARHGEF10L) induced the GDP/ GTP exchange at RhoA, but not at Rac1 or Cdc42. In intact cells, GrinchGEF induced specifically Rho activation and enhanced RhoA,B,C-specific downstream effect. GrinchGEF, similar to its relative p164-RhoGEF (ARHGEF17), is a Rho-specific GEF. Although RhoA, B, and C have different cellular functions, and some regulators and effectors show preferential interaction with these Rho isoforms, GrinchGEF apparently does not distinguish between RhoA,B,C and similarly activates these Rho proteins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF10L"/> <bbox w="74.0" h="16.0" x="5255.0" y="2076.643"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2244_emtc_emtc_sa1109" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: rhotekin HUGO:RTKN, HGNC:10466, ENTREZ:6242, GENECARDS:GC02M074653, UNIPROT:Q9BST9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RTKN"/> <bbox w="46.0" h="16.0" x="5253.0" y="2697.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2245_emtc_emtc_sa1110" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: rhophilin, Rho GTPase binding protein 2 HUGO:RHPN2, HGNC:19974, ENTREZ:85415, GENECARDS:GC19M033469, UNIPROT:Q8IUC4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHPN2"/> <bbox w="48.0" h="16.0" x="5248.0" y="2554.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2246_emtc_emtc_sa1111" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase N1 HUGO:PKN1, HGNC:9405, ENTREZ:5585, GENECARDS:GC19P014544, UNIPROT:Q16512 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8571126 PKN1 and RHPN1 as targets of small GTPase Rho. PMID:8662891 RTKN is a new putative target for Rho bearing homology to PKN1, and RHPN proteins in the rho-binding domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PKN1"/> <bbox w="42.0" h="17.0" x="5394.0" y="2491.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2247_emtc_emtc_sa1112" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phospholipase C, epsilon 1 HUGO:PLCE1, HGNC:17175, ENTREZ:51196, GENECARDS:GC10P095753, UNIPROT:Q9P212 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PLCE1"/> <bbox w="44.0" h="17.0" x="5254.0" y="2657.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2248_emtc_emtc_sa1113" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DIAPH1"/> <bbox w="60.0" h="20.0" x="5062.0" y="2412.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2249_emtc_emtc_sa1114" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: diaphanous homolog 3 (Drosophila) HUGO:DIAPH3, HGNC:15480, ENTREZ:81624, GENECARDS:GC13M060239, UNIPROT:Q9NSV4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DIAPH3"/> <bbox w="49.0" h="17.0" x="5023.5" y="2485.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2251_emtc_emtc_sa1116" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho guanine nucleotide exchange factor (GEF) 1 HUGO:ARHGEF1, HGNC:681, ENTREZ:9138, GENECARDS:GC19P042387, UNIPROT:Q92888 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9789025 PMID:9641915 p115RhoGEF(so-called ARHGEF1) is an Rho guanine nucleotide exchange factor. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF1"/> <bbox w="63.0" h="18.0" x="5260.5" y="1973.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2252_emtc_emtc_sa1117" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phospholipase D1, phosphatidylcholine-specific HUGO:PLD1, HGNC:9067, ENTREZ:5337, GENECARDS:GC03M171318, UNIPROT:Q13393 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PLD1"/> <bbox w="39.0" h="18.0" x="5256.5" y="2676.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2253_emtc_emtc_sa1118" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RAP1, GTP-GDP dissociation stimulator 1 HUGO:RAP1GDS1, HGNC:9859, ENTREZ:5910, GENECARDS:GC04P099182, UNIPROT:P52306 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8900189 SmgGDS (so-called RAP1GDS1) is a regulator having 2 activities on the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions (GEF activity), and the other is to inhibit their interactions with membranes. RAP1GDS1 bound with KAP3 also activates RhoA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAP1GDS1"/> <clone/> <bbox w="68.0" h="16.0" x="5258.0" y="2205.571"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2253_emtc_emtc_sa1514" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RAP1, GTP-GDP dissociation stimulator 1 HUGO:RAP1GDS1, HGNC:9859, ENTREZ:5910, GENECARDS:GC04P099182, UNIPROT:P52306 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8900189 SmgGDS (so-called RAP1GDS1) is a regulator having 2 activities on the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions (GEF activity), and the other is to inhibit their interactions with membranes. RAP1GDS1 bound with KAP3 also activates RhoA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAP1GDS1"/> <clone/> <bbox w="68.0" h="16.0" x="5141.0" y="2205.571"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2254_emtc_emtc_sa1119" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: kinesin-associated protein 3 HUGO:KIFAP3 HGNC:17060 ENTREZ:22920 UNIPROT:Q92845 Identifiers_end Maps_Modules_begin: MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KIFAP3"/> <bbox w="48.0" h="17.0" x="5125.0" y="2171.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2255_emtc_emtc_sa1120" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: neuronal guanine nucleotide exchange factor HUGO:NGEF, HGNC:7807, ENTREZ:25791 , GENECARDS:GC02M233707 , UNIPROT:Q8N5V2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11336673 EphA receptors (stimulated by Ephrin-A)associate with Ephexin (so-called NGEF or ARHGEF27) to modulates the activity of ephexin. Ephexin stimulates activity of RhoA, leading to Cdc42 and Rac1 inhibition, and cell morphology changes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF27*"/> <bbox w="74.0" h="16.0" x="5255.0" y="2154.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2256_emtc_emtc_sa1121" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ephrin-A1 EPLG1, TNFAIP4 HUGO:EFNA1 HGNC:3221 ENTREZ:1942 UNIPROT:P20827 ephrin-B1 EPLG2 HUGO:EFNB1 HGNC:3226 ENTREZ:1947 UNIPROT:P98172 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:19074825 The eight members of the ephrin family are divided into distinct A and B subclasses, indicating the manner in which they are anchored to the membrane: either by a glyco- sylphosphatidylinositol (GPI) linkage (ephrinA1-A5) or by a transmembrane domain (ephrinB1-B3). A unique property of ephrins that is a result of membrane localization is their ability to transduce ‘‘reverse’’ signals into the cells on which they are expressed in addition to eliciting ‘‘forward’’ signaling into Eph receptor-expressing cells Another unique aspect of ephrins that sets them apart from other RTK ligands is that their membrane- bound nature is thought to be required to elicit full Eph receptor activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Epherin family*"/> <bbox w="103.0" h="16.0" x="2489.5" y="70.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2257_emtc_emtc_sa1122" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: EPH receptor A2 "EphA2" HUGO:EPHA2 HGNC:3386 ENTREZ:1969 UNIPROT:P29317 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20179713 E-cadherin promotes EPHA2– ephrin-A1 localization at epithelial cell junctions EPHA2 is upregulated in many cancers and its expression has been linked to increased malignancy and a poor clinical prognosis. EPHA2 seems to be preferentially expressed in malignant breast and prostate cancers with a basal phenotype. EPHA1 is downregulated in advanced human skin and colorectal cancers, EphB receptors are downregulated in advanced colorectal cancer and ephrin-A5 is downregulated in glioblastomas TNF-alpha, VEGFA and HIF2A upregulate ephrin-A1 in cultured endothelial cells. Endothelial ephrin-B2 is upregulated by VEGF through the Notch pathway. PMID:19074825 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EPHA2"/> <bbox w="80.0" h="50.0" x="2170.5" y="156.5"/> <glyph class="state variable" id="_04b5cbf0-9cdd-490c-995c-da29893e1856"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2165.5" y="171.65071"/> </glyph> <glyph class="unit of information" id="_0da670cd-9b02-4112-a045-73c33c8e1a9d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2188.0" y="151.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2258_emtc_emtc_sa1123" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: insulin-like growth factor 1 (somatomedin C) HUGO:IGF1 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF1"/> <bbox w="36.0" h="18.0" x="1848.0" y="6621.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2259_emtc_emtc_sa1124" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: insulin-like growth factor 1 receptor HUGO:IGF1R HGNC:5465 ENTREZ:3480 UNIPROT:P08069 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF1R"/> <bbox w="80.0" h="50.0" x="1725.0" y="6029.5"/> <glyph class="state variable" id="_94660e9a-60e6-4f5d-b20d-c3dff3b513f8"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="1758.332" y="6024.5"/> </glyph> <glyph class="unit of information" id="_07fd2bdd-f4a9-447f-a717-c5ee5f3026ee"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1742.5" y="6024.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2260_emtc_emtc_sa1125" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho guanine nucleotide exchange factor (GEF) 12 HUGO:ARHGEF12, HGNC:14193, ENTREZ:23365, GENECARDS:GC11P120207, UNIPROT:Q9NZN5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11724822 Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton LARG is an Rho guanine nucleotide exchange factor, which contains a PDZ domain responsible for IGF-1 binding. LARG induced the formation of stress fibers in NIH 3T3 fibroblasts. MDCKII epithelial cells treated with IGF-1 results in activated Rho and its effector Rho-associated kinase and actin stress fibers were enhanced. IGF-1 activates the Rho pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrangements. PMID:15331592 LARG (so-called ARHGEF12) belongs to a small subfamily of RhoGEFs that are RhoA-selective and directly activated by the G-alpha 12/13 family of heterotrimeric G proteins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGEF12"/> <bbox w="73.0" h="18.0" x="5255.5" y="2102.429"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2263_emtc_emtc_sa1128" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine kinase 6 HUGO:PTK6 HGNC:9617 ENTREZ:5753 UNIPROT:Q13882 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:18829532 PTK6 phosphorylates ARHGAP35 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTK6"/> <bbox w="36.0" h="17.0" x="5921.0" y="1756.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2265_emtc_emtc_sa1130" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin IXB HUGO:MYO9B, HGNC:7609, ENTREZ:4650, GENECARDS:GC19P017186, UNIPROT:Q13459 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9490638 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYO9B"/> <bbox w="47.0" h="17.0" x="5482.0" y="3612.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2266_emtc_emtc_sa1131" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 26 HUGO:ARHGAP26, HGNC:17073, ENTREZ:23092, GENECARDS:GC05P142130, UNIPROT:Q9UNA1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10982819 GRAF (so-called ARHGAP26 or p50RhoGAP) exhibits GAP activity toward the RhoA and Cdc42 GTPases, but is only weakly active toward the closely related Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP26"/> <bbox w="69.0" h="17.0" x="5622.5" y="1786.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2267_emtc_emtc_sa1132" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Catenin*"/> <bbox w="68.0" h="19.0" x="1283.0" y="3460.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2268_emtc_emtc_sa1133" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p120*"/> <bbox w="52.0" h="16.0" x="1438.0" y="3500.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2270_emtc_emtc_sa1135" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: formin 1 FMN, "formin (limb deformity)", LD HUGO:FMN1 HGNC:3768 ENTREZ:342184 UNIPROT:Q68DA7 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Formin*"/> <bbox w="53.0" h="17.0" x="771.5" y="3789.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2271_emtc_emtc_sa1136" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Catenin* catenin (cadherin-associated protein), alpha 1, 102kDa "catenin (cadherin-associated protein), alpha 1 (102kD)" HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Catenin*"/> <bbox w="59.0" h="21.0" x="1343.0" y="3537.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2273_emtc_emtc_sa2472" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine phosphatase, non-receptor type 11 "Noonan syndrome 1", NS1 HUGO:PTPN11 HGNC:9644 ENTREZ:5781 UNIPROT:Q06124 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTPN11"/> <bbox w="51.0" h="16.0" x="770.5" y="3741.0"/> <glyph class="state variable" id="_c8161340-53fe-4a8f-9c20-a5134d40c4de"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="791.5304" y="3736.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2274_emtc_emtc_sa2572" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:18829532 PMID:9819392 PTK6 and CSK both can phosphorylate ARHGAP35 (p190) at Y1105 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-SRC*"/> <bbox w="57.0" h="22.0" x="1978.5" y="2989.5"/> <glyph class="state variable" id="_ca1cd5d7-8e5e-440a-b3bf-350fd3477fb0"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="2028.0" y="2985.456"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2278_emtc_emtc_sa85" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="40.0" h="20.0" x="2085.5" y="2423.8"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2281_emtc_emtc_sa1146" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cingulin HUGO:CGN, HGNC:17429, ENTREZ:57530, UNIPROT:Q9P2M7, GENECARDS:GC01P151483 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cingulin*"/> <bbox w="63.0" h="18.0" x="1283.5" y="2407.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2282_emtc_emtc_sa1147" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: multiple PDZ domain protein HUGO:MPDZ HGNC:7208 ENTREZ:8777 UNIPROT:O75970 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11689568 MPDZ accumulates at the TJ in epithelial cells through its binding to Claudins and JAMs. MPDZ is believed to function as a multivalent scaffold protein that recruits various proteins to TJ References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MPDZ"/> <bbox w="39.0" h="18.0" x="893.0" y="2640.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2283_emtc_emtc_sa1148" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1*"/> <bbox w="61.0" h="16.0" x="590.0" y="2688.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2284_emtc_emtc_sa1149" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="64.0" h="19.0" x="598.0" y="2769.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2285_emtc_emtc_sa1150" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 5 HUGO:CLDN5, HGNC:2047, ENTREZ:7122, UNIPROT:O00501, GENECARDS:GC22M019510 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin5*"/> <bbox w="61.0" h="16.0" x="600.0" y="3061.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2286_emtc_emtc_sa1151" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 8 HUGO:CLDN8, HGNC:2050, ENTREZ:9073, UNIPROT:P56748, GENECARDS:GC21M031586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin8*"/> <bbox w="58.0" h="18.0" x="604.0" y="3166.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2287_emtc_emtc_sa1152" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 11 HUGO:CLDN11, HGNC:8514, ENTREZ:5010099, UNIPROT:O75508, GENECARDS:GC03P170136 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:11309411 Claudin-11 forms a complex with TSPAN3 and ITGB1. This interaction potentially regulates proliferation and migration of oligodendrocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin11*"/> <bbox w="70.0" h="17.0" x="604.0" y="3189.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2288_emtc_emtc_sa1153" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 14 HUGO:CLDN14, HGNC:2035, ENTREZ:23562, UNIPROT:O95500, GENECARDS:GC21M037832 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin14*"/> <bbox w="66.0" h="16.0" x="604.0" y="3212.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2289_emtc_emtc_sa1154" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 16 HUGO:CLDN16, HGNC:2037, ENTREZ:10686, UNIPROT:Q9Y5I7, GENECARDS:GC03P190040 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin16*"/> <bbox w="71.0" h="16.0" x="602.0" y="3306.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2290_emtc_emtc_sa1155" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 19 HUGO:CLDN19, HGNC:2040, ENTREZ:149461, UNIPROT:Q8N6F1, GENECARDS:GC01M043174 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin19*"/> <bbox w="70.0" h="17.0" x="602.0" y="3349.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2291_emtc_emtc_sa1156" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 18 HUGO:CLDN18, HGNC:2039, ENTREZ:51208, UNIPROT:P56856, GENECARDS:GC03P137717 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin18*"/> <bbox w="68.0" h="16.0" x="602.0" y="3326.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2292_emtc_emtc_sa1157" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: WNK lysine deficient protein kinase 4 HUGO:WNK4, HGNC:14544, ENTREZ:65266, UNIPROT:Q96J92, GENECARDS:GC17P040932 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15070779 WNK4 binds and phosphorylates claudins 1–4. Claudins 1–4 are known to be involved in the regulation of paracellular ion permeability. The increases in phosphorylation of claudins were greater in cells expressing the mutant WNK4 than in cells expressing wild-type protein. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. So the phosphorylation of Claudins 1-4 by WNK4 involves in the regulation of paracellular ion permeability References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WNK4"/> <bbox w="37.0" h="20.0" x="809.0" y="2996.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2293_emtc_emtc_sa1158" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: metadherin HUGO:MTDH, HGNC:29608, ENTREZ:92140, UNIPROT:Q86UE4, GENECARDS:GC08P098658 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15383321 MTDH is so-called LYRIC LYRIC colocalizes with ZO1 and Occludin in polarized epithelial cells. This protein is most likely not involved in the TJ formation as a structural component. However, it is required for the maturation of the TJ complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LYRIC*"/> <bbox w="46.0" h="16.0" x="1307.0" y="2815.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2297_emtc_emtc_sa1162" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1"/> <bbox w="39.0" h="16.0" x="612.5" y="4974.5"/> <glyph class="state variable" id="_eeacea9c-e1bd-401f-ac64-8ff7b4c9dba3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="646.32135" y="4969.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2298_emtc_emtc_sa1163" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3"/> <bbox w="39.0" h="16.0" x="612.5" y="5134.5"/> <glyph class="state variable" id="_088f075f-e223-44af-b9c2-43b7d8aefb11"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="646.5" y="5130.341"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2299_emtc_emtc_sa1164" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA4 is so-called Connexin 37 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA4"/> <bbox w="37.0" h="16.0" x="612.75" y="5293.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2300_emtc_emtc_sa1165" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 5, 40kDa HUGO:GJA5, HGNC:4279, ENTREZ:2702, UNIPROT:P36382, GENECARDS:GC01M147228 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA5 is so-called Connexin 40 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA5"/> <bbox w="35.0" h="16.0" x="614.5" y="5394.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2301_emtc_emtc_sa1166" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA8 is so-called Connexin 50 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA8"/> <bbox w="36.0" h="16.0" x="614.0" y="5494.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2302_emtc_emtc_sa1167" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="614.5" y="5574.5"/> <glyph class="state variable" id="_6dc20b3f-8a24-487d-9295-7ee35f334836"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="644.5" y="5569.8965"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2303_emtc_emtc_sa1168" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 2, 26kDa HUGO:GJB2, HGNC:4284, ENTREZ:2706, UNIPROT:P29033, GENECARDS:GC13M020761 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB2 is so-called Connexin 26 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB2"/> <bbox w="37.0" h="17.0" x="613.5" y="5714.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2304_emtc_emtc_sa1169" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11557048 GJC1 interacts with the PDZ domains of ZO-1 and ZO-3 but not ZO-2 PMID:11313345 Connexin45 (GJC1) interacts with ZO-1 and connexin43 (GJA1) in osteoblastic cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1"/> <bbox w="35.0" h="16.0" x="614.5" y="5854.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2306_emtc_emtc_sa1172" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakoglobin*"/> <bbox w="80.0" h="21.0" x="1790.0" y="4504.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2307_emtc_emtc_sa1173" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 GENECARDS:GC02P159313 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin4*"/> <bbox w="89.0" h="17.0" x="1932.0" y="4444.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2308_emtc_emtc_sa1174" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein2*"/> <bbox w="88.0" h="18.0" x="1933.0" y="4309.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2310_emtc_emtc_sa1176" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type IV, alpha 1 HUGO:COL4A1 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL4A1"/> <bbox w="49.0" h="19.0" x="5211.75" y="5991.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2311_emtc_emtc_sa1177" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type II, alpha 1 "collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital)", SEDC HUGO:COL2A1 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL2A1"/> <bbox w="46.0" h="18.0" x="5029.75" y="6084.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2312_emtc_emtc_sa1178" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMA1"/> <bbox w="43.0" h="17.0" x="5917.25" y="5782.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2313_emtc_emtc_sa1179" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, alpha 4 HUGO:LAMA4 HGNC:6484 ENTREZ:3910 UNIPROT:Q16363 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMA4"/> <bbox w="43.0" h="16.0" x="5917.25" y="5865.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2314_emtc_emtc_sa1180" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, alpha 5 HUGO:LAMA5 HGNC:6485 ENTREZ:3911 UNIPROT:O15230 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMA5"/> <bbox w="45.0" h="16.0" x="5915.0" y="5892.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2315_emtc_emtc_sa1181" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 15 (membrane-inserted) "matrix metalloproteinase 15 (membrane-inserted)" HUGO:MMP15 HGNC:7161 ENTREZ:4324 UNIPROT:P51511 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP15"/> <bbox w="46.0" h="17.0" x="1048.0" y="6463.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2316_emtc_emtc_sa1182" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 16 (membrane-inserted) C8orf57, "chromosome 8 open reading frame 57", "matrix metalloproteinase 16 (membrane-inserted)" HUGO:MMP16 HGNC:7162 ENTREZ:4325 UNIPROT:P51512 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP16"/> <bbox w="46.0" h="17.0" x="1050.0" y="6488.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2317_emtc_emtc_sa1183" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 GENECARDS:GC01P201252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin1*"/> <bbox w="89.0" h="18.0" x="1932.0" y="4374.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2318_emtc_emtc_sa1184" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin2*"/> <bbox w="91.0" h="17.0" x="1930.0" y="4397.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2319_emtc_emtc_sa1185" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type I, alpha 1 HUGO:COL1A1 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL1A1"/> <bbox w="49.0" h="19.0" x="4784.75" y="5776.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2320_emtc_emtc_sa1186" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type V, alpha 1 HUGO:COL5A1 HGNC:2209 ENTREZ:1289 UNIPROT:P20908 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL5A1"/> <bbox w="49.0" h="18.0" x="5285.75" y="6084.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2321_emtc_emtc_sa1187" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type VI, alpha 3 HUGO:COL6A3 HGNC:2213 ENTREZ:1293 UNIPROT:P12111 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL6A3"/> <bbox w="47.0" h="18.0" x="5337.75" y="6085.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2322_emtc_emtc_sa1188" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type VI, alpha 2 HUGO:COL6A2 HGNC:2212 ENTREZ:1292 UNIPROT:P12110 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL6A2"/> <bbox w="49.0" h="17.0" x="5386.75" y="6086.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2324_emtc_emtc_sa1190" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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Identifiers_begin: TIMP metallopeptidase inhibitor 2 "tissue inhibitor of metalloproteinase 2" HUGO:TIMP2 HGNC:11821 ENTREZ:7077 UNIPROT:P16035 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP2"/> <bbox w="37.0" h="16.0" x="2076.0" y="4660.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2331_emtc_emtc_sa1197" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 3 SFD, "tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory)" HUGO:TIMP3 HGNC:11822 ENTREZ:7078 UNIPROT:P35625 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP3"/> <bbox w="39.0" h="17.0" x="2076.0" y="4694.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2339_emtc_emtc_sa1205" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: thrombospondin 2 HUGO:THBS2 HGNC:11786 ENTREZ:7058 UNIPROT:P35442 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="THBS2"/> <bbox w="42.0" h="17.0" x="840.969" y="6787.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2342_emtc_emtc_sa1208" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1*"/> <bbox w="64.0" h="16.0" x="489.0" y="2690.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2344_emtc_emtc_sa1210" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="64.0" h="19.0" x="482.0" y="2771.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2346_emtc_emtc_sa1212" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="59.0" h="16.0" x="481.0" y="2846.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2348_emtc_emtc_sa1214" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 14 HUGO:CLDN14, HGNC:2035, ENTREZ:23562, UNIPROT:O95500, GENECARDS:GC21M037832 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin14*"/> <bbox w="66.0" h="16.0" x="486.0" y="3219.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2353_emtc_emtc_sa79" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="593.5" y="2527.5"/> <glyph class="state variable" id="_e91fe07f-ed04-43ba-80c0-57a2c6927a9a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="647.5" y="2530.5254"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2358_emtc_emtc_sa1219" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="485.8" y="2525.0"/> <glyph class="state variable" id="_d90e4955-dd24-4061-b172-ccacf1a27aee"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="539.8" y="2528.0254"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2378_emtc_emtc_sa1143" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="40.0" h="17.0" x="603.75" y="2425.3"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2379_emtc_emtc_sa1144" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: junctional adhesion molecule 2 HUGO:JAM2, HGNC:14686, ENTREZ:58494, UNIPROT:P57087, GENECARDS:GC21P027011 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM2"/> <bbox w="40.0" h="16.0" x="603.25" y="2446.3"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2380_emtc_emtc_sa1145" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: junctional adhesion molecule 3 HUGO:JAM3, HGNC:15532, ENTREZ:83700, UNIPROT:Q9BX67, GENECARDS:GC11P133972 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM3"/> <bbox w="41.0" h="16.0" x="603.25" y="2468.3"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2390_emtc_emtc_sa1239" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4 HUGO:MLLT4, HGNC:7137, ENTREZ:4301, UNIPROT:P55196, GENECARDS:GC06P168227 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Afadin*"/> <bbox w="47.0" h="19.0" x="1488.5" y="2213.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2397_emtc_emtc_sa1244" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 1, skeletal muscle, adult HUGO:MYH1, HGNC:7567, ENTREZ:4619, GENECARDS:GC17M010395, UNIPROT:P12882 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH1"/> <bbox w="38.0" h="18.0" x="4828.0" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2426_emtc_emtc_sa1264" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: poliovirus receptor-related 1 (herpesvirus entry mediator C) HUGO:PVRL1, HGNC:9706, ENTREZ:5818, UNIPROT:Q15223, GENECARDS:GC11M119542 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:12354099 Interactions between Nectin, Afadin and Occludin suggest a role of the nectin-afadin system in the organization of TJs in epithelial cells References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Nectin*"/> <bbox w="46.0" h="18.0" x="1531.0" y="2408.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2442_emtc_emtc_sa1275" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: caveolin 1, caveolae protein, 22kDa HUGO:CAV1, HGNC:1527, ENTREZ:857, UNIPROT:Q03135, GENECARDS:GC07P116164 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22671595 Caveolin-1 is an endocytic scaffolding protein It binds independently to claudin-2 and occludin (co-immunoprecipitation assays). The finding that caveolin-1 interacts with claudin-2 and occludin, but notwith claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caveolin1*"/> <bbox w="75.0" h="19.0" x="1292.0" y="2989.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2450_emtc_emtc_sa1281" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tetraspanin 3 HUGO:TSPAN3, HGNC:17752, ENTREZ:10099, UNIPROT:O60637, GENECARDS:GC15M077336 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:11309411 PMID:14570575 TSPAN3 is a tetraspanin expressed at high levels in brain. Claudin-11 forms a complex with TSPAN3 and ITGB1. This interaction potentially regulates proliferation and migration of oligodendrocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TSPAN3"/> <bbox w="55.0" h="16.0" x="1070.0" y="3092.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2458_emtc_emtc_sa1287" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, UNIPROT:O14493, GENECARDS:GC07P073213 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin4*"/> <bbox w="59.0" h="16.75" x="977.5" y="3077.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2463_emtc_emtc_sa1294" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lymphoid enhancer-binding factor 1 HUGO:LEF1, HGNC:6551, ENTREZ:51176, UNIPROT:Q9UJU2, GENECARDS:GC04M108968 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LEF1"/> <bbox w="40.0" h="20.0" x="2180.0" y="3614.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2465_emtc_emtc_sa1295" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TCF4"/> <bbox w="40.0" h="20.0" x="2179.0" y="3579.5"/> <glyph class="state variable" id="_a9b78e84-dd32-4c32-bac9-4896b8783456"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2174.0" y="3584.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2466_emtc_emtc_sa1296" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1"/> <bbox w="39.0" h="16.0" x="502.5" y="4981.0"/> <glyph class="state variable" id="_b8d51b2c-6c15-4127-8d83-15a59728be81"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="536.32135" y="4976.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2469_emtc_emtc_sa1299" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3"/> <bbox w="39.0" h="16.0" x="502.5" y="5141.0"/> <glyph class="state variable" id="_e2ee1895-96f8-40e1-9017-1f14bd03f9fe"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="536.5" y="5136.841"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2473_emtc_emtc_sa1302" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA4 is so-called Connexin 37 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA4"/> <bbox w="37.0" h="16.0" x="502.75" y="5299.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2477_emtc_emtc_sa1305" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 5, 40kDa HUGO:GJA5, HGNC:4279, ENTREZ:2702, UNIPROT:P36382, GENECARDS:GC01M147228 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA5 is so-called Connexin 40 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA5"/> <bbox w="35.0" h="16.0" x="504.5" y="5401.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2478_emtc_emtc_sa1306" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA8 is so-called Connexin 50 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA8"/> <bbox w="35.0" h="16.0" x="504.5" y="5501.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2487_emtc_emtc_sa1313" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="504.5" y="5581.0"/> <glyph class="state variable" id="_74ea1896-c478-4722-9124-585c163a274d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="534.5" y="5576.3965"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2490_emtc_emtc_sa1316" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 2, 26kDa HUGO:GJB2, HGNC:4284, ENTREZ:2706, UNIPROT:P29033, GENECARDS:GC13M020761 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB2 is so-called Connexin 26 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB2"/> <bbox w="37.0" h="17.0" x="503.5" y="5720.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2491_emtc_emtc_sa1317" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:11557048 GJC1 interacts with the PDZ domains of ZO-1 and ZO-3 but not ZO-2 PMID:11313345 Connexin45 (GJC1) interacts with ZO-1 and connexin43 (GJA1) in osteoblastic cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJC1"/> <bbox w="35.0" h="16.0" x="504.5" y="5861.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2492_emtc_emtc_sa1318" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, delta 2, 36kDa HUGO:GJD2, HGNC:19154, ENTREZ:57369, UNIPROT:Q9UKL4, GENECARDS:GC15M035043 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJD2 is so-called Connexin 36 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2"/> <bbox w="34.0" h="16.0" x="505.0" y="5961.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2497_emtc_emtc_sa1321" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, alpha HUGO:PRKCA, HGNC:9393, ENTREZ:5578, UNIPROT:P17252, GENECARDS:GC17P064298 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCA"/> <bbox w="46.0" h="16.0" x="689.0" y="5014.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2498_emtc_emtc_sa1322" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, gamma HUGO:PRKCG, HGNC:9402, ENTREZ:5582, UNIPROT:P05129, GENECARDS:GC19P054382 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCG"/> <bbox w="45.0" h="16.0" x="809.5" y="4994.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2500_emtc_emtc_sa1323" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1"/> <bbox w="39.0" h="16.0" x="612.5" y="5054.5"/> <glyph class="state variable" id="_98f2a3b9-b3ba-452d-a936-a5c6ab0e45dc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="643.82135" y="5049.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2502_emtc_emtc_sa1326" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 PMID:19646399 Connexins 46 and 50 combine to form the gap junctions in ocular lens fiber cells 18 phosphorylation sites on connexin 50 (GJA8) and 9 phosphorylation sites on connexin 46 (GJA3) were identified, all on serine or threonine residues. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3"/> <bbox w="39.0" h="16.0" x="612.5" y="5194.5"/> <glyph class="state variable" id="_4d052230-15da-4b63-8d54-409801feabd3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="644.0" y="5190.341"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2503_emtc_emtc_sa1329" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, epsilon HUGO:PRKCE, HGNC:9401, ENTREZ:5581, UNIPROT:Q02156, GENECARDS:GC02P045790 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCE"/> <bbox w="46.0" h="16.0" x="769.0" y="4974.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2504_emtc_emtc_sa1330" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, beta HUGO:PRKCB, HGNC:9395, ENTREZ:5579, UNIPROT:P05771, GENECARDS:GC16P023847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCB"/> <bbox w="46.0" h="16.0" x="709.0" y="4994.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2505_emtc_emtc_sa1331" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) HUGO:SRC, HGNC:11283, ENTREZ:6714, UNIPROT:P12931, GENECARDS:GC20P035973 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:9278444 Reduction of gap junctional communication in v-src transformed cells is accompanied by tyrosine phosphorylation of the gap junction protein, connexin 43 SH3 and SH2 domains of v-Src bind to proline-rich motifs and a phosphorylated tyrosine residue in the C-terminal tail of Cx43 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="v-SRC*"/> <bbox w="54.0" h="21.0" x="1049.0" y="5166.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2507_emtc_emtc_sa1332" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB1"/> <bbox w="35.0" h="16.0" x="614.5" y="5634.5"/> <glyph class="state variable" id="_5c8661ba-e5f4-47ff-88ee-7e6351364c07"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="642.0" y="5629.8965"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2511_emtc_emtc_sa1337" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="59.0" h="16.0" x="713.0" y="2543.7"/> <glyph class="state variable" id="_c7f1a4f1-afdb-4978-a301-8b452d2bf325"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="764.5" y="2546.7253"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2515_emtc_emtc_sa1342" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: JAM1_2_3* F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, UNIPROT:Q9Y624, GENECARDS:GC01M160965 junctional adhesion molecule 2 HUGO:JAM2, HGNC:14686, ENTREZ:58494, UNIPROT:P57087, GENECARDS:GC21P027011 junctional adhesion molecule 3 HUGO:JAM3, HGNC:15532, ENTREZ:83700, UNIPROT:Q9BX67, GENECARDS:GC11P133972 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1_2_3*"/> <bbox w="80.0" h="20.0" x="764.0" y="2445.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2517_emtc_emtc_sa1344" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZO2_3* tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO2_3*"/> <bbox w="50.0" h="20.0" x="1012.0" y="2627.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2520_emtc_emtc_sa1346" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZO1_2_3* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2_3*"/> <bbox w="60.0" h="20.0" x="1531.0" y="2617.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2523_emtc_emtc_sa1348" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Occludin_Claudin1_2_4_5_7_8_16* occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, UNIPROT:O14493, GENECARDS:GC07P073213 claudin 5 HUGO:CLDN5, HGNC:2047, ENTREZ:7122, UNIPROT:O00501, GENECARDS:GC22M019510 Claudin 7 HUGO:CLDN7, HGNC:2049, ENTREZ:1366, UNIPROT:O95471, GENECARDS:GC17M007163 Claudin 8 HUGO:CLDN8, HGNC:2050, ENTREZ:9073, UNIPROT:P56748, GENECARDS:GC21M031586 Claudin 16 HUGO:CLDN16, HGNC:2037, ENTREZ:10686, UNIPROT:Q9Y5I7, GENECARDS:GC03P190040 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin_Claudin1_2_4_5_7_8_16*"/> <bbox w="205.0" h="21.0" x="712.0" y="2727.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2526_emtc_emtc_sa1350" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin1_5_8* claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 claudin 5 HUGO:CLDN5, HGNC:2047, ENTREZ:7122, UNIPROT:O00501, GENECARDS:GC22M019510 claudin 8 HUGO:CLDN8, HGNC:2050, ENTREZ:9073, UNIPROT:P56748, GENECARDS:GC21M031586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1_5_8*"/> <bbox w="100.0" h="20.0" x="787.0" y="2907.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2531_emtc_emtc_sa1353" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZO1_2* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 2 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766, UNIPROT:Q9UDY2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_2*"/> <bbox w="60.0" h="20.0" x="1299.0" y="2576.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2535_emtc_emtc_sa1355" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin1_2_3_4* claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, UNIPROT:O14493, GENECARDS:GC07P073213 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1_2_3_4*"/> <bbox w="100.0" h="20.0" x="767.0" y="3047.5"/> <glyph class="state variable" id="_56043ea2-1a1a-4690-91a1-e9f89577adfa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="862.0" y="3043.7292"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2536_emtc_emtc_sa1356" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin1_2_3_4* claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, UNIPROT:O95832, GENECARDS:GC03M190023 claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, UNIPROT:O14493, GENECARDS:GC07P073213 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1_2_3_4*"/> <bbox w="100.0" h="20.0" x="987.0" y="3047.5"/> <glyph class="state variable" id="_5817502f-d1ce-4803-bff0-d3c0dc327bd6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1079.5" y="3043.7292"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2539_emtc_emtc_sa1357" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: GJA1_4_GJC1* gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:16359940 PMID:14576341 Among the Connexins, Cx43 (GJA1) is the most ubiquitously expressed. Cx43 is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. Cx43 co-oligomerize with other Connexins like Cx26 (GJB2, keratinocytes and hepatocytes), Cx31 (GJB5, keratinocytes), Cx45 (GJC1, myocardium) and Cx46 (GJA3, trans-Golgi network). However Cx43 is unable to co-oligomerize with Cx32 (GJB1). PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 Cx43 binds with ZO-1 and ZO-2, at different stages of the cell cycle to regulate Gap Junctions size and stability; Cx43 interacts directly with b-Catenin to regulate Gap junctional intercelullar communication cross-talk activity with the WNT signaling (essential for cell survival); Binding of CIP85 to Cx43 regulates the turnover of Cx43-containing Gap Junctions, stabilizing the junctions. Drebrin 1 (Actin-binding protein) binds Cx43 and links Gap junctions to the sub-membrane cytoskeleton Other cytoskeletal proteins like a and b-Tubulin bind with Cx43 to facilitate Connexion transport. Binding of NOV to the C-terminus of Cx43 potentially regulates growth suppression. Binding of Cx43 to Caveolin-1 may play a role in internalization of Cx43. Connexin-specific selectivity: Homomeric Connexons made up of Cx32 are permeable both to cAMP and cGMP Heteromeric Connexons containing both Cx26 (GJB2) and Cx32 are not permeable to cAMP but allow passage of cGMP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1_4_GJC1*"/> <bbox w="100.0" h="20.0" x="362.0" y="5039.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2542_emtc_emtc_sa1359" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: GJA1_3_4_8_GJB2* gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 gap junction protein, alpha 4, 37kDa HUGO:GJA4, HGNC:4278, ENTREZ:2701 , UNIPROT:P35212, GENECARDS:GC01P035258 gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA3 is so-called Connexin 46 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1_3_4_8_GJB2*"/> <bbox w="120.0" h="20.0" x="362.0" y="5179.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2546_emtc_emtc_sa1361" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: GJA1_5_GJC1* gap junction protein, alpha 5, 40kDa HUGO:GJA5, HGNC:4279, ENTREZ:2702, UNIPROT:P36382, GENECARDS:GC01M147228 gap junction protein, alpha 1, 43kDa HUGO:GJA1, HGNC:4274, ENTREZ:2697, UNIPROT:P17302, GENECARDS:GC06P121756 gap junction protein, gamma 1, 45kDa HUGO:GJC1, HGNC:4280, ENTREZ:10052 , UNIPROT:P36383, GENECARDS:GC17M042875 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA5 is so-called Connexin 40 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA1_5_GJC1*"/> <bbox w="100.0" h="20.0" x="362.0" y="5379.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2551_emtc_emtc_sa1363" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: GJA3_8_GJB1_GJB2* gap junction protein, beta 1, 32kDa HUGO:GJB1, HGNC:4283, ENTREZ:2705, UNIPROT:P08034, GENECARDS:GC0XP070435 gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 gap junction protein, beta 2, 26kDa HUGO:GJB2, HGNC:4284, ENTREZ:2706, UNIPROT:P29033, GENECARDS:GC13M020761 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. Cx32-dependent inactivation of Src decreased the production of VEGF via the suppression of Stat3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3_8_GJB1_GJB2*"/> <bbox w="120.0" h="20.0" x="362.0" y="5619.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2556_emtc_emtc_sa1365" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: PRKCA_B_E_G* protein kinase C, alpha HUGO:PRKCA, HGNC:9393, ENTREZ:5578, UNIPROT:P17252, GENECARDS:GC17P064298 protein kinase C, beta HUGO:PRKCB, HGNC:9395, ENTREZ:5579, UNIPROT:P05771, GENECARDS:GC16P023847 protein kinase C, epsilon HUGO:PRKCE, HGNC:9401, ENTREZ:5581, UNIPROT:Q02156, GENECARDS:GC02P045790 protein kinase C, gamma HUGO:PRKCG, HGNC:9402, ENTREZ:5582, UNIPROT:P05129, GENECARDS:GC19P054382 protein kinase C, zeta HUGO:PRKCZ HGNC:9412 ENTREZ:5590 UNIPROT:Q05513 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PKC*"/> <bbox w="45.0" h="21.0" x="797.0" y="5057.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2558_emtc_emtc_sa1366" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Integrin A8B1_AVB1_AVB5_AVB6_AVB8* NAME:a8b1* ITGA8/ITGB1 NAME:aVb1* ITGAV/ITGB1 NAME:aVb5* ITGAV/ITGB5 NAME:aVb6* ITGAV/ITGB6 NAME:aVb8* ITGAV/ITGB8 HUGO:ITGA8, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB1, HUGO:ITGAV, HUGO:ITGB5, HUGO:ITGAV, HUGO:ITGB6, HUGO:ITGAV, HUGO:ITGB8 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Integrin A8B1_AVB1_AVB5_AVB6_AVB8*"/> <bbox w="240.0" h="20.0" x="4366.0" y="6292.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2563_emtc_emtc_sa1371" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LEF/TCF3* transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 lymphoid enhancer-binding factor 1 HUGO:LEF1, HGNC:6551, ENTREZ:51176, UNIPROT:Q9UJU2, GENECARDS:GC04M108968 transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, UNIPROT:P15923, GENECARDS:GC19M001609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LEF1_TCF3_4*"/> <bbox w="100.0" h="26.0" x="2363.0" y="3604.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2566_emtc_emtc_sa1372" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: GJA3_8* gap junction protein, alpha 3, 46kDa HUGO:GJA3, HGNC:4277, ENTREZ:2700 , UNIPROT:Q9Y6H8, GENECARDS:GC13M020712 gap junction protein, alpha 8, 50kDa HUGO:GJA8, HGNC:4281, ENTREZ:2703, UNIPROT:P48165, GENECARDS:GC01P147374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: PMID:12808044 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJA3_8*"/> <bbox w="60.0" h="20.0" x="742.0" y="5272.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2658_emtc_emtc_sa802" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 13 (membrane-inserted) HUGO:MMP13, HGNC:7159, ENTREZ:4322, GENECARDS:GC11M102847, UNIPROT:P45452 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 MMP13 activates TGFB by cleavage of LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP13"/> <bbox w="40.0" h="20.0" x="1052.0" y="6408.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2660_emtc_emtc_sa804" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) HUGO:MMP9, HGNC:7176, ENTREZ:4318, UNIPROT:P14780, GENECARDS:GC20P044637 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP9"/> <bbox w="40.0" h="20.0" x="1053.0" y="6321.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2661_emtc_emtc_sa805" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) HUGO:MMP2, HGNC:7166, ENTREZ:4313, GENECARDS:GC16P055478, P08253 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP2"/> <bbox w="40.0" h="20.0" x="1053.969" y="6257.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2830_emtc_emtc_sa527" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023, UNIPROT:P08123 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL1A2"/> <bbox w="60.0" h="20.0" x="4746.25" y="5739.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2850_emtc_emtc_sa1385" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZO1_3* tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991, UNIPROT:Q07157 tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659, UNIPROT:O95049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:Identifiers_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1_3*"/> <bbox w="60.0" h="20.0" x="1182.0" y="2512.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2869_emtc_emtc_sa1170" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, delta 2, 36kDa HUGO:GJD2, HGNC:19154, ENTREZ:57369, UNIPROT:Q9UKL4, GENECARDS:GC15M035043 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJD2 is so-called Connexin 36 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJD2"/> <bbox w="34.0" h="16.0" x="615.0" y="5954.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2877_emtc_emtc_sa1398" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 5, 31.1kDa HUGO:GJB5, HGNC:4287, ENTREZ:2709, UNIPROT:O95377, GENECARDS:GC01P035220 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJB5 is so-called Connexin 31.1 PMID:21777377 Cx31.1 (GJB5) is predominantly expressed in the testes and the skin epidermis. Cx31.1 rarely form functional gap junction channels, either with itself or with other Cx isoforms. Gap junctions play important roles in various physiologic functions such as regulation of cell proliferation, cell differentiation, tissue development and cell apoptosis. In most cases, Cxs act as tumour suppressors: Gap junctions play an important role as tumour suppressors in maintaining cell differentiation and preventing transformation Cx31.1 reduced tumour cell proliferation, anchorage-independent growth, migration and invasion. Moreover, development of tumours in a xenograft model was suppressed by Cx31.1, suggesting that Cx31.1 may act as a tumour suppressor in NSCLC cell lines. Expression of Cx31.1 reduced mesenchymal marker vimentin level and increased epithelial marker cytokeratin 18 level, indicating that Cx31.1 may regulate molecular pathways leading to a reverse of the EMT process. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB5"/> <bbox w="40.0" h="20.0" x="612.0" y="5812.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2880_emtc_emtc_sa1401" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D3 HUGO:CCND3, HGNC:1585, ENTREZ:896, GENECARDS:GC06M041949, UNIPROT:P30281 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21777377 Further studies are required to investigate the mechanism by which Cx31.1 repress cyclin D3 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD3*"/> <bbox w="60.0" h="20.0" x="2646.0" y="1633.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2881_emtc_emtc_sa131" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:2409071 Fibronectin is located on the apical and basal cell surfaces. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="72.0" h="20.0" x="2044.0" y="5096.969"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2893_emtc_emtc_sa1027" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cofilin 1 HUGO:CFL1, HGNC:1874, ENTREZ:1072, UNIPROT:P23528, GENECARDS:GC11M065622 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15866889 Cofilin is required for the maintenance of a polarized cytoskeleton and thus for directional cell miogration. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CFL1"/> <bbox w="36.0" h="19.0" x="4984.0" y="2815.0"/> <glyph class="state variable" id="_022aa0aa-e325-44d7-beab-16b73db5b6a5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4979.0" y="2810.442"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2894_emtc_emtc_sa1030" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LIM domain kinase 1 HUGO:LIMK1, HGNC:6613, ENTREZ:3984, UNIPROT:P53667, GENECARDS:GC07P073497 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIMK1"/> <bbox w="42.0" h="18.0" x="4825.5" y="2531.5"/> <glyph class="state variable" id="_f68e3d79-053a-45b8-a47d-91ccb735c179"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4820.759" y="2526.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2900_emtc_emtc_sa73" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:22881460 CRB3 is the only transmembrane protein among apical polarity regulators PMID:2344615 Link between Drosophila apical membrane Crb and epithelia organization References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: crumbs homolog 3 (Drosophila) HUGO:CRB3, HGNC:20237, ENTREZ:92359, UNIPROT:Q9BUF7, GENECARDS:GC19P006414 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:22881460 CRB3 is the only transmembrane protein among apical polarity regulators PMID:2344615 Link between Drosophila apical membrane Crb and epithelia organization References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3"/> <bbox w="44.0" h="17.0" x="6174.5" y="2867.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2901_emtc_emtc_sa1408" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoA_GAPs* myosin IXB HUGO:MYO9B, HGNC:7609, ENTREZ:4650, GENECARDS:GC19P017186, UNIPROT:Q13459 Rho GTPase activating protein 1 HUGO:ARHGAP1, HGNC:673, ENTREZ:392, GENECARDS:GC11M046698, UNIPROT:Q07960 Rho GTPase activating protein 26 HUGO:ARHGAP26, HGNC:17073, ENTREZ:23092, GENECARDS:GC05P142130, UNIPROT:Q9UNA1 Rho GTPase activating protein 32 HUGO:ARHGAP32, HGNC:17399, ENTREZ:9743, GENECARDS:GC11M128834, UNIPROT:A7KAX9 Rho GTPase activating protein 35 HUGO:ARHGAP35 HGNC:4591 ENTREZ:2909 UNIPROT:Q9NRY4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_GAPs*"/> <bbox w="78.0" h="18.0" x="5113.0" y="1861.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2902_emtc_emtc_sa1409" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoA_GDIs* Rho GDP dissociation inhibitor (GDI) alpha HUGO:ARHGDIA, HGNC:678, ENTREZ:396, GENECARDS:GC17M079825, UNIPROT:P52565 Rho GDP dissociation inhibitor (GDI) beta HUGO:ARHGDIB, HGNC:679, ENTREZ:397, GENECARDS:GC12M015094, UNIPROT:P52566 Rho GDP dissociation inhibitor (GDI) gamma HUGO:ARHGDIG, HGNC:680, ENTREZ:398, GENECARDS:GC16P000318, UNIPROT:Q99819 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. ARHGDIG is about 50 percent identical to ARHGDIA and ARHGDIB. ARHGFIG binds to CDC42 and RhoA with less affinity compared with ARHGDIA and does not bind with Rac1, Rac2, or Ras. ARHGDIG functions as a GDI for CDC42 but with about 20 times less efficiency than ARHGDIA. PMID:9490022 ARHGDIA,B,G are CDC42_GDIs References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_and_CDC42_GDIs*"/> <bbox w="149.0" h="19.0" x="5073.0" y="1936.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2903_emtc_emtc_sa1410" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoA_GEFs* Rho guanine nucleotide exchange factor (GEF) 1 HUGO:ARHGEF1, HGNC:681, ENTREZ:9138, GENECARDS:GC19P042387, UNIPROT:Q92888 Rho/Rac guanine nucleotide exchange factor (GEF) 2 HUGO:ARHGEF2, HGNC:682, ENTREZ:9181, GENECARDS:GC01M155916, UNIPROT:Q92974 Rho guanine nucleotide exchange factor (GEF) 3 HUGO:ARHGEF3, HGNC:683, ENTREZ:50650, GENECARDS:GC03M056736, UNIPROT:Q9NR81 Rho guanine nucleotide exchange factor (GEF) 4 HUGO:ARHGEF4, HGNC:684, ENTREZ:50649, GENECARDS:GC02P131595, UNIPROT:Q9NR80 Rho guanine nucleotide exchange factor (GEF) 10-like HUGO:ARHGEF10L, HGNC:25540, ENTREZ:55160, GENECARDS:GC01P017866, UNIPROT:Q9HCE6 Rho guanine nucleotide exchange factor (GEF) 12 HUGO:ARHGEF12, HGNC:14193, ENTREZ:23365, GENECARDS:GC11P120207, UNIPROT:Q9NZN5 MCF.2 cell line derived transforming sequence-like HUGO:MCF2L, HGNC:14576, ENTREZ:23263, GENECARDS:GC13P113548, UNIPROT:O15068 neuronal guanine nucleotide exchange factor HUGO:NGEF, HGNC:7807, ENTREZ:25791 , GENECARDS:GC02M233707 , UNIPROT:Q8N5V2 epithelial cell transforming sequence 2 oncogene HUGO:ECT2, HGNC:3155, ENTREZ:1894, GENECARDS:GC03P172468, UNIPROT:Q9H8V3 RAP1, GTP-GDP dissociation stimulator 1 HUGO:RAP1GDS1, HGNC:9859, ENTREZ:5910, GENECARDS:GC04P099182, UNIPROT:P52306 vav 2 guanine nucleotide exchange factor HUGO:VAV2, HGNC:12658, ENTREZ:7410, GENECARDS:GC09M136627, UNIPROT:P52735 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9789025 PMID:9641915 p115RhoGEF(so-called ARHGEF1) is an Rho guanine nucleotide exchange factor. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_GEFs*"/> <bbox w="78.0" h="19.0" x="5113.0" y="2117.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2909_emtc_emtc_sa1026" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ROCK Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 Rho-associated, coiled-coil containing protein kinase 2 HUGO:ROCK2, HGNC:10252, ENTREZ:9475, UNIPROT:O75116, GENECARDS:GC02M011272 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:12778124 In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop. Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK*"/> <bbox w="46.0" h="29.0" x="5167.5" y="2383.5"/> <glyph class="state variable" id="_a4d6edeb-24c9-4b3b-a50d-c56d32273c6f"> <state value="open" variable=""/> <bbox w="30.0" h="10.0" x="5175.5" y="2378.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2912_emtc_emtc_sa1415" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK1"/> <clone/> <bbox w="50.0" h="21.0" x="4848.0" y="2448.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2912_emtc_emtc_sa1438" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK1"/> <clone/> <bbox w="50.0" h="21.0" x="5229.0" y="2498.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2913_emtc_emtc_sa1439" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho-associated, coiled-coil containing protein kinase 2 HUGO:ROCK2, HGNC:10252, ENTREZ:9475, UNIPROT:O75116, GENECARDS:GC02M011272 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK2"/> <bbox w="52.0" h="19.0" x="5279.0" y="2479.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2918_emtc_emtc_sa1025" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ROCK Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 Rho-associated, coiled-coil containing protein kinase 2 HUGO:ROCK2, HGNC:10252, ENTREZ:9475, UNIPROT:O75116, GENECARDS:GC02M011272 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:12778124 In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop. Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK*"/> <bbox w="46.0" h="29.0" x="4822.0" y="2383.5"/> <glyph class="state variable" id="_d3c7137d-49d8-4666-81d1-29247fb51769"> <state value="closed" variable=""/> <bbox w="40.0" h="10.0" x="4825.0" y="2378.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2919_emtc_emtc_sa1420" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: DIA* diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 diaphanous homolog 3 (Drosophila) HUGO:DIAPH3, HGNC:15480, ENTREZ:81624, GENECARDS:GC13M060239, UNIPROT:Q9NSV4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DIA*"/> <bbox w="44.0" h="29.0" x="4968.0" y="2410.5"/> <glyph class="state variable" id="_99ab3c6a-9d1f-42a8-b55d-50b9b5a28363"> <state value="closed" variable=""/> <bbox w="40.0" h="10.0" x="4970.0" y="2405.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2924_emtc_emtc_sa1070" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 32 HUGO:ARHGAP32, HGNC:17399, ENTREZ:9743, GENECARDS:GC11M128834, UNIPROT:A7KAX9 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:12788081 p250GAP (so-called ARHGAP32 or p200RhoGAP) is a RhoGAP protein that is expressed predominantly in brain. ARHGAP32 is associated with and phosphorylated by Fyn, a member of Src-family protein tyrosine kinase. PMID:12857875 ARHGAP32 as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP32"/> <bbox w="75.0" h="17.0" x="5768.0" y="1786.0"/> <glyph class="state variable" id="_b5d43cde-495c-42b6-8815-248d89724299"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5833.0" y="1789.0554"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2925_emtc_emtc_sa1425" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: radixin HUGO:RDX, HGNC:9944, ENTREZ:5962, GENECARDS:GC11M110045 , UNIPROT:P35241 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9287351 ERM family (ezrin/radixin/moesin) Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein. PMID:10047517 Regulation of cortical structure by the ERM protein family. PMID:12045227 Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo. ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type. The Rho-independent activation mechanism of ERM proteins therefore exists. Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RDX"/> <bbox w="30.0" h="19.0" x="5271.0" y="1881.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2926_emtc_emtc_sa1427" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: moesinin HUGO:MSN, HGNC:7373, ENTREZ:4478, GENECARDS:GC0XP064887, UNIPROT:P26038 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9287351 ERM family (ezrin/radixin/moesin) Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein. PMID:10047517 Regulation of cortical structure by the ERM protein family. PMID:12045227 Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo. ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type. The Rho-independent activation mechanism of ERM proteins therefore exists. Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MSN"/> <bbox w="32.0" h="17.0" x="5302.0" y="1889.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2927_emtc_emtc_sa1428" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ERM* Ezrin HUGO:EZR, HGNC:12691, ENTREZ:7430, GENECARDS:GC06M159186, UNIPROT:P15311 radixin HUGO:RDX, HGNC:9944, ENTREZ:5962, GENECARDS:GC11M110045 , UNIPROT:P35241 moesinin HUGO:MSN, HGNC:7373, ENTREZ:4478, GENECARDS:GC0XP064887, UNIPROT:P26038 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9287351 ERM family (ezrin/radixin/moesin) Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein. PMID:8207064 Ezrin and radixin can be functionally substituted Moesin has some synergetic functional interaction with ezrin and radixin These ERM family members are involved in cell-cell and cell-substrate adhesion, as well as microvilli formation PMID:10047517 Regulation of cortical structure by the ERM protein family. PMID:12045227 Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo. ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type. The Rho-independent activation mechanism of ERM proteins therefore exists. Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo. PMID:12802084 ERM proteins exist in the cytoplasm as dormant monomers in which the F-actin cytoskeleton and the plasma membrane binding sites are masked. This closed conformation is due to an intramolecular N- to C-ERM association domain (ERMAD) interaction. PMID:7579708 Cell extracts contain ezrin dimers and ezrin-moesin heterodimers in addition to monomers. Dimerization in vivo requires an activation step that exposes this masked domain. The conformationally inaccessible C-terminal region included the F-actin binding site, suggesting that this activity is likewise regulated by masking. PMID:8527459 Ezrin, a membrane-microfilament linking protein, exists largely as a monomeric protein in solution. Purified ezrin monomers normally have a masked C-terminal domain (termed a C-ERMAD) that, upon exposure, can associate with an N-terminal domain (termed N-ERMAD) of another ezrin molecule. Purified ezrin dimers also have masked C-ERMADs. Since radixin and moesin, the two other members of the closely related ERM protein family, both contain N- and C-ERMADs, the results we have documented and models proposed for ezrin are likely to apply to radixin and moesin as well References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERM*"/> <bbox w="38.0" h="26.0" x="5215.0" y="1995.7"/> <glyph class="state variable" id="_b4a95163-ae43-4097-99af-4a0eed6c1d1c"> <state value="closed" variable=""/> <bbox w="38.0" h="10.0" x="5215.0" y="1990.7"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2928_emtc_emtc_sa1429" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ERM* Ezrin HUGO:EZR, HGNC:12691, ENTREZ:7430, GENECARDS:GC06M159186, UNIPROT:P15311 radixin HUGO:RDX, HGNC:9944, ENTREZ:5962, GENECARDS:GC11M110045 , UNIPROT:P35241 moesinin HUGO:MSN, HGNC:7373, ENTREZ:4478, GENECARDS:GC0XP064887, UNIPROT:P26038 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9287351 ERM family (ezrin/radixin/moesin) Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein. PMID:8207064 Ezrin and radixin can be functionally substituted Moesin has some synergetic functional interaction with ezrin and radixin These ERM family members are involved in cell-cell and cell-substrate adhesion, as well as microvilli formation PMID:10047517 Regulation of cortical structure by the ERM protein family. PMID:12045227 Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo. ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type. The Rho-independent activation mechanism of ERM proteins therefore exists. Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo. PMID:12802084 ERM proteins exist in the cytoplasm as dormant monomers in which the F-actin cytoskeleton and the plasma membrane binding sites are masked. This closed conformation is due to an intramolecular N- to C-ERM association domain (ERMAD) interaction. PMID:7579708 Cell extracts contain ezrin dimers and ezrin-moesin heterodimers in addition to monomers. Dimerization in vivo requires an activation step that exposes this masked domain. The conformationally inaccessible C-terminal region included the F-actin binding site, suggesting that this activity is likewise regulated by masking. PMID:8527459 Ezrin, a membrane-microfilament linking protein, exists largely as a monomeric protein in solution. Purified ezrin monomers normally have a masked C-terminal domain (termed a C-ERMAD) that, upon exposure, can associate with an N-terminal domain (termed N-ERMAD) of another ezrin molecule. Purified ezrin dimers also have masked C-ERMADs. Since radixin and moesin, the two other members of the closely related ERM protein family, both contain N- and C-ERMADs, the results we have documented and models proposed for ezrin are likely to apply to radixin and moesin as well References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERM*"/> <bbox w="38.0" h="26.0" x="5129.6" y="1997.7"/> <glyph class="state variable" id="_91ab0ef5-9e77-4527-bd78-5145bb9eb259"> <state value="open" variable=""/> <bbox w="30.0" h="10.0" x="5133.6" y="1992.7"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2931_emtc_emtc_sa1433" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: epidermal growth factor receptor HUGO:EGFR, HGNC:3236, ENTREZ:1956, UNIPROT:P00533, GENECARDS:GC07P055054 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR"/> <bbox w="80.0" h="50.0" x="2089.75" y="6036.0"/> <glyph class="unit of information" id="_6c389a48-94d9-4b24-8230-8083e569e3b1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2107.25" y="6031.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2932_emtc_emtc_sa1434" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-akt murine thymoma viral oncogene homolog 1 HUGO:AKT1, HGNC:391, ENTREZ:207, UNIPROT:P31749, GENECARDS:GC14M105235 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AKT1"/> <clone/> <bbox w="35.0" h="19.0" x="3039.75" y="1043.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2932_emtc_emtc_sa1435" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-akt murine thymoma viral oncogene homolog 1 HUGO:AKT1, HGNC:391, ENTREZ:207, UNIPROT:P31749, GENECARDS:GC14M105235 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AKT1"/> <clone/> <bbox w="38.0" h="17.0" x="3038.75" y="882.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2933_emtc_emtc_sa1437" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN HUGO:PTEN, HGNC:9588, ENTREZ:5728, UNIPROT:P60484, GENECARDS:GC10P089613 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTEN"/> <bbox w="43.0" h="17.0" x="4028.25" y="936.84"/> <glyph class="state variable" id="_8e0c9b1a-66f5-419b-b5e5-4e6570a35210"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4066.25" y="931.84"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2939_emtc_emtc_sa1444" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D2 HUGO:CCND2, HGNC:1583, ENTREZ:894, GENECARDS:GC12P004382, UNIPROT:P30279 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD2*"/> <bbox w="62.0" h="20.0" x="2726.0" y="1633.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2947_emtc_emtc_sa1449" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoB_GDIs* Rho GDP dissociation inhibitor (GDI) alpha HUGO:ARHGDIA, HGNC:678, ENTREZ:396, GENECARDS:GC17M079825, UNIPROT:P52565 Rho GDP dissociation inhibitor (GDI) gamma HUGO:ARHGDIG, HGNC:680, ENTREZ:398, GENECARDS:GC16P000318, UNIPROT:Q99819 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: The most known RhoB_GDIs are ARHGDIA and ARHGDIG. They bind to RhoB and suppress its activation. PMID:11368848 PMID:8939998 RhoGDI-3 (ARHGDIG) interacts specifically with GDP- and GTP-bound forms of post-translationally processed RhoB and RhoG proteins. No interaction is found with RhoA, RhoC, or Rac1 proteins. RhoGDI-3 is able to inhibit GDP/GTP exchange of RhoB and to release GDP-bound but not GTP-bound RhoB from cell membranes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB_GDIs*"/> <bbox w="80.0" h="20.0" x="5351.0" y="1908.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2948_emtc_emtc_sa1451" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoB_GEFs* Rho/Rac guanine nucleotide exchange factor (GEF) 2 HUGO:ARHGEF2, HGNC:682, ENTREZ:9181, GENECARDS:GC01M155916, UNIPROT:Q92974 Rho guanine nucleotide exchange factor (GEF) 3 HUGO:ARHGEF3, HGNC:683, ENTREZ:50650, GENECARDS:GC03M056736, UNIPROT:Q9NR81 Rho guanine nucleotide exchange factor (GEF) 10-like HUGO:ARHGEF10L, HGNC:25540, ENTREZ:55160, GENECARDS:GC01P017866, UNIPROT:Q9HCE6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB_GEFs*"/> <bbox w="80.0" h="20.0" x="5352.0" y="1992.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2949_emtc_emtc_sa1453" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: diaphanous homolog 2 (Drosophila) HUGO:DIAPH2, HGNC:2877, ENTREZ:1730, GENECARDS:GC0XP095939, UNIPROT:O60879 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DIAPH2"/> <bbox w="54.0" h="17.0" x="4910.0" y="2486.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2950_emtc_emtc_sa1454" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: rhophilin, Rho GTPase binding protein 1 HUGO:RHPN1, HGNC:19973, ENTREZ:114822, GENECARDS:GC08P144451, UNIPROT:114822 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RHPN1"/> <bbox w="47.0" h="17.0" x="5196.0" y="2554.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2951_emtc_emtc_sa1455" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoB_cytoskeletal_effectors* diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 diaphanous homolog 3 (Drosophila) HUGO:DIAPH3, HGNC:15480, ENTREZ:81624, GENECARDS:GC13M060239, UNIPROT:Q9NSV4 rhophilin, Rho GTPase binding protein 2 HUGO:RHPN2, HGNC:19974, ENTREZ:85415, GENECARDS:GC19M033469, UNIPROT:Q8IUC4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoB_cytoskeletal_effectors*"/> <bbox w="160.0" h="20.0" x="5352.0" y="2552.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2952_emtc_emtc_sa1456" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoA_cytoskeletal_effectors* diaphanous homolog 1 (Drosophila) HUGO:DIAPH1, HGNC:2876, ENTREZ:1729, GENECARDS:GC05M140875, UNIPROT:O60610 Rho-associated, coiled-coil containing protein kinase 1 HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529 rhophilin, Rho GTPase binding protein 1 HUGO:RHPN1, HGNC:19973, ENTREZ:114822, GENECARDS:GC08P144451, UNIPROT:114822 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_cytoskeletal_effectors*"/> <bbox w="170.0" h="19.0" x="4982.0" y="2552.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2964_emtc_emtc_sa1464" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: RhoA_B* ras homolog family member B HUGO:RHOB, HGNC:668, ENTREZ:388, GENECARDS:GC02P020568, UNIPROT:P62745 ras homolog family member A HUGO:RHOA, HGNC:667, ENTREZ:387, GENECARDS:GC03M049371, UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RhoA_B*"/> <bbox w="60.0" h="20.0" x="5391.0" y="2387.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2972_emtc_emtc_sa1470" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: PAK* p21 protein (Cdc42/Rac)-activated kinase 1 "p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)", "p21/Cdc42/Rac1-activated kinase 1 (yeast Ste20-related)" HUGO:PAK1 HGNC:8590 ENTREZ:5058 UNIPROT:Q13153 p21 protein (Cdc42/Rac)-activated kinase 2 "p21 (CDKN1A)-activated kinase 2" HUGO:PAK2 HGNC:8591 ENTREZ:5062 UNIPROT:Q13177 p21 protein (Cdc42/Rac)-activated kinase 3 "mental retardation, X-linked 47", MRX30, MRX47, "p21 (CDKN1A)-activated kinase 3" HUGO:PAK3 HGNC:8592 ENTREZ:5063 UNIPROT:O75914 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK*"/> <bbox w="40.0" h="30.0" x="5620.0" y="2347.5"/> <glyph class="state variable" id="_3a1b50a2-050b-4706-bdbe-0e6ace4e27fa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5634.6157" y="2342.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2973_emtc_emtc_sa1471" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: PAK* p21 protein (Cdc42/Rac)-activated kinase 1 "p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)", "p21/Cdc42/Rac1-activated kinase 1 (yeast Ste20-related)" HUGO:PAK1 HGNC:8590 ENTREZ:5058 UNIPROT:Q13153 p21 protein (Cdc42/Rac)-activated kinase 2 "p21 (CDKN1A)-activated kinase 2" HUGO:PAK2 HGNC:8591 ENTREZ:5062 UNIPROT:Q13177 p21 protein (Cdc42/Rac)-activated kinase 3 "mental retardation, X-linked 47", MRX30, MRX47, "p21 (CDKN1A)-activated kinase 3" HUGO:PAK3 HGNC:8592 ENTREZ:5063 UNIPROT:O75914 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAK*"/> <bbox w="40.0" h="30.0" x="5813.0" y="2348.5"/> <glyph class="state variable" id="_0c67dd14-d374-4eae-8be7-0188b97073b0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5825.1157" y="2343.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2975_emtc_emtc_sa1473" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 10 MLK2 HUGO:MAP3K10 HGNC:6849 ENTREZ:4294 UNIPROT:Q02779 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K10"/> <bbox w="60.0" h="20.0" x="5502.0" y="2357.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2976_emtc_emtc_sa1474" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MAP3K10_11* mitogen-activated protein kinase kinase kinase 11 MLK3, PTK1 HUGO:MAP3K11 HGNC:6850 ENTREZ:4296 UNIPROT:Q16584 mitogen-activated protein kinase kinase kinase 10 MLK2 HUGO:MAP3K10 HGNC:6849 ENTREZ:4294 UNIPROT:Q02779 mitogen-activated protein kinase kinase kinase 7 TAK1 HUGO:MAP3K7 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K7_10_11*"/> <clone/> <bbox w="103.0" h="18.0" x="5577.0" y="2447.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2976_emtc_emtc_sa1475" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MAP3K10_11* mitogen-activated protein kinase kinase kinase 11 MLK3, PTK1 HUGO:MAP3K11 HGNC:6850 ENTREZ:4296 UNIPROT:Q16584 mitogen-activated protein kinase kinase kinase 10 MLK2 HUGO:MAP3K10 HGNC:6849 ENTREZ:4294 UNIPROT:Q02779 mitogen-activated protein kinase kinase kinase 7 TAK1 HUGO:MAP3K7 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K7_10_11*"/> <clone/> <bbox w="111.0" h="18.0" x="5762.0" y="2448.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2977_emtc_emtc_sa1476" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog alpha" HUGO:PARD6A HGNC:15943 ENTREZ:50855 UNIPROT:Q9NPB6 par-6 partitioning defective 6 homolog beta (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog beta" HUGO:PARD6B HGNC:16245 ENTREZ:84612 UNIPROT:Q9BYG5 par-6 partitioning defective 6 homolog gamma (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog gamma" HUGO:PARD6G HGNC:16076 ENTREZ:84552 UNIPROT:Q9BYG4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR6*"/> <clone/> <bbox w="60.0" h="20.0" x="5595.0" y="2521.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2977_emtc_emtc_sa1480" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog alpha" HUGO:PARD6A HGNC:15943 ENTREZ:50855 UNIPROT:Q9NPB6 par-6 partitioning defective 6 homolog beta (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog beta" HUGO:PARD6B HGNC:16245 ENTREZ:84612 UNIPROT:Q9BYG5 par-6 partitioning defective 6 homolog gamma (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog gamma" HUGO:PARD6G HGNC:16076 ENTREZ:84552 UNIPROT:Q9BYG4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR6*"/> <clone/> <bbox w="60.0" h="20.0" x="5732.0" y="2521.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2979_emtc_emtc_sa1478" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog beta (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog beta" HUGO:PARD6B HGNC:16245 ENTREZ:84612 UNIPROT:Q9BYG5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6B"/> <bbox w="60.0" h="20.0" x="5502.0" y="2499.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2980_emtc_emtc_sa1479" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog gamma (C. elegans) "par-6 (partitioning defective 6, C.elegans) homolog gamma" HUGO:PARD6G HGNC:16076 ENTREZ:84552 UNIPROT:Q9BYG4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6G"/> <bbox w="60.0" h="20.0" x="5502.0" y="2529.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2981_emtc_emtc_sa1483" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-4-phosphate 5-kinase, type I, beta HUGO:PIP5K1B HGNC:8995 ENTREZ:8395 UNIPROT:O14986 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PIP5K1B"/> <bbox w="60.0" h="20.0" x="5522.0" y="2642.875"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2982_emtc_emtc_sa1484" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-4-phosphate 5-kinase, type I, gamma HUGO:PIP5K1C HGNC:8996 ENTREZ:23396 UNIPROT:O60331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PIP5K1C"/> <bbox w="60.0" h="20.0" x="5522.0" y="2672.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2983_emtc_emtc_sa1485" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: PIP4K1A_B_C* phosphatidylinositol-4-phosphate 5-kinase, type I, alpha HUGO:PIP5K1A HGNC:8994 ENTREZ:8394 UNIPROT:Q99755 phosphatidylinositol-4-phosphate 5-kinase, type I, beta HUGO:PIP5K1B HGNC:8995 ENTREZ:8395 UNIPROT:O14986 phosphatidylinositol-4-phosphate 5-kinase, type I, gamma HUGO:PIP5K1C HGNC:8996 ENTREZ:23396 UNIPROT:O60331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PIP5K1*"/> <clone/> <bbox w="60.0" h="19.0" x="5628.0" y="2640.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2983_emtc_emtc_sa1486" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: PIP4K1A_B_C* phosphatidylinositol-4-phosphate 5-kinase, type I, alpha HUGO:PIP5K1A HGNC:8994 ENTREZ:8394 UNIPROT:Q99755 phosphatidylinositol-4-phosphate 5-kinase, type I, beta HUGO:PIP5K1B HGNC:8995 ENTREZ:8395 UNIPROT:O14986 phosphatidylinositol-4-phosphate 5-kinase, type I, gamma HUGO:PIP5K1C HGNC:8996 ENTREZ:23396 UNIPROT:O60331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PIP5K1*"/> <clone/> <bbox w="81.0" h="19.0" x="5742.0" y="2640.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2984_emtc_emtc_sa1487" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ARP2/3* ARP2 actin-related protein 2 homolog (yeast) "ARP2 (actin-related protein 2, yeast) homolog" HUGO:ACTR2 HGNC:169 ENTREZ:10097 UNIPROT:P61160 ARP3 actin-related protein 3 homolog (yeast) "ARP3 (actin-related protein 3, yeast) homolog" HUGO:ACTR3 HGNC:170 ENTREZ:10096 UNIPROT:P61158 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARP2_3*"/> <clone/> <bbox w="60.0" h="20.0" x="5867.0" y="2830.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2984_emtc_emtc_sa1491" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ARP2/3* ARP2 actin-related protein 2 homolog (yeast) "ARP2 (actin-related protein 2, yeast) homolog" HUGO:ACTR2 HGNC:169 ENTREZ:10097 UNIPROT:P61160 ARP3 actin-related protein 3 homolog (yeast) "ARP3 (actin-related protein 3, yeast) homolog" HUGO:ACTR3 HGNC:170 ENTREZ:10096 UNIPROT:P61158 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARP2_3*"/> <clone/> <bbox w="60.0" h="20.0" x="5710.0" y="2830.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2986_emtc_emtc_sa1492" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actin, alpha 1, skeletal muscle ACTA HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α1-Actin*"/> <bbox w="62.0" h="19.0" x="5502.0" y="2903.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2987_emtc_emtc_sa1493" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α2-Actin*"/> <bbox w="63.0" h="18.0" x="5502.0" y="2927.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2988_emtc_emtc_sa1494" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actin, beta HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Actin*"/> <bbox w="63.0" h="18.0" x="5500.0" y="2948.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2989_emtc_emtc_sa1495" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actin, alpha, cardiac muscle 1 ACTC, "actin, alpha, cardiac muscle" HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Actin*"/> <bbox w="60.0" h="17.0" x="5503.0" y="2970.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s2990_emtc_emtc_sa1496" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actin, gamma 1 ACTG, "deafness, autosomal dominant 20; deafness, autosomal dominant 26", DFNA20, DFNA26 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="γ-Actin*"/> <bbox w="63.0" h="17.0" x="5499.0" y="2993.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3004_emtc_emtc_sa1507" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rac1_GAPs* Rho GTPase activating protein 1 HUGO:ARHGAP1, HGNC:673, ENTREZ:392, GENECARDS:GC11M046698, UNIPROT:Q07960 Rho GTPase activating protein 9 HUGO:ARHGAP9 HGNC:14130 ENTREZ:64333 UNIPROT:Q9BRR9 Rho GTPase activating protein 12 HUGO:ARHGAP12 HGNC:16348 ENTREZ:94134 UNIPROT:Q8IWW6 SLIT-ROBO Rho GTPase activating protein 3 "SLIT-ROBO Rho GTPase activating protein 2", SRGAP2 HUGO:SRGAP3 HGNC:19744 ENTREZ:9901 UNIPROT:O43295 Rho GTPase activating protein 24 HUGO:ARHGAP24 HGNC:25361 ENTREZ:83478 UNIPROT:Q8N264 Rho GTPase activating protein 32 HUGO:ARHGAP32, HGNC:17399, ENTREZ:9743, GENECARDS:GC11M128834, UNIPROT:A7KAX9 breakpoint cluster region BCR1, D22S11 HUGO:BCR HGNC:1014 ENTREZ:613 UNIPROT:P11274 ralA binding protein 1 HUGO:RALBP1 HGNC:9841 ENTREZ:10928 UNIPROT:Q15311 active BCR-related "active BCR-related gene" HUGO:ABR HGNC:81 ENTREZ:29 UNIPROT:Q12979 chimerin 2 "chimerin (chimaerin) 2" HUGO:CHN2 HGNC:1944 ENTREZ:1124 UNIPROT:P52757 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Rac1_GAPs*"/> <bbox w="80.0" h="20.0" x="5610.0" y="1866.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3005_emtc_emtc_sa1508" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rac1_GDIs* Rho GDP dissociation inhibitor (GDI) beta HUGO:ARHGDIB, HGNC:679, ENTREZ:397, GENECARDS:GC12M015094, UNIPROT:P52566 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Rac1_GDIs*"/> <bbox w="80.0" h="20.0" x="5613.0" y="1968.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3006_emtc_emtc_sa1509" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CASPASE* caspase 1, apoptosis-related cysteine peptidase "caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)", "caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase)", IL1BC HUGO:CASP1 HGNC:1499 ENTREZ:834 UNIPROT:P29466 caspase 3, apoptosis-related cysteine peptidase "caspase 3, apoptosis-related cysteine protease" HUGO:CASP3 HGNC:1504 ENTREZ:836 UNIPROT:P42574 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11989976 PMID:17959595 Caspase1,3 promote proteosomal degradation of ARHGDIB References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Caspase*"/> <bbox w="60.0" h="20.0" x="4737.0" y="1878.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3007_emtc_emtc_sa1510" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rac1_GEFs* Rho/Rac guanine nucleotide exchange factor (GEF) 2 HUGO:ARHGEF2, HGNC:682, ENTREZ:9181, GENECARDS:GC01M155916, UNIPROT:Q92974 Rho guanine nucleotide exchange factor (GEF) 4 HUGO:ARHGEF4, HGNC:684, ENTREZ:50649, GENECARDS:GC02P131595, UNIPROT:Q9NR80 epithelial cell transforming sequence 2 oncogene HUGO:ECT2, HGNC:3155, ENTREZ:1894, GENECARDS:GC03P172468, UNIPROT:Q9H8V3 RAP1, GTP-GDP dissociation stimulator 1 HUGO:RAP1GDS1, HGNC:9859, ENTREZ:5910, GENECARDS:GC04P099182, UNIPROT:P52306 vav 2 guanine nucleotide exchange factor HUGO:VAV2, HGNC:12658, ENTREZ:7410, GENECARDS:GC09M136627, UNIPROT:P52735 vav 1 guanine nucleotide exchange factor HUGO:VAV1, HGNC:12657, ENTREZ:7409, GENECARDS:GC19P006772, UNIPROT:P15498 MCF.2 cell line derived transforming sequence HUGO:MCF2 HGNC:6940 ENTREZ:4168 UNIPROT:P10911 differentially expressed in FDCP 6 homolog (mouse) "differentially expressed in FDCP (mouse homolog) 6" HUGO:DEF6 HGNC:2760 ENTREZ:50619 UNIPROT:Q9H4E7 T-cell lymphoma invasion and metastasis 1 HUGO:TIAM1 HGNC:11805 ENTREZ:7074 UNIPROT:Q13009 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Rac1_GEFs*"/> <bbox w="80.0" h="20.0" x="5611.0" y="2138.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3008_emtc_emtc_sa1511" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa) "lymphocyte cytosolic protein 2 (SH2 domain-containing leukocyte protein of 76kD)", SLP76 HUGO:LCP2 HGNC:6529 ENTREZ:3937 UNIPROT:Q13094 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LCP2"/> <bbox w="36.0" h="18.0" x="5094.0" y="2258.143"/> <glyph class="state variable" id="_806e6bf2-347d-4ba9-b45b-fa49d53adcd6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5086.5" y="2262.143"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3010_emtc_emtc_sa1086" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MCF.2 cell line derived transforming sequence HUGO:MCF2 HGNC:6940 ENTREZ:4168 UNIPROT:P10911 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11394904 PMID:10652228 GEF activity of MCF2 (DBL) towards CDC42 or Rac1 is enhanced upon TNK2 (ACK1) phosphorylation. PMID:18470881 Nm23-H1 binds Dbl-1 and thus interferes with the ability of Dbl-1 to load GTP onto CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MCF2"/> <bbox w="35.0" h="16.0" x="5294.5" y="2282.928"/> <glyph class="state variable" id="_4c4396c4-928e-4992-83de-5e470ea3fdc4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5321.7295" y="2293.928"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3016_emtc_emtc_sa1525" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LIM domain kinase 2 HUGO:LIMK2 HGNC:6614 ENTREZ:3985 UNIPROT:P53671 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HUGO:LIMK1, HGNC:6613, ENTREZ:3984, UNIPROT:P53667, GENECARDS:GC07P073497 LIM domain kinase 2 HUGO:LIMK2 HGNC:6614 ENTREZ:3985 UNIPROT:P53671 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIMK1_2*"/> <bbox w="70.0" h="19.0" x="4931.0" y="2695.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3018_emtc_emtc_sa1029" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: LIM domain kinase 1 HUGO:LIMK1, HGNC:6613, ENTREZ:3984, UNIPROT:P53667, GENECARDS:GC07P073497 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIMK1"/> <bbox w="48.0" h="18.0" x="4822.0" y="2608.0"/> <glyph class="state variable" id="_d7fda410-7cb1-4394-810e-3c187ddc2924"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4814.7954" y="2603.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3019_emtc_emtc_sa1529" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: destrin (actin depolymerizing factor) HUGO:DSTN HGNC:15750 ENTREZ:11034 UNIPROT:P60981 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DSTN"/> <bbox w="38.0" h="18.0" x="4952.0" y="2906.5"/> <glyph class="state variable" id="_e292c8a7-324f-46cc-bf69-ede6b7bbc28c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4947.234" y="2901.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3025_emtc_emtc_sa1028" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cofilin 1 HUGO:CFL1, HGNC:1874, ENTREZ:1072, UNIPROT:P23528, GENECARDS:GC11M065622 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15866889 Cofilin is required for the maintenance of a polarized cytoskeleton and thus for directional cell miogration. 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YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). 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YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). 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WASP and N-WASP binds to ARP2/3 and this lieads to actin cytoskeletal polymerization and filopodia formation. PMID:8625410 PMID:16293614 PMID:10467124 PMID:10511705 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASP_NWASP*"/> <clone/> <bbox w="96.0" h="16.0" x="5931.0" y="2564.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3036_emtc_emtc_sa1544" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: WASP_N-WASP* Wiskott-Aldrich syndrome IMD2, THC, "thrombocytopenia 1 (X-linked)", "Wiskott-Aldrich syndrome (eczema-thrombocytopenia)" HUGO:WAS HGNC:12731 ENTREZ:7454 UNIPROT:P42768 Wiskott-Aldrich syndrome-like HUGO:WASL HGNC:12735 ENTREZ:8976 UNIPROT:O00401 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 induces actin cytoskeleton changes by activating WASP and N-WASP. WASP and N-WASP binds to ARP2/3 and this lieads to actin cytoskeletal polymerization and filopodia formation. PMID:8625410 PMID:16293614 PMID:10467124 PMID:10511705 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WASP_NWASP*"/> <clone/> <bbox w="96.0" h="16.0" x="6081.5" y="2564.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3037_emtc_emtc_sa1545" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42EP* CDC42 effector protein (Rho GTPase binding) 2 HUGO:CDC42EP2 HGNC:16263 ENTREZ:10435 UNIPROT:O14613 CDC42 effector protein (Rho GTPase binding) 3 HUGO:CDC42EP3 HGNC:16943 ENTREZ:10602 UNIPROT:Q9UKI2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: CDC42 promotes cytoskeleton remodeling by binding to CDC42EPs (CDC42EP2 and CDC42EP3) PMID:10490598 PMID:11035016 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42EP*"/> <bbox w="73.0" h="21.0" x="6051.0" y="2229.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3040_emtc_emtc_sa1548" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42_GAPs* Rho GTPase activating protein 1 HUGO:ARHGAP1, HGNC:673, ENTREZ:392, GENECARDS:GC11M046698, UNIPROT:Q07960 Rho GTPase activating protein 5 GFI2, "growth factor independent 2" HUGO:ARHGAP5 HGNC:675 ENTREZ:394 UNIPROT:Q13017 Rho GTPase activating protein 17 HUGO:ARHGAP17 HGNC:18239 ENTREZ:55114 UNIPROT:Q68EM7 Rho GTPase activating protein 31 HUGO:ARHGAP31 HGNC:29216 ENTREZ:57514 UNIPROT:Q2M1Z3 Rho GTPase activating protein 32 HUGO:ARHGAP32, HGNC:17399, ENTREZ:9743, GENECARDS:GC11M128834, UNIPROT:A7KAX9 breakpoint cluster region BCR1, D22S11 HUGO:BCR HGNC:1014 ENTREZ:613 UNIPROT:P11274 ralA binding protein 1 HUGO:RALBP1 HGNC:9841 ENTREZ:10928 UNIPROT:Q15311 active BCR-related HUGO:ABR HGNC:81 ENTREZ:29 UNIPROT:Q12979 chimerin 2 HUGO:CHN2 HGNC:1944 ENTREZ:1124 UNIPROT:P52757 deleted in liver cancer 1 HUGO:DLC1 HGNC:2897 ENTREZ:10395 UNIPROT:Q96QB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42_GAPs*"/> <bbox w="95.0" h="21.0" x="5872.0" y="1866.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3041_emtc_emtc_sa1549" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDC42_GEFs* epithelial cell transforming sequence 2 oncogene HUGO:ECT2, HGNC:3155, ENTREZ:1894, GENECARDS:GC03P172468, UNIPROT:Q9H8V3 MCF.2 cell line derived transforming sequence HUGO:MCF2 HGNC:6940 ENTREZ:4168 UNIPROT:P10911 differentially expressed in FDCP 6 homolog (mouse) HUGO:DEF6 HGNC:2760 ENTREZ:50619 UNIPROT:Q9H4E7 FYVE, RhoGEF and PH domain containing 1 "faciogenital dysplasia (Aarskog-Scott syndrome)", FGDY HUGO:FGD1 HGNC:3663 ENTREZ:2245 UNIPROT:P98174 FYVE, RhoGEF and PH domain containing 4 "FGD1 family, member 4" HUGO:FGD4 HGNC:19125 ENTREZ:121512 UNIPROT:Q96M96 dedicator of cytokinesis 6 HUGO:DOCK6 HGNC:19189 ENTREZ:57572 UNIPROT:Q96HP0 dedicator of cytokinesis 9 HUGO:DOCK9 HGNC:14132 ENTREZ:23348 UNIPROT:Q9BZ29 dedicator of cytokinesis 11 HUGO:DOCK11 HGNC:23483 ENTREZ:139818 UNIPROT:Q5JSL3 spermatogenesis associated 13 HUGO:SPATA13 HGNC:23222 ENTREZ:221178 UNIPROT:Q96N96 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: GEFs are essential for CDC42 activation. They promote the exchange of GDP to GTP to generate the activated form of CDC42 capable of recognizing downstram targets. PMID:8836113 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDC42_GEFs*"/> <bbox w="86.0" h="21.0" x="5956.0" y="1903.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3042_emtc_emtc_sa1551" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2/adenovirus E1B 19kDa interacting protein 2 "BCL2/adenovirus E1B 19kD-interacting protein 2" HUGO:BNIP2 HGNC:1083 ENTREZ:663 UNIPROT:Q12982 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10551883 FGFR1 regulates activity of CDC42 by binding and phosphorylating thus inactivating BCL2. Phosphorylated BCL2 binds to another CDC42_GAP, ARHGAP1 and neutralize the GAP activity of ARHGAP1 as well. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BNIP2"/> <bbox w="39.0" h="17.0" x="6040.5" y="2429.5"/> <glyph class="state variable" id="_3a6713cc-e868-4271-aa8d-2f46e5562cf0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6033.0" y="2424.8953"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3060_emtc_emtc_sa801" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA, HGNC:12680, ENTREZ:7422, GENECARDS:GC06P043737, UNIPROT:P15692 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:15111329 VEGF is a predominant angiogenic factor that mediates ocular neovascularization. VEGF is increased by hypoxia, which is one of the primary stimuli for ocular neovascularization. VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is PKC/ERK pathway-dependent. Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases PMID:11166270 VEGF stands for the vascular Endothelial Growth Factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults PMID:13678960 VEGFs belong to a family of homodimeric glycoproteins that containts five members (VEGF-A, B, C, D, and Placenta growth factor PLGF). VEGFs bind to 3 different VEGF-receptor tyrosine kinases (VEGFR-1, 2, 3). Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular functions. PMID:10022831 PMID:15501236 VEGFA is a homodimer that exists in five different isoforms comprising 121, 145, 165, 189, and 206 amino acids per chain. The isoforms differ in their ability to bind heparan sulfate proteoglycans in the extracellular matrix (ECM). In adult Endothelial cells, VEGFA exhibits high affinity binding to tyrosine kinase receptors, VEGFR1 and VEGFR2. Although ECs express both receptors, recent findings suggest that only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFA"/> <bbox w="40.0" h="20.0" x="6231.0" y="5036.625"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3062_emtc_emtc_sa807" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 1 (interstitial collagenase) HUGO:MMP1, HGNC:7155, ENTREZ:4312, GENECARDS:GC11M102660, UNIPROT:P08254 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP1"/> <bbox w="40.0" h="20.0" x="1053.969" y="6217.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3063_emtc_emtc_sa806" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 3 (stromelysin 1, progelatinase) HUGO:MMP3, HGNC:7173, ENTREZ:4314, UNIPROT:P08254, GENECARDS:GC11M102706 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP3"/> <bbox w="40.0" h="20.0" x="1053.969" y="6281.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3064_emtc_emtc_sa1643" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MyosinLC* myosin, light chain 1, alkali; skeletal, fast "myosin, light polypeptide 1, alkali; skeletal, fast" HUGO:MYL1 HGNC:7582 ENTREZ:4632 UNIPROT:P05976 myosin, light chain 2, regulatory, cardiac, slow "myosin, light polypeptide 2, regulatory, cardiac, slow" HUGO:MYL2 HGNC:7583 ENTREZ:4633 UNIPROT:P10916 myosin, light chain 3, alkali; ventricular, skeletal, slow "myosin, light polypeptide 3, alkali; ventricular, skeletal, slow" HUGO:MYL3 HGNC:7584 ENTREZ:4634 UNIPROT:P08590 myosin, light chain 4, alkali; atrial, embryonic "myosin, light polypeptide 4, alkali; atrial, embryonic" HUGO:MYL4 HGNC:7585 ENTREZ:4635 UNIPROT:P12829 myosin, light chain 5, regulatory "myosin, light polypeptide 5, regulatory" HUGO:MYL5 HGNC:7586 ENTREZ:4636 UNIPROT:Q02045 myosin, light chain 6, alkali, smooth muscle and non-muscle "myosin, light polypeptide 6, alkali, smooth muscle and non-muscle" HUGO:MYL6 HGNC:7587 ENTREZ:4637 UNIPROT:P60660 myosin, light chain 6B, alkali, smooth muscle and non-muscle "myosin, light polypeptide 6B, alkali, smooth muscle and non-muscle" HUGO:MYL6B HGNC:29823 ENTREZ:140465 UNIPROT:P14649 myosin, light chain 7, regulatory "myosin, light polypeptide 7, regulatory" HUGO:MYL7 HGNC:21719 ENTREZ:58498 UNIPROT:Q01449 myosin, light chain 10, regulatory HUGO:MYL10 HGNC:29825 ENTREZ:93408 UNIPROT:Q9BUA6 myosin, light chain 12A, regulatory, non-sarcomeric "myosin, light polypeptide, regulatory, non-sarcomeric (20kD)" HUGO:MYL12A HGNC:16701 ENTREZ:10627 UNIPROT:P19105 myosin, light chain 12B, regulatory HUGO:MYL12B HGNC:29827 ENTREZ:103910 UNIPROT:O14950 myosin light chain, phosphorylatable, fast skeletal muscle HUGO:MYLPF HGNC:29824 ENTREZ:29895 UNIPROT:Q96A32 myosin, light chain, cardiac muscle-like 1 "myosin, light polypeptide, cardiac muscle-like 1" HUGO:MYLL1 HGNC:7592 ENTREZ:4639 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MyosinLC*"/> <bbox w="68.0" h="16.0" x="4836.0" y="3701.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3065_emtc_emtc_sa1645" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 2, regulatory, cardiac, slow "myosin, light polypeptide 2, regulatory, cardiac, slow" HUGO:MYL2 HGNC:7583 ENTREZ:4633 UNIPROT:P10916 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL2"/> <bbox w="44.0" h="18.0" x="4878.0" y="3747.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3066_emtc_emtc_sa1628" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: MyosinII* myosin, heavy chain 1, skeletal muscle, adult HUGO:MYH1, HGNC:7567, ENTREZ:4619, GENECARDS:GC17M010395, UNIPROT:P12882 myosin, heavy chain 2, skeletal muscle, adult HUGO:MYH2 HGNC:7572 ENTREZ:4620 UNIPROT:Q9UKX2 myosin, heavy chain 3, skeletal muscle, embryonic HUGO:MYH3 HGNC:7573 ENTREZ:4621 UNIPROT:P11055 myosin, heavy chain 4, skeletal muscle HUGO:MYH4 HGNC:7574 ENTREZ:4622 UNIPROT:Q9Y623 myosin, heavy chain 6, cardiac muscle, alpha "myosin, heavy polypeptide 6, cardiac muscle, alpha (cardiomyopathy, hypertrophic 1)" HUGO:MYH6 HGNC:7576 ENTREZ:4624 UNIPROT:P13533 myosin, heavy chain 7, cardiac muscle, beta CMH1, MPD1, "myopathy, distal 1", "myosin, heavy polypeptide 7, cardiac muscle, beta" HUGO:MYH7 HGNC:7577 ENTREZ:4625 UNIPROT:P12883 myosin, heavy chain 7B, cardiac muscle, beta "myosin, heavy polypeptide 7B, cardiac muscle, beta" HUGO:MYH7B HGNC:15906 ENTREZ:57644 UNIPROT:A7E2Y1 myosin, heavy chain 8, skeletal muscle, perinatal "myosin, heavy polypeptide 8, skeletal muscle, perinatal" HUGO:MYH8 HGNC:7578 ENTREZ:4626 UNIPROT:P13535 myosin, heavy chain 9, non-muscle DFNA17, "myosin, heavy polypeptide 9, non-muscle" HUGO:MYH9 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 myosin, heavy chain 10, non-muscle HUGO:MYH10 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 myosin, heavy chain 11, smooth muscle HUGO:MYH11 HGNC:7569 ENTREZ:4629 UNIPROT:P35749 myosin, heavy chain 13, skeletal muscle HUGO:MYH13 HGNC:7571 ENTREZ:8735 UNIPROT:Q9UKX3 myosin, heavy chain 14, non-muscle HUGO:MYH14 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 myosin, heavy chain 15 HUGO:MYH15 HGNC:31073 ENTREZ:22989 UNIPROT:Q9Y2K3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MyosinII*"/> <bbox w="72.0" h="19.0" x="4903.0" y="3610.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3068_emtc_emtc_sa1629" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 2, skeletal muscle, adult HUGO:MYH2 HGNC:7572 ENTREZ:4620 UNIPROT:Q9UKX2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH2"/> <bbox w="41.0" h="17.0" x="4870.857" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3069_emtc_emtc_sa1630" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 3, skeletal muscle, embryonic HUGO:MYH3 HGNC:7573 ENTREZ:4621 UNIPROT:P11055 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH3"/> <bbox w="43.0" h="16.0" x="4917.715" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3070_emtc_emtc_sa1631" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 4, skeletal muscle HUGO:MYH4 HGNC:7574 ENTREZ:4622 UNIPROT:Q9Y623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH4"/> <bbox w="40.0" h="17.0" x="4966.648" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3075_emtc_emtc_sa1636" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 9, non-muscle DFNA17, "myosin, heavy polypeptide 9, non-muscle" HUGO:MYH9 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH9"/> <bbox w="41.0" h="17.0" x="5214.473" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3078_emtc_emtc_sa1639" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 13, skeletal muscle HUGO:MYH13 HGNC:7571 ENTREZ:8735 UNIPROT:Q9UKX3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH13"/> <bbox w="46.0" h="17.0" x="5358.89" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3079_emtc_emtc_sa1640" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 14, non-muscle HUGO:MYH14 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH14"/> <bbox w="55.0" h="16.0" x="5410.516" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3080_emtc_emtc_sa1641" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 15 HUGO:MYH15 HGNC:31073 ENTREZ:22989 UNIPROT:Q9Y2K3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH15"/> <bbox w="54.0" h="17.0" x="5471.219" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3082_emtc_emtc_sa1644" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 1, alkali; skeletal, fast "myosin, light polypeptide 1, alkali; skeletal, fast" HUGO:MYL1 HGNC:7582 ENTREZ:4632 UNIPROT:P05976 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL1"/> <bbox w="35.0" h="20.0" x="4838.0" y="3746.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3083_emtc_emtc_sa1646" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 3, alkali; ventricular, skeletal, slow "myosin, light polypeptide 3, alkali; ventricular, skeletal, slow" HUGO:MYL3 HGNC:7584 ENTREZ:4634 UNIPROT:P08590 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL3"/> <bbox w="40.0" h="20.0" x="4926.0" y="3746.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3361_emtc_emtc_sa1567" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Collagen 1* collagen, type I, alpha 1 HUGO:COL1A1 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023, UNIPROT:P08123 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen1*"/> <bbox w="79.0" h="20.0" x="4759.0" y="6117.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3363_emtc_emtc_sa1568" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: a1b1*_a2b1* NAME:a1b1* ITGA1/ITGB1 integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME: a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a1b1*_a2b1*"/> <bbox w="88.0" h="22.0" x="3543.0" y="6262.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3368_emtc_emtc_sa1571" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: a2b1*_a3b1* NAME:a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:a3b1* ITGA3/ITGB1 integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrin a2b1 predominantly binds to fibrillar collagen Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a2b1*_a3b1*"/> <bbox w="84.0" h="21.0" x="3650.0" y="6263.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3373_emtc_emtc_sa1574" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:2409071 Fibronectin is located on the apical and basal cell surfaces. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="72.0" h="20.0" x="5224.5" y="6242.469"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3378_emtc_emtc_sa1578" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: a5b1*_aVb3* NAME:a5b1* ITGA5/ITGB1 integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a5b1*_aVb3*"/> <bbox w="82.0" h="19.0" x="4122.0" y="6247.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3380_emtc_emtc_sa1580" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: aVb3*_aVb5* NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 NAME:aVb5* ITGAV/ITGB5 integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="aVb3*_aVb5*"/> <bbox w="83.0" h="19.0" x="4539.0" y="6247.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3382_emtc_emtc_sa1581" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vitronectin "vitronectin (serum spreading factor, somatomedin B, complement S-protein)" HUGO:VTN HGNC:12724 ENTREZ:7448 UNIPROT:P04004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vitronectin*"/> <bbox w="76.0" h="20.0" x="4259.0" y="6235.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3385_emtc_emtc_sa1584" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, alpha 2 LAMM HUGO:LAMA2 HGNC:6482 ENTREZ:3908 UNIPROT:P24043 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMA2"/> <bbox w="42.0" h="18.0" x="5917.25" y="5809.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3386_emtc_emtc_sa1585" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, alpha 3 "laminin, alpha 3 (nicein (150kD), kalinin (165kD), BM600 (150kD), epilegrin)", LAMNA HUGO:LAMA3 HGNC:6483 ENTREZ:3909 UNIPROT:Q16787 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMA3"/> <bbox w="42.0" h="18.0" x="5917.25" y="5837.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3387_emtc_emtc_sa1586" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMB1"/> <bbox w="45.0" h="16.0" x="5993.0" y="5765.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3388_emtc_emtc_sa1587" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, beta 2 (laminin S) LAMS HUGO:LAMB2 HGNC:6487 ENTREZ:3913 UNIPROT:P55268 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMB2"/> <bbox w="44.0" h="17.0" x="5993.0" y="5793.084"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3389_emtc_emtc_sa1588" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, beta 3 "laminin, beta 3 (nicein (125kD), kalinin (140kD), BM600 (125kD))", LAMNB1 HUGO:LAMB3 HGNC:6490 ENTREZ:3914 UNIPROT:Q13751 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMB3"/> <bbox w="44.0" h="16.0" x="5993.0" y="5820.666"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3390_emtc_emtc_sa1589" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, beta 4 HUGO:LAMB4 HGNC:6491 ENTREZ:22798 UNIPROT:A4D0S4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMB4"/> <bbox w="44.0" h="16.0" x="5993.0" y="5848.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3391_emtc_emtc_sa1590" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMC1"/> <bbox w="46.0" h="17.0" x="6122.0" y="5793.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3392_emtc_emtc_sa1591" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, gamma 2 EBR2, EBR2A, LAMB2T, "laminin, gamma 2 (nicein (100kD), kalinin (105kD), BM600 (100kD), Herlitz junctional epidermolysis bullosa))", LAMNB2 HUGO:LAMC2 HGNC:6493 ENTREZ:3918 UNIPROT:Q13753 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMC2"/> <bbox w="50.0" h="17.0" x="6122.0" y="5820.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3393_emtc_emtc_sa1592" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: laminin, gamma 3 HUGO:LAMC3 HGNC:6494 ENTREZ:10319 UNIPROT:Q9Y6N6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LAMC3"/> <bbox w="48.0" h="17.0" x="6122.0" y="5846.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3397_emtc_emtc_sa1595" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: a6b1*_a6b4* NAME:a6b1* ITGA6/ITGB1 integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:a6b4* ITGA6/ITGB4 integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:22118458 Integrins a3b1, a6b1, a6b4 and a7b1 engage with laminins References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="a6b1*_a6b4*"/> <bbox w="79.0" h="20.0" x="3891.5" y="6247.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3403_emtc_emtc_sa1599" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type IV, alpha 2 HUGO:COL4A2 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL4A2"/> <bbox w="50.0" h="18.0" x="5153.0" y="5976.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3404_emtc_emtc_sa1600" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type IV, alpha 3 (Goodpasture antigen) HUGO:COL4A3 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL4A3"/> <bbox w="50.0" h="18.0" x="5116.0" y="5945.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3405_emtc_emtc_sa1601" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type IV, alpha 4 HUGO:COL4A4 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL4A4"/> <bbox w="50.0" h="16.0" x="5058.0" y="5908.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3406_emtc_emtc_sa1602" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type IV, alpha 5 "Alport syndrome", ASLN, ATS HUGO:COL4A5 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL4A5"/> <bbox w="52.0" h="17.0" x="5044.0" y="5943.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3407_emtc_emtc_sa1603" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Collagen 4* collagen, type IV, alpha 1 HUGO:COL4A1 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 collagen, type IV, alpha 2 HUGO:COL4A2 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 collagen, type IV, alpha 3 (Goodpasture antigen) HUGO:COL4A3 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 collagen, type IV, alpha 4 HUGO:COL4A4 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 collagen, type IV, alpha 5 "Alport syndrome", ASLN, ATS HUGO:COL4A5 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 collagen, type IV, alpha 6 HUGO:COL4A6 HGNC:2208 ENTREZ:1288 UNIPROT:Q14031 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen4*"/> <bbox w="70.0" 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id="emtc_emtc_s3410_emtc_emtc_sa1611" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 35 HUGO:ARHGAP35 HGNC:4591 ENTREZ:2909 UNIPROT:Q9NRY4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9819392 The GAP activity of ARHGAP35 (p190RhoGAP) is specific for RhoA inhibition. PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by PTK6.. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP35"/> <bbox w="62.0" h="19.0" x="5854.0" y="1726.5"/> <glyph class="state variable" id="_afdf02bc-246b-4e3b-9143-0a17f0a9bc4a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5911.0" y="1731.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3417_emtc_emtc_sa1606" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho GTPase activating protein 35 HUGO:ARHGAP35 HGNC:4591 ENTREZ:2909 UNIPROT:Q9NRY4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9819392 The GAP activity of ARHGAP35 (p190RhoGAP) is specific for RhoA inhibition. PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by PTK6.. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARHGAP35"/> <bbox w="62.0" h="19.0" x="5853.0" y="1784.5"/> <glyph class="state variable" id="_b74a8cfa-d934-459a-abe8-4229c67c5604"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5907.5" y="1789.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3420_emtc_emtc_sa1613" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HRAS_GAPs* RAS p21 protein activator (GTPase activating protein) 1 RASA HUGO:RASA1 HGNC:9871 ENTREZ:5921 UNIPROT:P20936 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) PMID:8360177 RASA1 is a GAP for HRAS. PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HRAS_GAPs*"/> <bbox w="80.0" h="16.0" x="5943.0" y="884.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3425_emtc_emtc_sa1618" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: paxillin HUGO:PXN HGNC:9718 ENTREZ:5829 UNIPROT:P49023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PXN"/> <bbox w="35.0" h="29.0" x="5327.0" y="5532.75"/> <glyph class="state variable" id="_1eada69d-309c-437f-b8a6-d6c33ca71447"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5323.5464" y="5527.75"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3426_emtc_emtc_sa1619" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vinculin HUGO:VCL HGNC:12665 ENTREZ:7414 UNIPROT:P18206 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vinculin*"/> <bbox w="66.0" h="16.0" x="5217.0" y="5569.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3427_emtc_emtc_sa1620" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: talin 1 TLN HUGO:TLN1 HGNC:11845 ENTREZ:7094 UNIPROT:Q9Y490 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TLN1"/> <bbox w="39.0" h="16.0" x="4910.0" y="5435.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3428_emtc_emtc_sa1621" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: talin 2 HUGO:TLN2 HGNC:15447 ENTREZ:83660 UNIPROT:Q9Y4G6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TLN2"/> <bbox w="40.0" h="16.0" x="4994.0" y="5435.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3429_emtc_emtc_sa1622" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actinin, alpha 1 HUGO:ACTN1 HGNC:163 ENTREZ:87 UNIPROT:P12814 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ACTN1"/> <bbox w="50.0" h="18.0" x="5518.0" y="3033.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3431_emtc_emtc_sa1624" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actinin, alpha 2 HUGO:ACTN2 HGNC:164 ENTREZ:88 UNIPROT:P35609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ACTN2"/> <bbox w="49.0" h="18.0" x="5518.0" y="3060.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3432_emtc_emtc_sa1625" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: actinin, alpha 4 "focal segmental glomerulosclerosis 1", FSGS1 HUGO:ACTN4 HGNC:166 ENTREZ:81 UNIPROT:O43707 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ACTN4"/> <bbox w="47.0" h="17.0" x="5519.0" y="3084.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3434_emtc_emtc_sa1627" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actinin* actinin, alpha 1 HUGO:ACTN1 HGNC:163 ENTREZ:87 UNIPROT:P12814 actinin, alpha 2 HUGO:ACTN2 HGNC:164 ENTREZ:88 UNIPROT:P35609 actinin, alpha 4 "focal segmental glomerulosclerosis 1", FSGS1 HUGO:ACTN4 HGNC:166 ENTREZ:81 UNIPROT:O43707 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:15688067 Alpha-actinin is a cytoskeletal protein that binds to viculin (VCL). Via this binding, Alpha-actinin crosslinks actin (in actomyosin stress fibres) and tether them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 (PTK2) reduces the crossliking of stress fibres and prevents the maturation of focal contacts. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actinin*"/> <bbox w="62.0" h="18.0" x="5690.0" y="3062.484"/> <glyph class="state variable" id="_490d864b-cbe8-491a-9850-09aad44f92ae"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5746.716" y="3057.484"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3436_emtc_emtc_sa1632" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 6, cardiac muscle, alpha "myosin, heavy polypeptide 6, cardiac muscle, alpha (cardiomyopathy, hypertrophic 1)" HUGO:MYH6 HGNC:7576 ENTREZ:4624 UNIPROT:P13533 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH6"/> <bbox w="45.0" h="16.0" x="5011.66" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3437_emtc_emtc_sa1633" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 7, cardiac muscle, beta CMH1, MPD1, "myopathy, distal 1", "myosin, heavy polypeptide 7, cardiac muscle, beta" HUGO:MYH7 HGNC:7577 ENTREZ:4625 UNIPROT:P12883 Identifiers_end 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MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH7B"/> <bbox w="51.0" h="17.0" x="5109.912" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3439_emtc_emtc_sa1635" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 8, skeletal muscle, perinatal "myosin, heavy polypeptide 8, skeletal muscle, perinatal" HUGO:MYH8 HGNC:7578 ENTREZ:4626 UNIPROT:P13535 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH8"/> <bbox w="42.0" h="16.0" x="5167.154" y="3669.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3440_emtc_emtc_sa1637" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, heavy chain 10, non-muscle HUGO:MYH10 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYH10"/> <bbox w="45.0" 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compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 4, alkali; atrial, embryonic "myosin, light polypeptide 4, alkali; atrial, embryonic" HUGO:MYL4 HGNC:7585 ENTREZ:4635 UNIPROT:P12829 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL4"/> <bbox w="40.0" h="20.0" x="4968.0" y="3746.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3443_emtc_emtc_sa1648" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 6, alkali, smooth muscle and non-muscle "myosin, light polypeptide 6, alkali, smooth muscle and non-muscle" HUGO:MYL6 HGNC:7587 ENTREZ:4637 UNIPROT:P60660 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL6"/> <bbox w="33.5" h="20.0" x="5045.5" y="3747.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3445_emtc_emtc_sa1650" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 6B, alkali, smooth muscle and non-muscle "myosin, light polypeptide 6B, alkali, smooth muscle and non-muscle" HUGO:MYL6B HGNC:29823 ENTREZ:140465 UNIPROT:P14649 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL6B"/> <bbox w="41.0" h="23.0" x="5080.0" y="3746.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3446_emtc_emtc_sa1651" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 7, regulatory "myosin, light polypeptide 7, regulatory" HUGO:MYL7 HGNC:21719 ENTREZ:58498 UNIPROT:Q01449 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL7"/> <bbox w="33.0" h="20.0" x="5123.0" y="3748.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3449_emtc_emtc_sa1654" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain, cardiac muscle-like 1 "myosin, light polypeptide, cardiac muscle-like 1" HUGO:MYLL1 HGNC:7592 ENTREZ:4639 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYLL1"/> <bbox w="40.0" h="16.0" x="5420.0" y="3752.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3450_emtc_emtc_sa1655" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin light chain, phosphorylatable, fast skeletal muscle HUGO:MYLPF HGNC:29824 ENTREZ:29895 UNIPROT:Q96A32 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYLPF"/> <bbox w="45.0" h="17.0" x="5369.0" y="3750.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3451_emtc_emtc_sa1656" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 12B, regulatory HUGO:MYL12B HGNC:29827 ENTREZ:103910 UNIPROT:O14950 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL12B"/> <bbox w="60.0" h="17.0" x="5305.0" y="3749.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3452_emtc_emtc_sa1657" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 12A, regulatory, non-sarcomeric "myosin, light polypeptide, regulatory, non-sarcomeric (20kD)" HUGO:MYL12A HGNC:16701 ENTREZ:10627 UNIPROT:P19105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL12A"/> <bbox w="48.0" h="17.0" x="5252.0" y="3748.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3453_emtc_emtc_sa1658" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: myosin, light chain 10, regulatory HUGO:MYL10 HGNC:29825 ENTREZ:93408 UNIPROT:Q9BUA6 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYL10"/> <bbox w="42.0" h="19.0" x="5205.0" y="3746.791"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3455_emtc_emtc_sa1660" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Nischarin HUGO:NISCH HGNC:18006 ENTREZ:11188 UNIPROT:Q9Y2I1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NISCH"/> <bbox w="49.0" h="16.0" x="4820.0" y="3550.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3463_emtc_emtc_sa1667" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Src family kinases* v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) HUGO:SRC, HGNC:11283, ENTREZ:6714, UNIPROT:P12931, GENECARDS:GC20P035973 c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 FYN oncogene related to SRC, FGR, YES HUGO:FYN HGNC:4037 ENTREZ:2534 UNIPROT:P06241 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS MODULE:ADHERENS_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:9278444 Reduction of gap junctional communication in v-src transformed cells is accompanied by tyrosine phosphorylation of the gap junction protein, connexin 43 SH3 and SH2 domains of v-Src bind to proline-rich motifs and a phosphorylated tyrosine residue in the C-terminal tail of Cx43 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. 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HUGO:PTK2 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAK1*"/> <bbox w="64.0" h="21.0" x="5127.5" y="5753.5"/> <glyph class="state variable" id="_62da1f54-720b-4c69-b214-0287fb331dcc"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5117.5" y="5748.9883"/> </glyph> <glyph class="state variable" id="_91a9ecfb-277c-4a85-a098-b381b318d2f0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5181.2656" y="5748.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3476_emtc_emtc_sa1668" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine kinase 2 "PTK2 protein tyrosine kinase 2" HUGO:PTK2 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAK1*"/> <bbox w="63.0" h="23.0" x="5128.0" y="5619.5"/> <glyph class="state variable" id="_4cf719b5-65d3-4172-a462-abc05d83f322"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5120.5" y="5615.0347"/> </glyph> <glyph class="state variable" id="_05a52f8d-2399-4d20-b43a-e173f9c21ea7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5180.8086" y="5614.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3480_emtc_emtc_sa1682" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: paxillin HUGO:PXN HGNC:9718 ENTREZ:5829 UNIPROT:P49023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PXN"/> <bbox w="32.0" h="28.0" x="5449.361" y="5532.75"/> <glyph class="state variable" id="_9f665b17-7c8d-424f-8219-f30d71c21658"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5443.275" y="5527.75"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3481_emtc_emtc_sa1683" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-crk sarcoma virus CT10 oncogene homolog (avian) "v-crk avian sarcoma virus CT10 oncogene homolog" HUGO:CRK HGNC:2362 ENTREZ:1398 UNIPROT:P46108 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRK"/> <bbox w="32.0" h="16.0" x="5482.0" y="5497.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3485_emtc_emtc_sa1686" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: dedicator of cytokinesis 1 "dedicator of cyto-kinesis 1" HUGO:DOCK1 HGNC:2987 ENTREZ:1793 UNIPROT:Q14185 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:15308668 DOCK1 (so-called DOCK180) is a GEF of Rac1. DOCK1 together with paxillin-Crk constitutes the main pathway transducing collagen-mediated signals for the activation of Rac1. This signaling pathway is down-regulated when cell migration is counteracted by C3G/Rap1 activation. A balance between Rac1 and Rap1 GTPases in controlling the migratory versus the stationary state of the cell is suggested. PMID:12432077 DOCK1 is a GEF for Rac1 and possibly for CDC42 PMID:9808620 DOCK1 is involved in integrin signaling through Crk-p130Cas complexes. DOCK1 activates JNK in a Rac1, Cdc42 - dependent manner Overexpression of DOCK1 increases the amount of GTP-bound Rac1 Coexpression of Crk2 and p130Cas (BCAR1) enhances this DOCK1-dependent activation of Rac1. Direct binding of DOCK1 to Rac1, but not to RhoA or Cdc42. To sum up, DOCK1 is a novel activator of Rac1 and involved in integrin signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="DOCK1"/> <bbox w="48.0" h="19.0" x="6118.0" y="1854.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3488_emtc_emtc_sa1689" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: breast cancer anti-estrogen resistance 1 HUGO:BCAR1 HGNC:971 ENTREZ:9564 UNIPROT:P56945 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCAR1"/> <bbox w="50.0" h="19.0" x="5451.0" y="5686.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3502_emtc_emtc_sa803" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 14 (membrane-inserted) HUGO:MMP14, HGNC:7160, ENTREZ:4323, UNIPROT:P50281, GENECARDS:GC14P023305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:23737743 The characterization of ECM degradation by MT1-MMP indicate a dynamic nature of MMP14 (MT1-MMP) at invadopodia and its importance in the degradation of the ECM References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP14"/> <bbox w="40.0" h="20.0" x="1052.0" y="6433.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3531_emtc_emtc_sa1719" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zyxin HUGO:ZYX HGNC:13200 ENTREZ:7791 UNIPROT:Q15942 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:15688067 Zyxin is an alpha-actinin- and stress-fibre- binding protein that is present in mature contacts References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZYX"/> <bbox w="29.0" h="17.0" x="5785.0" y="5794.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3557_emtc_emtc_sa1740" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Actinin* actinin, alpha 1 HUGO:ACTN1 HGNC:163 ENTREZ:87 UNIPROT:P12814 actinin, alpha 2 HUGO:ACTN2 HGNC:164 ENTREZ:88 UNIPROT:P35609 actinin, alpha 4 "focal segmental glomerulosclerosis 1", FSGS1 HUGO:ACTN4 HGNC:166 ENTREZ:81 UNIPROT:O43707 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:15688067 Alpha-actinin is a cytoskeletal protein that binds to viculin (VCL). Via this binding, Alpha-actinin crosslinks actin (in actomyosin stress fibres) and tether them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 (PTK2) reduces the crossliking of stress fibres and prevents the maturation of focal contacts. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Actinin*"/> <bbox w="62.0" h="18.0" x="5688.0" y="3172.734"/> <glyph class="state variable" id="_dc32f720-4e95-4bbb-8c98-94e06f54c7a8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5742.216" y="3167.734"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3562_emtc_emtc_sa1744" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="20.0" x="1103.5" y="3327.5"/> <glyph class="state variable" id="_d393f31c-0936-4a54-813c-7c16725bf8d7"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="1096.0" y="3323.3398"/> </glyph> <glyph class="state variable" id="_017ff8c0-04f6-4dd3-9e28-d1a05aafed2e"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="1173.5" y="3323.7292"/> </glyph> <glyph class="state variable" id="_6ee0a20b-f72b-4797-b053-8bea4cb5d56d"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1175.3818" y="3342.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3563_emtc_emtc_sa1745" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: casein kinase 2, alpha 1 polypeptide HUGO:CSNK2A1 HGNC:2457 ENTREZ:1457 UNIPROT:P68400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CK2α*"/> <bbox w="61.0" h="19.0" x="821.0" y="3380.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3564_emtc_emtc_sa1746" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="20.0" x="1100.5" y="3476.5"/> <glyph class="state variable" id="_2100075d-b4a2-4d16-b169-956fef786bb5"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="1093.0" y="3472.3398"/> </glyph> <glyph class="state variable" id="_2bff04c5-12f0-4136-9468-3f84d7f89b31"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1173.0" y="3472.7292"/> </glyph> <glyph class="state variable" id="_af381428-d2b2-41b8-902f-16e8df4f1f49"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="1169.8818" y="3491.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3565_emtc_emtc_sa1747" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="N-Cadherin*"/> <bbox w="80.0" h="20.0" x="1395.5" y="3879.5"/> <glyph class="state variable" id="_2b4f895a-53bf-4d98-a7e3-3d53e83fce69"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1468.0" y="3894.0654"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3566_emtc_emtc_sa1748" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="78.0" h="28.0" x="758.5" y="3895.5"/> <glyph class="state variable" id="_cf906d0a-8dca-4185-87d7-f630bb87ef06"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="753.5" y="3892.1816"/> </glyph> <glyph class="state variable" id="_4bc56b10-43ef-4009-9cbf-3fc19c6e23ab"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="792.53107" y="3890.5"/> </glyph> <glyph class="state variable" id="_6a31a59f-18ba-46f3-98c2-7fadd8d36501"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="831.5" y="3890.5"/> </glyph> <glyph class="state variable" id="_987aafdc-fe51-43b0-98f4-0c2051237a45"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="808.1131" y="3890.5"/> </glyph> <glyph class="state variable" id="_3f715998-2e8a-46b4-8242-bf0e0173f13a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="776.04767" y="3890.5"/> </glyph> <glyph class="state variable" id="_3e48920a-c710-4afd-a68b-331a90e47f9b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="829.0" y="3916.8582"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3574_emtc_emtc_sa1753" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein phosphatase 1, catalytic subunit, alpha isozyme PPP1A, "protein phosphatase 1, catalytic subunit, alpha isoform" HUGO:PPP1CA HGNC:9281 ENTREZ:5499 UNIPROT:P62136 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PPP1CA"/> <bbox w="52.0" h="18.0" x="1092.0" y="3741.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3575_emtc_emtc_sa1754" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein phosphatase 1, catalytic subunit, beta isozyme "protein phosphatase 1, catalytic subunit, beta isoform" HUGO:PPP1CB HGNC:9282 ENTREZ:5500 UNIPROT:P62140 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PPP1CB"/> <bbox w="52.0" h="20.0" x="1157.0" y="3741.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3576_emtc_emtc_sa1755" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein phosphatase 1, catalytic subunit, gamma isozyme "protein phosphatase 1, catalytic subunit, gamma isoform" HUGO:PPP1CC HGNC:9283 ENTREZ:5501 UNIPROT:P36873 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PPP1CC"/> <bbox w="53.0" h="16.0" x="1220.0" y="3741.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3577_emtc_emtc_sa1756" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein phosphatase 1, catalytic subunit, alpha isozyme PPP1A, "protein phosphatase 1, catalytic subunit, alpha isoform" HUGO:PPP1CA HGNC:9281 ENTREZ:5499 UNIPROT:P62136 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PPP1C*"/> <bbox w="45.0" h="18.0" x="1162.0" y="3696.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3591_emtc_emtc_sa1766" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: frequently rearranged in advanced T-cell lymphomas HUGO:FRAT1 HGNC:3944 ENTREZ:10023 UNIPROT:Q92837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FRAT1"/> <bbox w="52.0" h="20.0" x="851.0" y="3614.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3596_emtc_emtc_sa1771" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: conserved helix-loop-helix ubiquitous kinase TCF16 HUGO:CHUK HGNC:1974 ENTREZ:1147 UNIPROT:O15111 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:12799363 CTNNB1 can be phosphorylated by CHUK (inhibitor of NF fappa-B) at S45, independent of CSNKA1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CHUK"/> <bbox w="40.0" h="16.0" x="1560.0" y="3704.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3601_emtc_emtc_sa1775" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Catenin*"/> <bbox w="77.0" h="25.0" x="1536.0" y="3457.5"/> <glyph class="unit of information" id="_2b102eb1-b060-44ba-a788-ceae7cda3a26"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1564.5" y="3452.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3610_emtc_emtc_sa948" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:11413131 E-cadherin dimerization is essential for adhesion to the integrin aEb7 PMID:17325197 Interaction between E-cadherin and aEb7 integrin plays major role in effective tumor cell lysis, during cytolytic granule polarization and subsequent exocytosis References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="86.0" h="26.0" x="467.0" y="3439.0"/> <glyph class="unit of information" id="_2f9322c3-69d4-47bd-8736-2a25d31c8af3"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="500.0" y="3434.0"/> </glyph> <glyph class="state variable" id="_66437902-5ea1-47a0-9da0-d3c5a0187250"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="459.5" y="3435.0918"/> </glyph> <glyph class="state variable" id="_5f2c376e-d378-4e64-a257-d2001ece881f"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="545.5" y="3435.5981"/> </glyph> <glyph class="state variable" id="_dd41fc49-1b7b-46df-ae9c-4a7cef129db9"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="544.83545" y="3460.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3611_emtc_emtc_sa1783" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: _beta_-Catenin*_p120*_JUP_PKP4* catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*_p120*1_Plakoglobin*_Plakophilin4*"/> <bbox w="289.0" h="22.0" x="748.0" y="4307.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3614_emtc_emtc_sa1785" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 GENECARDS:GC01P201252 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 GENECARDS:GC02P159313 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin*"/> <bbox w="79.0" h="16.0" x="1781.0" y="4637.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3615_emtc_emtc_sa1786" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Armadillo proteins* Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 GENECARDS:GC01P201252 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 GENECARDS:GC02P159313 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Armadillo proteins*"/> <bbox w="122.0" h="19.0" x="1605.0" y="4635.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3616_emtc_emtc_sa1787" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocolin1*"/> <bbox w="88.0" h="21.0" x="1935.0" y="4157.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3617_emtc_emtc_sa1788" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmocollin 3 HUGO:DSC3, HGNC:3037, ENTREZ:1825, UNIPROT:Q14574, GENECARDS:GC18M028593 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocolin3*"/> <bbox w="88.0" h="20.0" x="1935.0" y="4204.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3619_emtc_emtc_sa1790" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein1*"/> <bbox w="87.0" h="19.0" x="1933.0" y="4286.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3620_emtc_emtc_sa1791" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: desmoglein 3 HUGO:DSG3 HGNC:3050 ENTREZ:1830 UNIPROT:P32926 GENECARDS:GC18P029050 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein3*"/> <bbox w="91.0" h="18.0" x="1929.0" y="4330.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3621_emtc_emtc_sa1792" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Desmosomal cadherins* Desmoglein* desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 desmoglein 3 HUGO:DSG3 HGNC:3050 ENTREZ:1830 UNIPROT:P32926 GENECARDS:GC18P029050 Desmocollin* democollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 desmocollin 3 HUGO:DSC3, HGNC:3037, ENTREZ:1825, UNIPROT:Q14574, GENECARDS:GC18M028593 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmosomal cadherins*"/> <bbox w="145.0" h="17.0" x="1598.0" y="4253.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3622_emtc_emtc_sa1793" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Desmocollin* democollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 desmocollin 3 HUGO:DSC3, HGNC:3037, ENTREZ:1825, UNIPROT:Q14574, GENECARDS:GC18M028593 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocolin*"/> <bbox w="74.0" h="20.0" x="1779.0" y="4188.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3623_emtc_emtc_sa1794" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Desmoglein* desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 desmoglein 3 HUGO:DSG3 HGNC:3050 ENTREZ:1830 UNIPROT:P32926 GENECARDS:GC18P029050 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein*"/> <bbox w="77.0" h="17.0" x="1780.0" y="4307.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3624_emtc_emtc_sa1795" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Desmocollin 1 binding partners* desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 GENECARDS:GC01P201252 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569, GENECARDS:GC02P159313 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmocolin1 binding partners*"/> <bbox w="193.0" h="21.0" x="1391.0" y="4210.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3628_emtc_emtc_sa1798" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Desmoglein 1 binding partners* desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoglein1 binding partners*"/> <bbox w="199.0" h="18.0" x="1395.0" y="4432.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3632_emtc_emtc_sa1801" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Plakoglobin binding partners* Desmosomal cadherins* Desmocollin* democollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 desmocollin 3 HUGO:DSC3, HGNC:3037, ENTREZ:1825, UNIPROT:Q14574, GENECARDS:GC18M028593 Desmoglein* desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 desmoglein 3 HUGO:DSG3 HGNC:3050 ENTREZ:1830 UNIPROT:P32926 GENECARDS:GC18P029050 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) NGL, "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 Rho GDP dissociation inhibitor (GDI) alpha HUGO:ARHGDIA, HGNC:678, ENTREZ:396, GENECARDS:GC17M079825, UNIPROT:P52565 catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 adenomatous polyposis coli HUGO:APC, HGNC:583, ENTREZ:324, UNIPROT:P25054 , GENECARDS:GC05P112101 cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakoglobin binding partners*"/> <bbox w="180.0" h="22.0" x="1392.0" y="4496.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3633_emtc_emtc_sa1802" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) NGL, "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HER2*"/> <bbox w="80.0" h="50.0" x="1239.5" y="160.5"/> <glyph class="unit of information" id="_2c01ca14-d4fc-4ee9-af5b-190de1fad549"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1257.0" y="155.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3637_emtc_emtc_sa1805" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Plakophilin 2 binding partners* desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 desmocollin 2 HUGO:DSC2, HGNC:3036, ENTREZ:1824, UNIPROT:Q02487, GENECARDS:GC18M028670 desmoglein 1 HUGO:DSG1 HGNC:3048 ENTREZ:1828 UNIPROT:Q02413 GENECARDS:GC18P028921 desmoglein 2 HUGO:DSG2 HGNC:3049 ENTREZ:1829 UNIPROT:Q14126 GENECARDS:GC18P029101 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, UNIPROT:P08670, GENECARDS:GC10P017310 keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343, UNIPROT:P05783 keratin 14 HUGO:KRT14, HGNC:6416, ENTREZ:3861, GENECARDS:GC17M039738, UNIPROT:P02533 keratin 8 HUGO:KRT8 HGNC:6446 ENTREZ:3856 UNIPROT:P05787 GENECARDS:GC12M053290 keratin 5 EBS2, "epidermolysis bullosa simplex 2 Dowling-Meara/Kobner/Weber-Cockayne types", "keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)" HUGO:KRT5 HGNC:6442 ENTREZ:3852 UNIPROT:P13647 GENECARDS:GC12M052908 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin2 binding partners*"/> <bbox w="185.0" h="19.0" x="1388.0" y="4642.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3638_emtc_emtc_sa1806" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 5 EBS2, "epidermolysis bullosa simplex 2 Dowling-Meara/Kobner/Weber-Cockayne types", "keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types)" HUGO:KRT5 HGNC:6442 ENTREZ:3852 UNIPROT:P13647 GENECARDS:GC12M052908 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT5"/> <bbox w="58.0" h="16.0" x="4833.5" y="3171.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3639_emtc_emtc_sa1807" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 8 HUGO:KRT8 HGNC:6446 ENTREZ:3856 UNIPROT:P05787 GENECARDS:GC12M053290 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT8"/> <bbox w="54.0" h="16.0" x="4833.5" y="3145.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3643_emtc_emtc_sa1810" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Desmoplakin binding partners* desmocollin 1 HUGO:DSC1, HGNC:3035, ENTREZ:1823, UNIPROT:Q08554, GENECARDS:GC18M028732 junction plakoglobin "catenin (cadherin-associated protein), gamma 80kDa", CTNNG HUGO:JUP HGNC:6207 ENTREZ:3728 UNIPROT:P14923 GENECARDS:GC17M039776 Plakophilin* plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) HUGO:PKP1 HGNC:9023 ENTREZ:5317 UNIPROT:Q13835 GENECARDS:GC01P201252 plakophilin 2 HUGO:PKP2 HGNC:9024 ENTREZ:5318 UNIPROT:Q99959 GENECARDS:GC12M032943 plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, UNIPROT:Q9Y446, GENECARDS:GC11P000394 plakophilin 4 HUGO:PKP4 HGNC:9026 ENTREZ:8502 UNIPROT:Q99569 GENECARDS:GC02P159313 desmoplakin HUGO:DSP, HGNC:3052, ENTREZ:1832, UNIPROT:P15924, GENECARDS:GC06P007541 vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, UNIPROT:P08670, GENECARDS:GC10P017310 keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343, UNIPROT:P05783 keratin 8 HUGO:KRT8 HGNC:6446 ENTREZ:3856 UNIPROT:P05787 GENECARDS:GC12M053290 keratin 1 EHK1, "epidermolytic hyperkeratosis 1" HUGO:KRT1 HGNC:6412 ENTREZ:3848 UNIPROT:P04264 GENECARDS:GC12M053069 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: PMID:19955337 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Desmoplakin binding partners*"/> <bbox w="182.0" h="21.0" x="1393.0" y="4863.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3647_emtc_emtc_sa1812" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 1 EHK1, "epidermolytic hyperkeratosis 1" HUGO:KRT1 HGNC:6412 ENTREZ:3848 UNIPROT:P04264 GENECARDS:GC12M053069 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT1"/> <bbox w="41.0" h="18.0" x="4833.5" y="3199.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3649_emtc_emtc_sa1813" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lymphotoxin alpha (TNF superfamily, member 1) HUGO:6709 HGNC:6709 ENTREZ:4049 UNIPROT:P01374 GENECARDS:GC06P031541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LTA"/> <bbox w="46.0" h="18.0" x="5232.0" y="2383.7"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3656_emtc_emtc_sa885" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: kinase insert domain receptor (a type III receptor tyrosine kinase) HUGO:KDR, HGNC:6307, ENTREZ:3791, GENECARDS:GC04M055944, UNIPROT:P35968 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:11166270 VEGFR2 is highly specific towards VEGFA. PMID:11741095 PMID:13678960 However VEGFR2 also binds to processed forms of VEGF-C, D, E. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. PMID:15501236 PMID:14739162 Although Endothelial cells express both receptors VEGFR1 and VEGFR2, only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR2*"/> <bbox w="55.0" h="25.75" x="6168.0" y="4987.068"/> <glyph class="state variable" id="_52081bf8-a729-413c-b1dc-ebfa1cf0057b"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="6160.5" y="4982.4185"/> </glyph> <glyph class="unit of information" id="_3b6276e5-a2e0-47f5-a14d-08fe4177be41"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6173.0" y="4982.068"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3660_emtc_emtc_sa795" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF1"/> <bbox w="40.0" h="20.0" x="2930.0" y="6477.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3682_emtc_emtc_sa1822" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, UNIPROT:P19022, GENECARDS:GC18M025465 cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, UNIPROT:P22223, GENECARDS:GC16P068679 cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, UNIPROT:P55283, GENECARDS:GC20P059827 cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Cadherin*"/> <bbox w="75.0" h="20.0" x="793.0" y="3478.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3698_emtc_emtc_sa50" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA, HGNC:12680, ENTREZ:7422, GENECARDS:GC06P043737, UNIPROT:P15692 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:15111329 VEGF is a predominant angiogenic factor that mediates ocular neovascularization. VEGF is increased by hypoxia, which is one of the primary stimuli for ocular neovascularization. VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is PKC/ERK pathway-dependent. Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases PMID:11166270 VEGF stands for the vascular Endothelial Growth Factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults PMID:13678960 VEGFs belong to a family of homodimeric glycoproteins that containts five members (VEGF-A, B, C, D, and Placenta growth factor PLGF). VEGFs bind to 3 different VEGF-receptor tyrosine kinases (VEGFR-1, 2, 3). Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular functions. PMID:10022831 PMID:15501236 VEGFA is a homodimer that exists in five different isoforms comprising 121, 145, 165, 189, and 206 amino acids per chain. The isoforms differ in their ability to bind heparan sulfate proteoglycans in the extracellular matrix (ECM). In adult Endothelial cells, VEGFA exhibits high affinity binding to tyrosine kinase receptors, VEGFR1 and VEGFR2. Although ECs express both receptors, recent findings suggest that only VEGFR2 is able to mediate angiogenic effects of VEGFA References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFA"/> <bbox w="40.0" h="20.0" x="4854.0" y="5030.125"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3703_emtc_emtc_sa698" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) HUGO:ETS1, HGNC:3488, ENTREZ:2113, UNIPROT:P14921, GENECARDS:GC11M128328 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16391805 Ets-1 is a transcription factor Ets-1 involves in inducing MMP2 expression by EMT in human squamous carcinoma cells PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:15111329 The Ets gene family conserves an 85-amino acid DNA-binding ETS domain that binds the consensus sequence 5'-GGA(A/T)-3' in the promoter region of the target genes. Ets has various biological functions, including cellular growth, differentiation, and organ development. Ets-1, first identified among the Ets gene family, has been shown to also be associated with pathological angiogenesis. A number of angiogenesis-related molecules, including MMP-1, MMP-3, MMP-9, integrin 3, vascular endothelial cadherin (VE-cadherin), and neuropilin-1 (NRP1) are reported to be targets of Ets-1 in endothelial cells PMID:21081489 Endogenous Ets-1 is a key mediator of cell migration and Matrigel tube formation in HMECs (human microvascular endothelial cells) PMID:21041997 In cells induced to undergo EMT, TGFB also activates the expresion of ZEB1 and ZEB2 through upregulation of ETS1 expression, which then may cooperate with the bHLH transcription factor E47 (TCF3) PMID:17615296 TGFB induces ETS1 transcriptional expression. TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457) ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1. Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ETS1"/> <bbox w="40.0" h="20.0" x="2076.0" y="4760.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3759_emtc_emtc_sa1873" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="52.0" h="45.0" x="6167.922" y="3542.238"/> <glyph class="unit of information" id="_8b033d7c-138d-4186-8700-2312a65e562c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6183.922" y="3537.238"/> </glyph> <glyph class="state variable" id="_c1fb98a5-37df-4c86-ac5a-cb8358717061"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="6209.922" y="3537.4797"/> </glyph> <glyph class="state variable" id="_20295fd5-4728-48bf-b37a-f8167f11562a"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6155.422" y="3538.2847"/> </glyph> <glyph class="unit of information" id="_6a34ed42-9105-4e6a-849d-add7c50e79cf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6171.422" y="3537.238"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3768_emtc_emtc_sa1416" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Rho-associated, coiled-coil containing protein kinase 2 HUGO:ROCK2, HGNC:10252, ENTREZ:9475, UNIPROT:O75116, GENECARDS:GC02M011272 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ROCK2"/> <bbox w="52.0" h="19.0" x="4818.0" y="2471.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3790_emtc_emtc_sa1876" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="54.0" h="40.0" x="6167.344" y="3782.791"/> <glyph class="state variable" id="_581bffee-e57e-4903-815d-022407a53818"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6216.344" y="3778.0059"/> </glyph> <glyph class="state variable" id="_9359a579-4838-48a2-a4da-3f3b39952949"> <state value="" variable="Ser"/> <bbox w="25.0" h="10.0" x="6154.844" y="3778.7212"/> </glyph> <glyph class="unit of information" id="_efe332d0-3b62-454e-a7ed-4e6e69555364"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6171.844" y="3777.791"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3801_emtc_emtc_sa1885" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SIN3 transcription regulator homolog A (yeast) SIN3A HUGO:SIN3A HGNC:19353 ENTREZ:25942 UNIPROT:Q96ST3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SIN3A"/> <bbox w="45.0" h="16.0" x="2713.0" y="3560.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3808_emtc_emtc_sa1896" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 11 HUGO:MAPK11 HGNC:6873, ENTREZ:5600 , UNIPROT:Q15759 mitogen-activated protein kinase 12 HUGO:MAPK12 HGNC:6874, ENTREZ:6300 , UNIPROT:P53778 mitogen-activated protein kinase 13 HUGO:MAPK13 HGNC:6875, ENTREZ:5603 , UNIPROT:O15264 mitogen-activated protein kinase 14 HUGO:MAPK14 HGNC:6876, ENTREZ:1432, UNIPROT:Q16539 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p38*"/> <bbox w="34.0" h="20.0" x="2727.0" y="3804.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3809_emtc_emtc_sa1897" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 11 HUGO:MAPK11 HGNC:6873, ENTREZ:5600 , UNIPROT:Q15759 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAPK11"/> <bbox w="58.0" h="21.0" x="2562.5" y="3798.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3810_emtc_emtc_sa1898" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 12 HUGO:MAPK12 HGNC:6874, ENTREZ:6300 , UNIPROT:P53778 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAPK12"/> <bbox w="59.0" h="19.0" x="2562.5" y="3826.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3811_emtc_emtc_sa1899" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 13 HUGO:MAPK13 HGNC:6875, ENTREZ:5603 , UNIPROT:O15264 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAPK13"/> <bbox w="59.0" h="20.0" x="2562.5" y="3852.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3812_emtc_emtc_sa1900" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 14 HUGO:MAPK14 HGNC:6876, ENTREZ:1432, UNIPROT:Q16539 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23869868 Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence PMID:24954210 PMID:17254968 MAPK3 and MAPK6 induces p38 which induces p16 and p53 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAPK14"/> <bbox w="60.0" h="16.0" x="2562.5" y="3880.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3813_emtc_emtc_sa1901" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 8 JNK1 HUGO:MAPK8 HGNC:6881, ENTREZ:5599, UNIPROT:P45983 mitogen-activated protein kinase 9 JNK2 HUGO:MAPK9 HGNC:6886, ENTREZ:5601, UNIPROT:P45984 mitogen-activated protein kinase 10 JNK3 HUGO:MAPK10 HGNC:6872, ENTREZ:5602, UNIPROT:P53779 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JNK*"/> <bbox w="39.0" h="17.0" x="2769.0" y="3829.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3814_emtc_emtc_sa1902" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 8 JNK1 HUGO:MAPK8 HGNC:6881, ENTREZ:5599, UNIPROT:P45983 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JNK1*"/> <bbox w="43.0" h="16.0" x="2967.5" y="3822.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3815_emtc_emtc_sa1903" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 9 JNK2 HUGO:MAPK9 HGNC:6886, ENTREZ:5601, UNIPROT:P45984 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JNK2*"/> <bbox w="44.0" h="17.0" x="2966.5" y="3845.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3816_emtc_emtc_sa1904" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 10 JNK3 HUGO:MAPK10 HGNC:6872, ENTREZ:5602, UNIPROT:P53779 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JNK3*"/> <bbox w="42.0" h="16.0" x="2968.5" y="3871.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3817_emtc_emtc_sa1895" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: itwist homolog 1 (Drosophila) HUGO:TWIST1 HGNC:12428, ENTREZ:7291, UNIPROT:Q15672, GENECARDS:GC07M019121 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15640618 Twist induces an epithelial-mesenchymal transition to facilitate tumor metastasis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TWIST1"/> <bbox w="106.0" h="21.0" x="2562.5" y="3765.5"/> <glyph class="state variable" id="_9c1049c2-ca47-4993-bed6-383f731c8999"> <state value="P" variable="S68"/> <bbox w="30.0" h="10.0" x="2547.5" y="3771.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3818_emtc_emtc_sa1905" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1 polycomb ring finger oncogene "B lymphoma Mo-MLV insertion region 1 homolog (mouse)", PCGF4, "polycomb group ring finger 4" HUGO:BMI1 HGNC:1066 ENTREZ:648 UNIPROT:P35226 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1"/> <bbox w="42.0" h="16.0" x="2099.5" y="4078.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3821_emtc_emtc_sa1911" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOX2"/> <bbox w="36.0" h="22.0" x="4375.0" y="4624.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3837_emtc_emtc_sa1924" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: CDK4_6* cyclin-dependent kinase 4 HUGO:CDK4, HGNC:1773, ENTREZ:1019, GENECARDS:GC12M058142, UNIPROT:P11802 cyclin-dependent kinase 6 HUGO:CDK6, HGNC:1777, ENTREZ:1021, GENECARDS:GC07M092234, UNIPROT:Q00534 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK4_6*"/> <bbox w="60.0" h="19.0" x="3201.0" y="1606.5"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3846_emtc_emtc_sa235" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <clone/> <bbox w="47.5" h="28.0" x="588.25" y="6464.0"/> <glyph class="unit of information" id="_17742547-0984-447f-8c99-322d578b2f76"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="602.0" y="6459.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s3846_emtc_emtc_sa239" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 1 HUGO:TGFB1, HGNC:11766, ENTREZ:7040, UNIPROT:P01137, GENECARDS:GC19M041837 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. PMID:15548370 TGFB1 is a prominent EMT-inducing factor. The induction of EMT by TGFB1 is associated with the activation of JNK, p38, Erk, PI3k–Akt, and RhoA. Activation of the Erk pathway is required for TGFB1–induced EMT In Vitro PMID:11133108 C. parvum infection stimulates both IL8, TGFB secretion by both the basal and apical side of caco-2 cells PMID:19920116 LAP is known to bind to ITG heterodimers and activate TGFB. LAP and TGFB were also prominently expressed at the basal surface of endometrial epithelia PMID:19010789 In early stages of carcinogenesis, TGBF has an anti-oncogenic effects: TGFB inhibits the growth of epithelial cells. In later stage, sensitivity to these effects of TGFB is frequently lost and TGFB would favor the development of tumors progression and metastasis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB1"/> <clone/> <bbox w="47.0" h="25.0" x="774.5" y="6934.5"/> <glyph class="unit of information" id="_a114e34a-8b09-486b-aad7-9401384fe229"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="788.0" y="6929.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3847_emtc_emtc_sa1930" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="50.0" h="48.0" x="4057.0" y="2207.5"/> <glyph class="state variable" id="_03942afb-846b-4bee-bfdb-7d03e8179a73"> <state value="" variable="S395"/> <bbox w="30.0" h="10.0" x="4042.0" y="2205.3826"/> </glyph> <glyph class="state variable" id="_c8ce4d09-f583-400e-be37-e2922cb5492f"> <state value="P" variable="S186"/> <bbox w="35.0" h="10.0" x="4039.5" y="2247.4822"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3849_emtc_emtc_sa1933" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tumor protein p53 HUGO:TP53, HGNC:11998, ENTREZ:7157, UNIPROT:P04637, GENECARDS:GC17M007565 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21518799 p53 activates MIR200C PMID:21483453 p53 activates microRNAs PMID:21336307 p53 activates MIR34 PMID:17823410 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p53*"/> <bbox w="39.0" h="19.0" x="3835.5" y="2010.5"/> <glyph class="state variable" id="_9655cdf1-d0be-4cc4-9939-52fe7bad4c40"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3867.0" y="2011.065"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3856_emtc_emtc_sa1931" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="50.0" h="48.0" x="3765.0" y="2207.5"/> <glyph class="state variable" id="_02c0ae12-d514-42ad-9b95-648a0e16ba89"> <state value="" variable="S395"/> <bbox w="30.0" h="10.0" x="3750.0" y="2205.3826"/> </glyph> <glyph class="state variable" id="_f17cfe9f-d731-476e-99a6-99f359ff0fea"> <state value="" variable="S186"/> <bbox w="30.0" h="10.0" x="3750.0" y="2247.4822"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3863_emtc_emtc_sa1945" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: COP9 signalosome subunit 2 HUGO:COPS2 HGNC:30747 ENTREZ:9318 UNIPROT:P61201 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19411070 TNFa dramatically enhanced the protein stabilization of Snail1 through NF-kB mediated CSN2 induction. CSN2 induces Snail stabilization by inhibiting its ubiquitination References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CSN2*"/> <bbox w="45.0" h="20.0" x="2974.0" y="760.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3864_emtc_emtc_sa1946" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Kruppel-like factor 8 HUGO:KLF8, HGNC:6351, ENTREZ:11279, UNIPROT:O95600 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17671186 KLF8 directly bound to the promotor of Snail and repressed Snail expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KLF8"/> <bbox w="34.0" h="17.0" x="3185.0" y="3622.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3865_emtc_emtc_sa1947" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-rel reticuloendotheliosis viral oncogene homolog A (avian) HUGO:RELA HGNC:9955 ENTREZ:5970 UNIPROT:Q04206 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19411070 TNFa dramatically enhanced the protein stabilization of Snail1 through NF-kB mediated CSN2 induction. CSN2 induces Snail stabilization by inhibiting its ubiquitination PMID:17563753 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NF-κB_p65*"/> <bbox w="80.0" h="40.0" x="2957.0" y="388.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3868_emtc_emtc_sa1950" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box C2 (MFH-1, mesenchyme forkhead 1) HUGO:FOXC2, HGNC:3801, ENTREZ:2303 , UNIPROT:Q99958 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17537911 Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXC2"/> <bbox w="47.0" h="20.0" x="3793.0" y="4342.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3869_emtc_emtc_sa1951" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: goosecoid homeobox HUGO:GSC, HGNC:4612, ENTREZ:145258 , UNIPROT:P56915 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17537911 Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Goosecoid*"/> <bbox w="76.0" h="22.0" x="3592.0" y="4378.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3872_emtc_emtc_sa1954" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 1, dominant negative helix-loop-helix protein HUGO:ID1, HGNC:5360, ENTREZ:3397 , UNIPROT:P41134 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17490644 Snai1 and TCF3 (E47) upregulate both mRNA and protein level of ID1 This upregulation depends on SP1 or AP1 co-transcription factors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID1"/> <bbox w="26.0" h="19.0" x="4285.0" y="4336.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3875_emtc_emtc_sa1957" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="42.0" h="18.0" x="2083.5" y="5168.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3876_emtc_emtc_sa1958" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:21667018 PMID:16001073 Rac1B is an alternatively spliced form of Rac1 gene. Rac1B does not lead to lamellipodia formation, or the activation of PAK1, AKT1, or c-Jun-NH2- kinase activities. However, Rac1B retains the ability to stimulate the NF-kappa-B pathway. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1B*"/> <bbox w="42.0" h="21.0" x="2086.0" y="5269.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3877_emtc_emtc_sa2024" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 1 HUGO:MAPK1, HGNC:6871, ENTREZ:5594, GENECARDS:GC22M022108, UNIPROT:P28482 mitogen-activated protein kinase 3 HUGO:MAPK3, HGNC:6877, ENTREZ:5595, GENECARDS:GC16M030125, UNIPROT:P27361 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK2 (phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK2 phosphorylates the critical Tyr and Thr on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK1_2*"/> <bbox w="66.0" h="17.0" x="5451.5" y="1373.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3878_emtc_emtc_sa1959" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Sp1 transcription factor HUGO:SP1, HGNC:11205, ENTREZ:6667, GENECARDS:GC12P053801, UNIPROT:P08047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SP1"/> <bbox w="40.0" h="20.0" x="3520.5" y="3646.5"/> <glyph class="state variable" id="_ec82e102-fc2f-404d-9790-7b1a0a68e715"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3513.0" y="3651.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3879_emtc_emtc_sa1962" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) HUGO:RAC1 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:21667018 PMID:16001073 Rac1B is an alternatively spliced form of Rac1 gene. Rac1B does not lead to lamellipodia formation, or the activation of PAK1, AKT1, or c-Jun-NH2- kinase activities. However, Rac1B retains the ability to stimulate the NF-kappa-B pathway. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1B*"/> <bbox w="44.0" h="18.0" x="2275.5" y="5271.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3887_emtc_emtc_sa1970" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: endothelin 1 HUGO:EDN1, HGNC:3176, ENTREZ:1906, GENECARDS:GC06P012290, UNIPROT:P05305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9588211 Endothelin1 is target gene of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Endothelin1*"/> <bbox w="78.0" h="20.0" x="4865.0" y="4805.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3890_emtc_emtc_sa1973" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 2, dominant negative helix-loop-helix protein HUGO:ID2, HGNC:5361, ENTREZ:3398, UNIPROT:Q02363, GENECARDS:GC02P008818 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11708773 PMID:15252039 ID2 is target of HIF1 upon hypoxic conditions PMID:15121845 PMID:18832382 Id2 or Id3 can form complexes with TCF3 (E47), and inhibit the process of EMT. Id2 and Id3 define the epithelial context that allows proper growth and differentiation responses to specific TGFB superfamily factors PMID:15689496 Id2 (and Id3) must be down-regulated by TGFB pathway in order for EMT to occur. ID2 is repressed by TGFB1 but induced by BMP7 Under conditions of Id2 knockdown, BMP-7 is capable of inducing significant alpha-smooth Actin level References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID2"/> <bbox w="26.0" h="21.0" x="4285.0" y="4385.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3891_emtc_emtc_sa1974" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 1, dominant negative helix-loop-helix protein HUGO:ID1, HGNC:5360, ENTREZ:3397 , UNIPROT:P41134 inhibitor of DNA binding 2, dominant negative helix-loop-helix protein HUGO:ID2, HGNC:5361, ENTREZ:3398, UNIPROT:Q02363, GENECARDS:GC02P008818 inhibitor of DNA binding 3, dominant negative helix-loop-helix protein HUGO:ID3, HGNC:5362, ENTREZ:3399, UNIPROT:Q02535 , GENECARDS:GC01M023884 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15252039 ID is so-called Inhibitor of differentiation/DNA binding proteins ID proteins is frequently deregulated in advanced human malignancies. ID proteins can participate in blocking differentiation, increasing proliferation, tissue invasiveness, and angiogenesis. PMID:17615296 Through constitutive association with bHLH E12/E47 proteins, Id proteins maintain epithelial phenotypes by repressing the function of E12/E47, which acts as a repressor of E-cadherin. Down-regulation of ID1 by Smad2/3/ATF3 complex and of ID2 as well as ID3 by TGFB thus relieve this inhibition, permitting conversion of epithelial cells to cells with mesenchymal phenotypes TGFB induces ETS1 transcriptional expression. TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457) ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1. Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID*"/> <bbox w="25.0" h="22.0" x="4411.0" y="4360.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3892_emtc_emtc_sa1975" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162, UNIPROT:Q16665 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: The gene HIF1A gives rise to 3 different isoforms: HIF1_alpha_, HIF2_alpha_ and HIF3_alpha References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF2α*"/> <bbox w="48.0" h="18.0" x="3840.0" y="1765.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3893_emtc_emtc_sa1976" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162, UNIPROT:Q16665 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: The gene HIF1A gives rise to 3 different isoforms: HIF1_alpha_, HIF2_alpha_ and HIF3_alpha References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF3α*"/> <bbox w="49.0" h="17.0" x="3770.0" y="1765.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3894_emtc_emtc_sa1977" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162, UNIPROT:Q16665 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: The gene HIF1A gives rise to 3 different isoforms: HIF1_alpha_, HIF2_alpha_ and HIF3_alpha PMID:17533374 HIF-1 and NF-kappaB upregulates CXCR1 and CXCR2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF1A"/> <bbox w="49.0" h="16.0" x="3917.0" y="1764.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3895_emtc_emtc_sa1978" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: high mobility group AT-hook 2 HUGO:HMGA2 HGNC:5009 ENTREZ:8091 UNIPROT:P52926 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HMGA2"/> <bbox w="48.0" h="19.0" x="3508.5" y="3734.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3902_emtc_emtc_sa1987" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 3, dominant negative helix-loop-helix protein HUGO:ID3, HGNC:5362, ENTREZ:3399, UNIPROT:Q02535 , GENECARDS:GC01M023884 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15121845 PMID:18832382 Id2 or Id3 can form complexes with TCF3 (E47), and inhibit the process of EMT. Id2 and Id3 define the epithelial context that allows proper growth and differentiation responses to specific TGFB superfamily factors PMID:15689496 Id2 (and Id3) must be down-regulated by TGFB pathway in order for EMT to occur. ID2 is repressed by TGFB1 but induced by BMP7 Under conditions of Id2 knockdown, BMP-7 is capable of inducing significant alpha-smooth Actin level References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID3"/> <bbox w="24.0" h="21.0" x="4287.0" y="4428.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3908_emtc_emtc_sa1992" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: activating transcription factor 3 HUGO:ATF3, HGNC:785, ENTREZ:467, GENECARDS:GC01P212738, UNIPROT:P18847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ATF3"/> <bbox w="32.0" h="19.0" x="4279.0" y="4290.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3913_emtc_emtc_sa1995" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_3*"/> <bbox w="71.0" h="20.0" x="5627.0" y="4385.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3930_emtc_emtc_sa2011" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: jun B proto-oncogene HUGO:JUNB, HGNC:6205, ENTREZ:3726, GENECARDS:GC19P012902 UNIPROT:P17275 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JUNB"/> <bbox w="41.0" h="17.0" x="3799.0" y="4209.25"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3931_emtc_emtc_sa2012" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SHC (Src homology 2 domain containing) transforming protein 1 HUGO:SHC1, HGNC:10840, ENTREZ:6464, UNIPROT:P29353 , GENECARDS:GC01M154934 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SHC1_p66_p52*"/> <bbox w="104.0" h="26.0" x="5921.0" y="3701.5"/> <glyph class="state variable" id="_6cc7fe91-2c4b-4dc5-853e-95c1a29d303d"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="5914.14" y="3696.5"/> </glyph> <glyph class="state variable" id="_3a772162-c002-45b8-b1dc-ed4a77a22688"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="6017.0234" y="3696.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3933_emtc_emtc_sa2013" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SHC (Src homology 2 domain containing) transforming protein 1 HUGO:SHC1, HGNC:10840, ENTREZ:6464, UNIPROT:P29353 , GENECARDS:GC01M154934 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SHC1_p66_p52*"/> <bbox w="96.0" h="28.0" x="5925.75" y="3527.5"/> <glyph class="state variable" id="_ff6553b0-edd0-4c09-b5ae-40f63709ac42"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="5916.341" y="3522.5"/> </glyph> <glyph class="state variable" id="_27f675d1-ae46-4360-a95c-b6030f6cefb7"> <state value="P" variable="S"/> <bbox w="20.0" h="10.0" x="6011.31" y="3522.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3934_emtc_emtc_sa2014" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: son of sevenless homolog 1 (Drosophila) HUGO:SOS1, HGNC:11187, ENTREZ:6654, UNIPROT:Q07889 , GENECARDS:GC02M039208 son of sevenless homolog 2 (Drosophila) HUGO:SOS2, HGNC:11188, ENTREZ:6655, UNIPROT:Q07890, GENECARDS:GC14M050583 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos SOS is an GTP-exchange factor for Ras References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOS*"/> <bbox w="35.0" h="17.0" x="5893.0" y="3356.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3935_emtc_emtc_sa2015" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: son of sevenless homolog 1 (Drosophila) HUGO:SOS1, HGNC:11187, ENTREZ:6654, UNIPROT:Q07889 , GENECARDS:GC02M039208 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOS1"/> <bbox w="39.0" h="19.0" x="5802.0" y="3333.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3936_emtc_emtc_sa2016" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: son of sevenless homolog 2 (Drosophila) HUGO:SOS2, HGNC:11188, ENTREZ:6655, UNIPROT:Q07890, GENECARDS:GC14M050583 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOS2"/> <bbox w="39.0" h="18.0" x="5802.0" y="3369.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3937_emtc_emtc_sa2017" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: growth factor receptor-bound protein 2 HUGO:GRB2, HGNC:4566, ENTREZ:2885, UNIPROT:P62993, GENECARDS:GC17M073313 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos GRB2 is an adaptator for Ras References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GRB2"/> <bbox w="38.0" h="17.0" x="5919.0" y="3470.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3948_emtc_emtc_sa2023" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 2 HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. PMID:11074002 Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="118.0" h="51.0" x="5937.0" y="4546.5"/> <glyph class="state variable" id="_358474cd-e6ac-447a-87a9-7d74ec7eaaed"> <state value="P" variable="S465"/> <bbox w="35.0" h="10.0" x="6037.5" y="4574.977"/> </glyph> <glyph class="state variable" id="_235e4ccb-9ee7-4c49-be8b-3c5c9d42e4d9"> <state value="P" variable="T8"/> <bbox w="25.0" h="10.0" x="5984.539" y="4592.5"/> </glyph> <glyph class="state variable" id="_237950b1-6a71-4a61-bd39-d39c99cdc44d"> <state value="P" variable="S467"/> <bbox w="35.0" h="10.0" x="6037.5" y="4587.7554"/> </glyph> <glyph class="state variable" id="_6332407f-6337-4fb1-bfea-9414ad8c63a6"> <state value="" variable="S464"/> <bbox w="30.0" h="10.0" x="6040.0" y="4564.9556"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3949_emtc_emtc_sa2022" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 3 HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="115.0" h="49.0" x="5763.0" y="4547.5"/> <glyph class="state variable" id="_aacd325c-c7e0-4338-b373-f2001aaa9cdc"> <state value="P" variable="S204"/> <bbox w="35.0" h="10.0" x="5745.5" y="4570.663"/> </glyph> <glyph class="state variable" id="_c44ac711-eeca-4c40-b9cd-da3f969dc4f9"> <state value="" variable="S422"/> <bbox w="30.0" h="10.0" x="5863.0" y="4563.797"/> </glyph> <glyph class="state variable" id="_7572d621-32fe-4ae4-b64d-346ad25e0805"> <state value="P" variable="T179"/> <bbox w="35.0" h="10.0" x="5745.5" y="4586.7476"/> </glyph> <glyph class="state variable" id="_7b285e0b-ad45-40bf-886d-cee27be7a9c7"> <state value="P" variable="S423"/> <bbox w="35.0" h="10.0" x="5860.5" y="4573.601"/> </glyph> <glyph class="state variable" id="_9b83beff-2744-413b-bb19-f684df3fcbaa"> <state value="P" variable="S425"/> <bbox w="35.0" h="10.0" x="5860.5" y="4586.9414"/> </glyph> <glyph class="state variable" id="_648fa0f8-45eb-49d9-9cae-7f79ba7bdb7a"> <state value="P" variable="S208"/> <bbox w="35.0" h="10.0" x="5745.5" y="4559.3784"/> </glyph> <glyph class="state variable" id="_38f246c9-e182-480c-afe8-61159570faed"> <state value="P" variable="S213"/> <bbox w="35.0" h="10.0" x="5745.5" y="4545.443"/> </glyph> <glyph class="state variable" id="_8758325a-8da2-43f6-bdf2-da901fe10a81"> <state value="" variable="T8"/> <bbox w="20.0" h="10.0" x="5809.2124" y="4591.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3950_emtc_emtc_sa1960" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 1 HUGO:MAPK1, HGNC:6871, ENTREZ:5594, GENECARDS:GC22M022108, UNIPROT:P28482 mitogen-activated protein kinase 3 HUGO:MAPK3, HGNC:6877, ENTREZ:5595, GENECARDS:GC16M030125, UNIPROT:P27361 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK2 (phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK2 phosphorylates the critical Tyr and Thr on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity. PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ERK1_2*"/> <bbox w="57.0" h="21.0" x="3206.0" y="3194.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3952_emtc_emtc_sa2026" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="I-SMAD*"/> <bbox w="61.0" h="19.0" x="5022.0" y="4283.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3953_emtc_emtc_sa2027" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="I-SMAD*"/> <bbox w="61.0" h="19.0" x="4712.5" y="4335.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3954_emtc_emtc_sa2028" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1, HGNC:16807, ENTREZ:57154, GENECARDS:GC07M098627, UNIPROT:Q9HCE7 SMAD specific E3 ubiquitin protein ligase 2 HUGO:SMURF2, HGNC:16809, ENTREZ:64750, GENECARDS:GC17M062540, UNIPROT:Q9HAU4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:22921829 SMAD7 binds to SMURF1 and SMURF2. The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 PMID:15761153 SMAD7, SMURF1, SMURF2, SMAD2, SMAD3 all bind to TGFBR1 Inhibitory Smads (I-Smads) represented by Smad6 and Smad7, negatively regulates TGFB signaling by interacting with the activated TGFBR1 PMID:9335507 Smad7 associates stably with the TGFB receptor complex, but is not phosphorylated upon TGFB stimulation PMID:9335505 Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with TGFBR1. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the BMP type IB receptor PMID:9215638 Smad7 prevents TGFB-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFBR1, thereby blocking the association, phosphorylation, and activation of Smad2 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF*"/> <bbox w="59.0" h="16.0" x="4562.0" y="4393.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3955_emtc_emtc_sa2029" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1, HGNC:16807, ENTREZ:57154, GENECARDS:GC07M098627, UNIPROT:Q9HCE7 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:21572392 SMURF1 is an E3 ubiquitin ligase SMURF1 performs a crucial role in the regulation of the BMP signalling pathway in both embryonic development and bone remodelling. PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation stimulates the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. TGFB regulation of the Par6-Smurf1-RhoA pathway is required for EMT. PMID:14657501 Smurf1 functions as an effector of the polarity complex by mediating localized ubiquitination and degradation of RhoA in cellular protrusions. Atypical protein kinase C (aPKCZ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14744429 RhoA is the prototypical member of the Rho GTPase family, which regulates many cellular processes, including cellular adhesion, motility, and polarity Need more reference 34-36 from PMID15761148: RhoA is an important modulator of cell junction formation and stability. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF1"/> <bbox w="55.0" h="16.0" x="4527.0" y="4328.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3956_emtc_emtc_sa2030" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 2 HUGO:SMURF2, HGNC:16809, ENTREZ:64750, GENECARDS:GC17M062540, UNIPROT:Q9HAU4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMURF2"/> <bbox w="52.0" h="17.0" x="4589.0" y="4328.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3970_emtc_emtc_sa2044" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: KIT ligand HUGO:KITLG HGNC:6343 ENTREZ:4254 UNIPROT:P21583 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KITLG"/> <bbox w="42.0" h="18.0" x="753.5" y="97.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3975_emtc_emtc_sa2048" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: C-terminal binding protein 2 HUGO:CTBP2 HGNC:2495 ENTREZ:1488 UNIPROT:P56545 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTBP2"/> <bbox w="43.0" h="21.0" x="3341.0" y="4257.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3976_emtc_emtc_sa2049" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: C-terminal binding protein 1 HUGO:CTBP1 HGNC:2494 ENTREZ:1487 UNIPROT:Q13363 C-terminal binding protein 2 HUGO:CTBP2 HGNC:2495 ENTREZ:1488 UNIPROT:P56545 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTBP1_2*"/> <bbox w="62.0" h="22.0" x="3242.0" y="4242.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s3977_emtc_emtc_sa2050" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 3 HUGO:HDAC3 HGNC:4854 ENTREZ:8841 UNIPROT:O15379 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC3"/> <bbox w="56.0" h="17.0" x="2609.0" y="3644.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4275_emtc_emtc_sa2064" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-akt murine thymoma viral oncogene homolog 2 HUGO:AKT2 HGNC:392 ENTREZ:208 UNIPROT:P31751 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:17332325 Of the 3 AKT isofomrs, AKT2 has been shown to promote cell motility, invasiveness and metastasis PMID:19825827 Decrease in the ratio of AKT1 versus AKT2 in cells induced the down-regulation of miR200 and promoted EMT and a stem cell-like phenotype. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AKT2"/> <bbox w="39.0" h="17.0" x="2953.5" y="965.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4281_emtc_emtc_sa2070" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CDK2 HUGO:CDK4 Identifiers_end Maps_Modules_begin: MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CDK2_4*"/> <bbox w="59.0" h="17.0" x="3203.0" y="1686.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4287_emtc_emtc_sa2073" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1B (p27, Kip1) HUGO:CDKN1B, HGNC:1785, ENTREZ:1027, GENECARDS:GC12P012867, UNIPROT:P46527 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:24954210 p27, p16 and p15 inhibits CDK4_6. This induces a G1 cell cycle arrest. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p27KIP1*"/> <bbox w="64.0" h="20.0" x="3337.0" y="1446.0"/> <glyph class="state variable" id="_500d07b8-bd2e-4cb0-97eb-2ab0df95739b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3329.5" y="1460.8612"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4291_emtc_emtc_sa2077" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box O3 HUGO:FOXO3, HGNC:3821, ENTREZ:2309, GENECARDS:GC06P108881, UNIPROT:O43524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19564415 The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression. This explains the role of FOXO3 in promoting tumor invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXO3"/> <bbox w="45.0" h="19.0" x="3244.0" y="2104.5"/> <glyph class="state variable" id="_a3a0e7b6-a7e3-447d-b5e6-0a175f25ac43"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3239.0" y="2099.572"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4294_emtc_emtc_sa2082" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mindbomb E3 ubiquitin protein ligase 2 HUGO:MIB2, HGNC:30577, ENTREZ:142678, UNIPROT:Q96AX9, GENECARDS:GC01P001540 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MIB2"/> <bbox w="45.0" h="17.0" x="408.0" y="1802.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4295_emtc_emtc_sa2083" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: neuralized homolog HUGO:NEURL, HGNC:7761, ENTREZ:9148, UNIPROT:O76050, GENECARDS:GC10P105244 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NEURL"/> <bbox w="53.0" h="18.0" x="401.0" y="1772.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4296_emtc_emtc_sa2084" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: jagged 1 HUGO:JAG1, HGNC:6188, ENTREZ:182, UNIPROT:P78504, GENECARDS:GC20M010618 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAG1"/> <bbox w="41.0" h="20.0" x="506.0" y="1820.0"/> <glyph class="state variable" id="_028933f5-89a5-42b5-a689-df5213d97b34"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="542.0" y="1835.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4297_emtc_emtc_sa2085" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: jagged 1 HUGO:JAG1, HGNC:6188, ENTREZ:182, UNIPROT:P78504, GENECARDS:GC20M010618 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAG1"/> <bbox w="41.0" h="20.0" x="506.0" y="1755.0"/> <glyph class="state variable" id="_17dacb63-6381-4ee4-b561-774aaf06627e"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="537.0" y="1770.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4298_emtc_emtc_sa2086" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein numb homolog HUGO:NUMB, HGNC:8060, ENTREZ:8650, UNIPROT:P49757, GENECARDS:GC14M073741 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NUMB"/> <bbox w="49.0" h="19.0" x="779.0" y="1709.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4300_emtc_emtc_sa2091" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: presenilin 1 HUGO:PSEN1, HGNC:9508, ENTREZ:5663, UNIPROT:P49768, GENECARDS:GC14P073603 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PSEN1"/> <bbox w="46.0" h="18.0" x="634.0" y="1797.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4301_emtc_emtc_sa2093" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="50.0" h="19.0" x="778.0" y="1906.5"/> <glyph class="state variable" id="_388c42aa-8008-4c5e-a169-65ae864144a5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="823.0" y="1901.5"/> </glyph> <glyph class="state variable" id="_132295f9-bbe6-4f07-b218-68237a5df4e0"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="768.0" y="1901.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4302_emtc_emtc_sa2095" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="49.0" h="21.0" x="778.0" y="1793.5"/> <glyph class="state variable" id="_eb39211f-8bc4-4cd1-af84-3ed403c9abc7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="822.0" y="1788.5"/> </glyph> <glyph class="state variable" id="_a7f77c9d-3697-440f-a110-2d8f4f683453"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="773.0" y="1788.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4338_emtc_emtc_sa2152" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="49.0" h="21.0" x="2179.0" y="1938.0"/> <glyph class="state variable" id="_b85368e6-d0de-4596-ab97-2e4c03f49ee6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2223.0" y="1933.0"/> </glyph> <glyph class="state variable" id="_130c42bb-7fb5-4ecd-9529-4ed7b5a3ec9b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2174.0" y="1933.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4340_emtc_emtc_sa2088" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ubiquitin-conjugating enzyme E2D1 HUGO:UBE2D1, HGNC:12474, ENTREZ:7321, UNIPROT:P51668, GENECARDS:GC10P060094 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="UBE2D1"/> <bbox w="55.0" h="19.0" x="896.0" y="1868.667"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4341_emtc_emtc_sa2154" compartmentRef="emtc_emtc_c24_emtc_emtc_ca24"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:20351093 PMID:22363487 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NOTCH1"/> <bbox w="62.0" h="30.0" x="1528.75" y="1385.0"/> <glyph class="unit of information" id="_403ee64e-a127-4c13-8a24-7b7b92db4bc1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1537.25" y="1380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4342_emtc_emtc_sa2156" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="49.0" h="21.0" x="2338.5" y="1999.0"/> <glyph class="state variable" id="_713f613d-6342-43b9-8363-816ab79bb8f2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2380.0" y="1994.0"/> </glyph> <glyph class="state variable" id="_21a66c9f-bc37-476c-9480-58da2f13cac0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2333.5" y="1994.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4343_emtc_emtc_sa2155" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Notch homolog 1 NOTCH intracellular domains NICD HUGO:NOTCH1, HGNC:7881, ENTREZ:4851, UNIPROT:P46531, GENECARDS:GC09M139388 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21828089 Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD*"/> <bbox w="49.0" h="21.0" x="2334.5" y="1939.0"/> <glyph class="state variable" id="_94b4a236-2870-4edb-8101-c01be5f1c2a5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2378.5" y="1934.0"/> </glyph> <glyph class="state variable" id="_6924a458-5c17-4e4e-be8d-b90ced8986b9"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="2324.5" y="1934.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4348_emtc_emtc_sa2161" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: E-protein* transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, UNIPROT:P15923, GENECARDS:GC19M001609 transcription factor 12 HUGO:TCF12 HGNC:11623, ENTREZ:6938, UNIPROT:Q99081, GENECARDS:GC15P057210 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19240756 4 human E-proteins from 3 genes: E47 (TCF3) and E12 (TCF3) from E2A gene, HEB (TCF12) and E2-2 (TCF4) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-protein*"/> <bbox w="76.0" h="23.0" x="4080.0" y="4172.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4352_emtc_emtc_sa2165" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 7 TAK1 HUGO:MAP3K7 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:21041997 TGFB has been shown to induce p38 and JNK MAP kinase signaling through activation of TAK1 (MAP3K7) by the ubiquitin ligase TRAF6 that interacts with the TGFB receptor complex PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K7"/> <clone/> <bbox w="62.0" h="22.0" x="5503.0" y="2413.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4352_emtc_emtc_sa2166" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 7 TAK1 HUGO:MAP3K7 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:21041997 TGFB has been shown to induce p38 and JNK MAP kinase signaling through activation of TAK1 (MAP3K7) by the ubiquitin ligase TRAF6 that interacts with the TGFB receptor complex PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K7"/> <clone/> <bbox w="62.0" h="22.0" x="5667.5" y="2418.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4353_emtc_emtc_sa2167" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TNF receptor-associated factor 6, E3 ubiquitin protein ligase HUGO:TRAF6, HGNC:12036, ENTREZ:7189, UNIPROT:Q9Y4K3, GENECARDS:GC11M036467 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18758450 The ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TGFBR1. The TGFBR1–TRAF6 interaction is required for TGFB-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway TGFB specifically activates TAK1 (MAP3K7) through interaction of TGFBRI with TRAF6. The kinase activity of TGFBRI is not required for activation of TAK1 and p38. Model in which TGFB - induced activation of TAK1 is initiated by ligand-induced oligomerization of TGFBreceptors. This in turn cause dimerization of TRAF6, followed by auto-ubiquitylation and activation. This possibility is consistent with the observation that artifical dimerization of TRAF6 causes its auto-ubiquitylation. Activated TRAF6 then causes Lys 63-linked ubiquitylation and activation of TAK1 (MAP3K7). TAK1 may be further activated by juxtaposition-induced autophosphorylation. The recruitment of TAK1 may be facilitated by Smad7, which has been shown to have an adaptor function in the pathway PMID:18922473 TRAF6 is specifically required for the Smad-independent activation of JNK and p38. The carboxyl TRAF homology domain physically interacts with TGFB receptors. TGFB induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1 (MAP3K7). TGFB activates JNK and p38 through a mechanism similar to that operating in the interleukin1B/Toll- like receptor pathway. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TRAF6"/> <bbox w="52.0" h="21.0" x="5958.0" y="3172.5"/> <glyph class="state variable" id="_6ca0be1c-a3a0-43d7-89fa-fb372594733b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5953.0" y="3167.5796"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4354_emtc_emtc_sa2169" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TNF receptor-associated factor 6, E3 ubiquitin protein ligase HUGO:TRAF6, HGNC:12036, ENTREZ:7189, UNIPROT:Q9Y4K3, GENECARDS:GC11M036467 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18758450 The ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TGFBR1. The TGFBR1–TRAF6 interaction is required for TGFB-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway TGFB specifically activates TAK1 (MAP3K7) through interaction of TGFBRI with TRAF6. The kinase activity of TGFBRI is not required for activation of TAK1 and p38. Model in which TGFB - induced activation of TAK1 is initiated by ligand-induced oligomerization of TGFBreceptors. This in turn cause dimerization of TRAF6, followed by auto-ubiquitylation and activation. This possibility is consistent with the observation that artifical dimerization of TRAF6 causes its auto-ubiquitylation. Activated TRAF6 then causes Lys 63-linked ubiquitylation and activation of TAK1 (MAP3K7). TAK1 may be further activated by juxtaposition-induced autophosphorylation. The recruitment of TAK1 may be facilitated by Smad7, which has been shown to have an adaptor function in the pathway PMID:18922473 TRAF6 is specifically required for the Smad-independent activation of JNK and p38. The carboxyl TRAF homology domain physically interacts with TGFB receptors. TGFB induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1 (MAP3K7). TGFB activates JNK and p38 through a mechanism similar to that operating in the interleukin1B/Toll- like receptor pathway. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TRAF6"/> <bbox w="58.0" h="27.0" x="5813.0" y="3169.5"/> <glyph class="unit of information" id="_0a6e6582-794f-4b42-bf87-8d67d6babc53"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5832.0" y="3164.5"/> </glyph> <glyph class="state variable" id="_1fb36e98-3437-4579-9f22-db4a1a49ee6f"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="5803.0" y="3164.6023"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4355_emtc_emtc_sa2170" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: recombination signal binding protein for immunoglobulin kappa J region HUGO:RBPJ, HGNC:5724, ENTREZ:3516, UNIPROT:Q06330 , GENECARDS:GC04P026165 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CBF1*"/> <bbox w="39.0" h="18.0" x="2219.0" y="2022.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4359_emtc_emtc_sa2173" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: nuclear receptor corepressor 2 HUGO:NCOR2, HGNC:7673, ENTREZ:9612, UNIPROT:Q9Y618, GENECARDS:GC12M124808 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCOR2"/> <bbox w="47.0" h="18.0" x="2398.0" y="2033.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4360_emtc_emtc_sa2174" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: nuclear receptor corepressor 1 HUGO:NCOR1, HGNC:7672, ENTREZ:9611, UNIPROT:O75376, GENECARDS:GC17M015933 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NCOR1"/> <bbox w="44.0" h="18.0" x="2340.0" y="2033.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4361_emtc_emtc_sa2175" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: corepressor interacting with RBPJ, 1 HUGO:CIR1, HGNC:24217, ENTREZ:9541, UNIPROT:Q86X95, GENECARDS:GC02M175212 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CIR1"/> <bbox w="36.0" h="19.0" x="2568.0" y="2037.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4382_emtc_emtc_sa2189" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 1 HUGO:HEY1, HGNC:4880, ENTREZ:23462, UNIPROT:Q9Y5J3, GENECARDS:GC08M080676 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY1"/> <bbox w="38.0" h="21.0" x="2461.0" y="2171.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4383_emtc_emtc_sa2190" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 2 HUGO:HEY2, HGNC:4881, ENTREZ:23493, UNIPROT:Q9UBP5, GENECARDS:GC06P126068 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY2"/> <bbox w="36.0" h="20.0" x="2463.0" y="2209.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4384_emtc_emtc_sa2191" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 1 HUGO:HEY1, HGNC:4880, ENTREZ:23462, UNIPROT:Q9Y5J3, GENECARDS:GC08M080676 hes-related family bHLH transcription factor with YRPW motif 2 HUGO:HEY2, HGNC:4881, ENTREZ:23493, UNIPROT:Q9UBP5, GENECARDS:GC06P126068 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY1_2*"/> <bbox w="56.0" h="21.0" x="2586.0" y="2171.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4388_emtc_emtc_sa2195" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: runt-related transcription factor 2 HUGO:RUNX2, HGNC:10427, ENTREZ:860, UNIPROT:Q13950 , GENECARDS:GC06P045295 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RUNX2"/> <bbox w="42.0" h="19.0" x="2460.0" y="2247.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4392_emtc_emtc_sa2198" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: NICD-cofactors* recombination signal binding protein for immunoglobulin kappa J region HUGO:RBPJ, HGNC:5724, ENTREZ:3516, UNIPROT:Q06330 , GENECARDS:GC04P026165 hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162, UNIPROT:Q16665 axin 1 HUGO:AXIN1, HGNC:903, ENTREZ:8312, UNIPROT:O15169 , GENECARDS:GC16M000338 catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21828089 These proteins synergizes with NICD on Notch target genes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NICD co-factors*"/> <bbox w="114.0" h="23.0" x="2573.0" y="2314.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4395_emtc_emtc_sa2201" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 10 (stromelysin 2) HUGO:MMP10, HGNC:7156, ENTREZ:4319, UNIPROT:P09238, GENECARDS:GC11M102641 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP10"/> <bbox w="46.0" h="20.0" x="2073.0" y="4983.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4396_emtc_emtc_sa2202" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 10 (stromelysin 2) HUGO:MMP10, HGNC:7156, ENTREZ:4319, UNIPROT:P09238, GENECARDS:GC11M102641 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP10"/> <bbox w="46.0" h="20.0" x="1051.5" y="6349.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4401_emtc_emtc_sa2207" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 1 (Drosophila) "enhancer of zeste (Drosophila) homolog 1" HUGO:EZH1 HGNC:3526 ENTREZ:2145 UNIPROT:Q92800 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16567498 PMID:17587822 EZH1 and EZH2 are targets of HEYs-mediated transcriptional repression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH1"/> <bbox w="42.0" h="17.0" x="2964.0" y="3250.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4418_emtc_emtc_sa2221" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: low density lipoprotein receptor-related protein 5 HUGO:LRP5 HGNC:6697 ENTREZ:4041 UNIPROT:O75197 low density lipoprotein receptor-related protein 6 HUGO:LRP6 HGNC:6698 ENTREZ:4040 UNIPROT:O75581 HUGO:LRP6 HGNC:6698 ENTREZ:4040 UNIPROT:075581 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17143292 PMID:16443747 WNT3a requires LRP6 to activate wnt PMID:22433869 PMID:19072724 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LRP5_6*"/> <bbox w="63.0" h="49.0" x="1014.25" y="6042.0"/> <glyph class="unit of information" id="_4ab9d5c7-1757-4b01-9df4-cf424cbb55d5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1023.25" y="6037.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4427_emtc_emtc_sa2237" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: axin 2 HUGO:AXIN2, HGNC:904, ENTREZ:8313, GENECARDS:GC17M063524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN2"/> <bbox w="45.0" h="22.0" x="2312.0" y="3683.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4440_emtc_emtc_sa2247" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: wingless-type MMTV integration site family member 1 HUGO:WNT1 HGNC:12774 ENTREZ:7471 UNIPROT:P04628 wingless-type MMTV integration site family member 2 HUGO:WNT2 HGNC:12780 ENTREZ:7472 UNIPROT:P09544 wingless-type MMTV integration site family member 2B HUGO:WNT2B HGNC:12781 ENTREZ:7482 UNIPROT:Q93097 wingless-type MMTV integration site family member 3 HUGO:WNT3 HGNC:12782 ENTREZ:7473 UNIPROT:P56703 wingless-type MMTV integration site family member 3A HUGO:WNT3A HGNC:15983 ENTREZ:89780 UNIPROT:P56704 wingless-type MMTV integration site family member 4 HUGO:WNT4 HGNC:12783 ENTREZ:54361 UNIPROT:P56705 wingless-type MMTV integration site family member 5A HUGO:WNT5A HGNC:12784 ENTREZ:7474 UNIPROT:P41221 wingless-type MMTV integration site family member 5B HUGO:WNT5B HGNC:16265 ENTREZ:81029 UNIPROT:Q9H1J7 wingless-type MMTV integration site family member 6 HUGO:WNT6 HGNC:12785 ENTREZ:7475 UNIPROT:Q9Y6F9 wingless-type MMTV integration site family member 7A HUGO:WNT7A HGNC:12786 ENTREZ:7476 UNIPROT:O00755 wingless-type MMTV integration site family member 7B HUGO:WNT7B HGNC:12787 ENTREZ:7477 UNIPROT:P56706 wingless-type MMTV integration site family member 8A HUGO:WNT8A HGNC:12788 ENTREZ:7478 UNIPROT:Q9H1J5 wingless-type MMTV integration site family member 8B HUGO:WNT8B HGNC:12789 ENTREZ:7479 UNIPROT:Q93098 wingless-type MMTV integration site family member 9A HUGO:WNT9A HGNC:12778 ENTREZ:7483 UNIPROT:O14904 wingless-type MMTV integration site family member 9B HUGO:WNT9B HGNC:12779 ENTREZ:7484 UNIPROT:O14905 wingless-type MMTV integration site family member 10A HUGO:WNT10A HGNC:13829 ENTREZ:80326 UNIPROT:Q9GZT5 wingless-type MMTV integration site family member 10B HUGO:WNT10B HGNC:12775 ENTREZ:7480 UNIPROT:O00744 wingless-type MMTV integration site family member 11 HUGO:WNT11 HGNC:12776 ENTREZ:7481 UNIPROT:O96014 wingless-type MMTV integration site family member 16 HUGO:WNT16 HGNC/16267 ENTREZ:51384 UNIPROT:Q9UBV4 wingless-type MMTV integration site family member 5 WNT5A antisense RNA 1 HUGO:WNT5A-AS1 HGNC:40616 ENTREZ:100874008 HUGO:WNT16 HGNC:16267 ENTREZ:51384 UNIPROT:Q9UBV4 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Class I: WNT-1,3a,7,8a,8b activates canonical PMID:14747478 PMID:15265686 PMID:8655584 PMID:22017973 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="WNT*"/> <bbox w="40.0" h="20.0" x="1055.5" y="6167.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4448_emtc_emtc_sa2253" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: endothelin 1 HUGO:EDN1, HGNC:3176, ENTREZ:1906, GENECARDS:GC06P012290, UNIPROT:P05305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9588211 Endothelin1 is target gene of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Endothelin1*"/> <bbox w="78.0" h="20.0" x="1643.909" y="6185.182"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4450_emtc_emtc_sa2255" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phospholipase C, beta 1 (phosphoinositide-specific) HUGO:PLCB1, HGNC:15917, ENTREZ:23236, GENECARDS:GC20P008061, UNIPROT:Q9NQ66 phospholipase C, beta 2 HUGO:PLCB2, HGNC:9055, ENTREZ:5330, GENECARDS:GC15M040580, UNIPROT:Q00722 phospholipase C, beta 3 (phosphatidylinositol-specific) HUGO:PLCB3, HGNC:9056, ENTREZ:5331, GENECARDS:GC11P064019, UNIPROT:Q01970 phospholipase C, beta 4 HUGO:PLCB4, HGNC:9059, ENTREZ:5332, GENECARDS:GC20P009024, UNIPROT:Q15147 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PLCβ*"/> <bbox w="41.0" h="18.0" x="1777.0" y="5972.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4457_emtc_emtc_sa2261" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, delta HUGO:PRKCD, HGNC:9399, ENTREZ:5580, UNIPROT:Q05655 , GENECARDS:GC03P053190 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCD"/> <bbox w="54.0" h="20.0" x="4527.5" y="873.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4501_emtc_emtc_sa2321" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 alpha HUGO:PIK3C2A HGNC:8971 ENTREZ:5286 UNIPROT:O00443 phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 beta HUGO:PIK3C2B HGNC:8972 ENTREZ:5287 UNIPROT:O00750 phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 gamma HUGO:PIK3C2G HGNC:8973 ENTREZ:5288 UNIPROT:O75747 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI3KC2*"/> <bbox w="64.0" h="20.0" x="5194.0" y="930.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4512_emtc_emtc_sa896" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2-associated X protein HUGO:BAX, HGNC:959, ENTREZ:581, UNIPROT:Q07812, GENECARDS:GC19P049458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. PMID:7644501 The susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner. Multiple BCL2 family members demonstrate selective dimerizations with Bax PMID:21641962 The pro-apoptototic protein Bax plays a central role in the mitochondria- dependent apoptotic pathway. In healthy mammalian cells, Bax is essentially cytosolic and inactive. Following a death signal, the protein is translocated to the outer mitochondrial membrane, where it promotes a permeabilization that favors the release of different apoptogenic factors, such as cytochrome c. PMID:23064052 Inactive Bax can be directly converted into an active conformation following the interaction with activator Bid , Bim (BCL2L11) or Puma (BBC3) The interaction of Bax with BCL2 or BCL2L1 drives the translocation of Bax to the outer mitochondrial membrane Under this condition, active Bax can be liberated from its interaction with BCL2L1 by a derepressor BH3-only protein, such as Bad. Other experiments have shown that Bax can be translocated to the outer mitochondrial membrane and further activated by different proteins such as Myc or p38MapK References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX"/> <bbox w="34.0" h="19.0" x="4558.0" y="1402.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4529_emtc_emtc_sa2342" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: heparin-binding EGF-like growth factor HUGO:HBEGF, HGNC:3059, ENTREZ:1839, UNIPROT:Q99075 , GENECARDS:GC05M139694 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HBEGF"/> <bbox w="47.0" h="20.0" x="5768.5" y="118.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4532_emtc_emtc_sa2346" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: heparin-binding EGF-like growth factor HUGO:HBEGF, HGNC:3059, ENTREZ:1839, UNIPROT:Q99075 , GENECARDS:GC05M139694 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HBEGF*"/> <bbox w="80.0" h="40.0" x="5576.5" y="109.5"/> <glyph class="unit of information" id="_9d9d357f-1bfe-405b-b330-9e7442e50519"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5591.5" y="104.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4533_emtc_emtc_sa2348" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ADAM metallopeptidase domain 9 HUGO:ADAM9, HGNC:216, ENTREZ:8754 , UNIPROT:Q13443, GENECARDS:GC08P038871 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ADAM9"/> <bbox w="56.0" h="20.0" x="4289.5" y="1092.0"/> <glyph class="state variable" id="_cc4b25af-385d-4064-b0a2-aab0464b2989"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4313.0825" y="1087.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4534_emtc_emtc_sa2347" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ADAM metallopeptidase domain 9 HUGO:ADAM9, HGNC:216, ENTREZ:8754 , UNIPROT:Q13443, GENECARDS:GC08P038871 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ADAM9"/> <bbox w="56.0" h="20.0" x="4299.0" y="793.5"/> <glyph class="state variable" id="_c931054d-a0d8-4361-a5c8-09e16b78e7c8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4320.0825" y="788.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4540_emtc_emtc_sa2351" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, alpha HUGO:TGFA HGNC:11765 ENTREZ:7039 UNIPROT:P01135 heparin-binding EGF-like growth factor HUGO:HBEGF, HGNC:3059, ENTREZ:1839, UNIPROT:Q99075 , GENECARDS:GC05M139694 epidermal growth factor "epidermal growth factor (beta-urogastrone)" HUGO:EGF HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGF family*"/> <bbox w="76.0" h="21.0" x="2266.0" y="6509.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4544_emtc_emtc_sa2353" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3 HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HER3*"/> <bbox w="80.0" h="50.0" x="1326.5" y="158.5"/> <glyph class="unit of information" id="_2c094efc-e5d6-44c0-81e0-426d333a6e16"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1344.0" y="153.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4545_emtc_emtc_sa2354" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ERBB4 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: erb-b2 receptor tyrosine kinase 4 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HER4*"/> <bbox w="80.0" h="50.0" x="1414.5" y="159.5"/> <glyph class="unit of information" id="_ede04239-19c5-4c75-9bd7-d865d0063658"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1432.0" y="154.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4546_emtc_emtc_sa2355" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR family*"/> <bbox w="80.0" h="50.0" x="577.5" y="454.5"/> <glyph class="state variable" id="_29fc41ed-675c-4c39-9c50-10591a493ae1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="611.73175" y="449.5"/> </glyph> <glyph class="unit of information" id="_3b5f2101-1e9a-42d8-93f8-ef570610527b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="595.0" y="449.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4547_emtc_emtc_sa2356" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Fibroblas growth factors FGF fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 fms-related tyrosine kinase 1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR family*"/> <bbox w="80.0" h="50.0" x="578.5" y="523.5"/> <glyph class="unit of information" id="_d6db3a18-ff07-482c-a932-7278195489c3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="596.0" y="518.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4548_emtc_emtc_sa2358" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR2"/> <bbox w="80.0" h="50.0" x="1628.5" y="159.5"/> <glyph class="unit of information" id="_d34dd037-a9c0-45f2-98c1-6d125dc388c8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1646.0" y="154.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4549_emtc_emtc_sa2359" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR3"/> <bbox w="80.0" h="50.0" x="1716.5" y="158.5"/> <glyph class="unit of information" id="_282d6190-0524-4f11-838b-52a5ab5f3aa7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1734.0" y="153.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4550_emtc_emtc_sa2360" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR4"/> <bbox w="80.0" h="50.0" x="1805.5" y="158.5"/> <glyph class="unit of information" id="_2872750a-bf16-4709-95c6-81c234919ca6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1823.0" y="153.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4553_emtc_emtc_sa2363" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFR family*"/> <bbox w="80.0" h="50.0" x="578.5" y="587.5"/> <glyph class="unit of information" id="_ae2213de-9515-4aa3-aaf4-5cdd7a420691"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="596.0" y="582.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4554_emtc_emtc_sa2364" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFRA"/> <bbox w="80.0" h="50.0" x="1950.5" y="158.5"/> <glyph class="unit of information" id="_4beaf809-1e1c-4844-8e17-d428552606eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1968.0" y="153.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4555_emtc_emtc_sa2365" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFRB"/> <bbox w="80.0" h="50.0" x="2041.5" y="157.5"/> <glyph class="unit of information" id="_56e307c3-a16d-4c31-8e11-51906aa2372c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2059.0" y="152.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4557_emtc_emtc_sa2367" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 fms-related tyrosine kinase 1 FLT "fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)" HUGO:FLT1 HGNC:3763 ENTREZ:2321 UNIPROT:P17948 fms-related tyrosine kinase 3 HUGO:FLT3 HGNC:3765 ENTREZ:2322 UNIPROT:P36888 fms-related tyrosine kinase 4 HUGO:FLT4 HGNC:3767 ENTREZ:2324 UNIPROT:P35916 platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog HUGO:KIT HGNC:6342 ENTREZ:3815 UNIPROT:P10721 insulin-like growth factor 1 receptor HUGO:IGF1R HGNC:5465 ENTREZ:3480 UNIPROT:P08069 met proto-oncogene synonym "hepatocyte growth factor receptor", HGFR HUGO:MET HGNC:7029 ENTREZ:4233 UNIPROT:P08581 EPH receptor A1 HUGO:EPHA1 HGNC:3385 ENTREZ:2041 UNIPROT:P21709 EPH receptor A2 HUGO:EPHA2 HGNC:3386 ENTREZ:1969 UNIPROT:P29317 EPH receptor B1 HUGO:EPHB1 HGNC:3392 ENTREZ:2047 UNIPROT:P54762 EPH receptor B2 HUGO:EPHB2 HGNC:3393 ENTREZ:2048 UNIPROT:P29323 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RTK*"/> <bbox w="86.0" h="56.0" x="574.5" y="373.5"/> <glyph class="unit of information" id="_914c4b37-1217-4bac-9704-7f6577f7f81c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="607.5" y="368.5"/> </glyph> <glyph class="unit of information" id="_5c2ae6ba-f2c9-440f-b6f3-049c617fe556"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="595.0" y="368.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4559_emtc_emtc_sa2368" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 fms-related tyrosine kinase 1 FLT "fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)" HUGO:FLT1 HGNC:3763 ENTREZ:2321 UNIPROT:P17948 fms-related tyrosine kinase 3 HUGO:FLT3 HGNC:3765 ENTREZ:2322 UNIPROT:P36888 fms-related tyrosine kinase 4 HUGO:FLT4 HGNC:3767 ENTREZ:2324 UNIPROT:P35916 platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog HUGO:KIT HGNC:6342 ENTREZ:3815 UNIPROT:P10721 insulin-like growth factor 1 receptor HUGO:IGF1R HGNC:5465 ENTREZ:3480 UNIPROT:P08069 met proto-oncogene synonym "hepatocyte growth factor receptor", HGFR HUGO:MET HGNC:7029 ENTREZ:4233 UNIPROT:P08581 EPH receptor A1 HUGO:EPHA1 HGNC:3385 ENTREZ:2041 UNIPROT:P21709 EPH receptor A2 HUGO:EPHA2 HGNC:3386 ENTREZ:1969 UNIPROT:P29317 EPH receptor B1 HUGO:EPHB1 HGNC:3392 ENTREZ:2047 UNIPROT:P54762 EPH receptor B2 HUGO:EPHB2 HGNC:3393 ENTREZ:2048 UNIPROT:P29323 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RTK*"/> <clone/> <bbox w="80.0" h="50.0" x="577.0" y="221.0"/> <glyph class="unit of information" id="_ccd03999-74f5-4337-91b6-0766a89f095c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="594.5" y="216.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4559_emtc_emtc_sa2366" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 fms-related tyrosine kinase 1 FLT "fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)" HUGO:FLT1 HGNC:3763 ENTREZ:2321 UNIPROT:P17948 fms-related tyrosine kinase 3 HUGO:FLT3 HGNC:3765 ENTREZ:2322 UNIPROT:P36888 fms-related tyrosine kinase 4 HUGO:FLT4 HGNC:3767 ENTREZ:2324 UNIPROT:P35916 platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog HUGO:KIT HGNC:6342 ENTREZ:3815 UNIPROT:P10721 insulin-like growth factor 1 receptor HUGO:IGF1R HGNC:5465 ENTREZ:3480 UNIPROT:P08069 met proto-oncogene synonym "hepatocyte growth factor receptor", HGFR HUGO:MET HGNC:7029 ENTREZ:4233 UNIPROT:P08581 EPH receptor A1 HUGO:EPHA1 HGNC:3385 ENTREZ:2041 UNIPROT:P21709 EPH receptor A2 HUGO:EPHA2 HGNC:3386 ENTREZ:1969 UNIPROT:P29317 EPH receptor B1 HUGO:EPHB1 HGNC:3392 ENTREZ:2047 UNIPROT:P54762 EPH receptor B2 HUGO:EPHB2 HGNC:3393 ENTREZ:2048 UNIPROT:P29323 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RTK*"/> <clone/> <bbox w="80.0" h="50.0" x="577.5" y="281.5"/> <glyph class="unit of information" id="_3c9a7b67-c6e8-4f09-822a-cb2daddc753c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="595.0" y="276.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4583_emtc_emtc_sa2379" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Janus kinase 1 HUGO:JNK1 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Janus kinase 2 HUGO:JNK2 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 tyrosine kinase 2 HUGO:TYK2 HGNC:12440 ENTREZ:7297 UNIPROT:P29597 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAK family*"/> <bbox w="79.0" h="21.0" x="5349.0" y="1255.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4584_emtc_emtc_sa2380" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Janus kinase 1 HUGO:JNK1 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAK1"/> <bbox w="39.0" h="20.0" x="5369.0" y="1184.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4585_emtc_emtc_sa2381" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Janus kinase 2 HUGO:JNK2 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAK2"/> <bbox w="38.0" h="20.0" x="5421.0" y="1184.5"/> 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Confidence_end</body> </html> </notes> <label text="STAT5*"/> <bbox w="50.0" h="18.0" x="5216.0" y="1291.5"/> <glyph class="state variable" id="_38c49b56-532b-437d-a5c5-6321ef8db67c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5261.0" y="1295.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4588_emtc_emtc_sa2384" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: signal transducer and activator of transcription 3 (acute-phase response factor) HUGO:STAT3 HGNC:11364 ENTREZ:6774 UNIPROT:P40763 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="STAT3"/> <bbox w="47.0" h="17.0" x="5147.0" y="1291.5"/> <glyph class="state variable" id="_f117f38d-97ee-4a51-afc0-33efb23d7de1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5189.0" y="1295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4589_emtc_emtc_sa2385" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: signal transducer and activator of transcription 1, 91kDa HUGO:STAT1 HGNC:11362 ENTREZ:6772 UNIPROT:P42224 signal transducer and activator of transcription 3 (acute-phase response factor) HUGO:STAT3 HGNC:11364 ENTREZ:6774 UNIPROT:P40763 signal transducer and activator of transcription 5A HUGO:STAT5A HGNC:11366 ENTREZ:6776 UNIPROT:P42229 signal transducer and activator of transcription 5B HUGO:STAT5B HGNC:11367 ENTREZ:6777 UNIPROT:P51692 signal transducer and activator of transcription 6, interleukin-4 induced HUGO:STAT6 HGNC:11368 ENTREZ:6778 UNIPROT:P42226 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="STAT family*"/> <bbox w="79.0" h="21.0" x="5169.0" y="1176.5"/> <glyph class="state variable" id="_b34af88c-bc72-491a-b1d9-af856c8caf30"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5243.0" y="1171.6128"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4590_emtc_emtc_sa2386" 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Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP2"/> <bbox w="37.0" h="16.0" x="1462.5" y="6179.75"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4620_emtc_emtc_sa2411" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 1 "tissue inhibitor of metalloproteinase 1" HUGO:TIMP1 HGNC:11820 ENTREZ:7076 UNIPROT:P01033 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP1"/> <bbox w="38.0" h="18.0" x="1462.5" y="6145.25"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4626_emtc_emtc_sa2416" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFRA"/> <bbox w="86.0" h="56.0" x="2556.0" y="6032.5"/> <glyph class="unit of information" id="_e5c6e805-6113-4e0a-b2c3-0fc4b112d9d5"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2589.0" y="6027.5"/> </glyph> <glyph class="unit of information" id="_15ef40db-4b28-4b6c-bd5b-a16defabd99b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2576.5" y="6027.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4627_emtc_emtc_sa2417" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFRB"/> <bbox w="86.0" h="56.0" x="2860.0" y="6033.5"/> <glyph class="unit of information" id="_8e7b6ee0-ea9d-4640-aad3-7bbf95dd9a2a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2893.0" y="6028.5"/> </glyph> <glyph class="unit of information" id="_847fdeb9-0a54-48a3-be93-2bbebc47bcde"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2880.5" y="6028.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4630_emtc_emtc_sa2420" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor alpha polypeptide HUGO:PDGFA HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet-derived growth factor beta polypeptide HUGO:PDGFA HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 platelet derived growth factor D HUGO:PDGFD HGNC:30620 ENTREZ:80310 UNIPROT:Q9GZP0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGF family*"/> <bbox w="77.0" h="24.0" x="2517.0" y="6509.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4631_emtc_emtc_sa2421" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor alpha polypeptide HUGO:PDGFA HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet-derived growth factor beta polypeptide HUGO:PDGFA HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 platelet derived growth factor D HUGO:PDGFD HGNC:30620 ENTREZ:80310 UNIPROT:Q9GZP0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGF family*"/> <bbox w="95.0" h="33.0" x="2689.0" y="6509.0"/> <glyph class="unit of information" id="_658bf6ed-e746-496d-be7f-0fd1b4966b1d"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2726.5" y="6504.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4633_emtc_emtc_sa2423" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor alpha polypeptide HUGO:PDGFA HGNC:8799 ENTREZ:5154 UNIPROT:P04085 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFA"/> <bbox w="55.0" h="20.0" x="2419.0" y="6620.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4634_emtc_emtc_sa2424" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor beta polypeptide HUGO:PDGFA HGNC:8800 ENTREZ:5155 UNIPROT:P01127 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFB"/> <bbox w="57.0" h="19.0" x="2493.0" y="6623.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4635_emtc_emtc_sa2425" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet derived growth factor C HUGO:PDGFC HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFC"/> <bbox w="51.0" h="22.0" x="2570.0" y="6624.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4636_emtc_emtc_sa2426" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet derived growth factor D HUGO:PDGFD HGNC:30620 ENTREZ:80310 UNIPROT:Q9GZP0 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:18403754 PMID:16607286 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFD"/> <bbox w="50.0" h="22.0" x="2658.0" y="6625.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4637_emtc_emtc_sa2427" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 fibroblast growth factor 3 "fibroblast growth factor 3 (murine mammary tumor virus integration site (v-int-2) oncogene homolog)", INT2, HBGF-3, "INT-2 proto-oncogene protein", "murine mammary tumor virus integration site 2, mouse", HUGO:FGF3 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 fibroblast growth factor 4 "heparin secretory transforming protein 1", HSTF1 HUGO:FGF4 HGNC:3682 ENTREZ:2249 UNIPROT:P08620 fibroblast growth factor 6 HUGO:FGF6 HGNC:3684 ENTREZ:2251 UNIPROT:P10767 fibroblast growth factor 7 HUGO:FGF7 HGNC:3685 ENTREZ:2252 UNIPROT:P21781 fibroblast growth factor 8 (androgen-induced) HUGO:FGF8 HGNC:3686 ENTREZ:2253 UNIPROT:P55075 "fibroblast growth factor 9 (glia-activating factor)" HUGO:FGF9 HGNC:3687 ENTREZ:2254 UNIPROT:P31371 fibroblast growth factor 10 HUGO:FGF10 HGNC:3666 ENTREZ:2255 UNIPROT:O15520 fibroblast growth factor 16 HUGO:FGF16 HGNC:3672 ENTREZ:8823 UNIPROT:O43320 fibroblast growth factor 19 HUGO:FGF19 HGNC:3675 ENTREZ:9965 UNIPROT:O95750 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF family*"/> <bbox w="72.0" h="22.0" x="3210.0" y="6603.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4638_emtc_emtc_sa2430" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 3 "fibroblast growth factor 3 (murine mammary tumor virus integration site (v-int-2) oncogene homolog)", INT2, HBGF-3, "INT-2 proto-oncogene protein", "murine mammary tumor virus integration site 2, mouse", HUGO:FGF3 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF3"/> <bbox w="40.0" h="18.0" x="2930.0" y="6536.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4639_emtc_emtc_sa2431" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 4 "heparin secretory transforming protein 1", HSTF1 HUGO:FGF4 HGNC:3682 ENTREZ:2249 UNIPROT:P08620 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF4"/> <bbox w="41.0" h="18.0" x="2930.0" y="6563.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4640_emtc_emtc_sa2432" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 6 HUGO:FGF6 HGNC:3684 ENTREZ:2251 UNIPROT:P10767 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF6"/> <bbox w="41.0" h="19.0" x="2930.0" y="6588.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4641_emtc_emtc_sa2433" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 7 HUGO:FGF7 HGNC:3685 ENTREZ:2252 UNIPROT:P21781 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF7"/> <bbox w="42.0" h="18.0" x="2930.0" y="6613.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4642_emtc_emtc_sa2434" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 8 (androgen-induced) HUGO:FGF8 HGNC:3686 ENTREZ:2253 UNIPROT:P55075 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF8"/> <bbox w="42.0" h="18.0" x="2930.0" y="6637.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4643_emtc_emtc_sa2435" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: "fibroblast growth factor 9 (glia-activating factor)" HUGO:FGF9 HGNC:3687 ENTREZ:2254 UNIPROT:P31371 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF9"/> <bbox w="41.0" h="19.0" x="2931.0" y="6662.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4644_emtc_emtc_sa2436" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 10 HUGO:FGF10 HGNC:3666 ENTREZ:2255 UNIPROT:O15520 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF10"/> <bbox w="42.0" h="20.0" x="2931.0" y="6688.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4645_emtc_emtc_sa2437" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 16 HUGO:FGF16 HGNC:3672 ENTREZ:8823 UNIPROT:O43320 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF16"/> <bbox w="41.0" h="20.0" x="2932.0" y="6714.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4646_emtc_emtc_sa2438" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 19 HUGO:FGF19 HGNC:3675 ENTREZ:9965 UNIPROT:O95750 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF19"/> <bbox w="43.0" h="19.0" x="2931.0" y="6741.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4647_emtc_emtc_sa2439" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 fibroblast growth factor 3 "fibroblast growth factor 3 (murine mammary tumor virus integration site (v-int-2) oncogene homolog)", INT2, HBGF-3, "INT-2 proto-oncogene protein", "murine mammary tumor virus integration site 2, mouse", HUGO:FGF3 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 fibroblast growth factor 4 "heparin secretory transforming protein 1", HSTF1 HUGO:FGF4 HGNC:3682 ENTREZ:2249 UNIPROT:P08620 fibroblast growth factor 10 HUGO:FGF10 HGNC:3666 ENTREZ:2255 UNIPROT:O15520 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR1-ligands*"/> <bbox w="101.0" h="22.0" x="3051.0" y="6532.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4648_emtc_emtc_sa2440" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 fibroblast growth factor 3 "fibroblast growth factor 3 (murine mammary tumor virus integration site (v-int-2) oncogene homolog)", INT2, HBGF-3, "INT-2 proto-oncogene protein", "murine mammary tumor virus integration site 2, mouse", HUGO:FGF3 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 fibroblast growth factor 4 "heparin secretory transforming protein 1", HSTF1 HUGO:FGF4 HGNC:3682 ENTREZ:2249 UNIPROT:P08620 fibroblast growth factor 7 HUGO:FGF7 HGNC:3685 ENTREZ:2252 UNIPROT:P21781 fibroblast growth factor 10 HUGO:FGF10 HGNC:3666 ENTREZ:2255 UNIPROT:O15520 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR2-ligands*"/> <bbox w="101.0" h="21.0" x="3051.0" y="6582.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4649_emtc_emtc_sa2441" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 fibroblast growth factor 8 (androgen-induced) HUGO:FGF8 HGNC:3686 ENTREZ:2253 UNIPROT:P55075 "fibroblast growth factor 9 (glia-activating factor)" HUGO:FGF9 HGNC:3687 ENTREZ:2254 UNIPROT:P31371 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR3-ligands*"/> <bbox w="103.0" h="22.0" x="3051.0" y="6631.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4650_emtc_emtc_sa2442" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953, UNIPROT:P05230 fibroblast growth factor 2 (basic) FGFB HUGO:FGF2 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 fibroblast growth factor 6 HUGO:FGF6 HGNC:3684 ENTREZ:2251 UNIPROT:P10767 fibroblast growth factor 16 HUGO:FGF16 HGNC:3672 ENTREZ:8823 UNIPROT:O43320 fibroblast growth factor 19 HUGO:FGF19 HGNC:3675 ENTREZ:9965 UNIPROT:O95750 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR4-ligands*"/> <bbox w="102.0" h="21.0" x="3051.0" y="6681.0"/> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4660_emtc_emtc_sa2451" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Fibroblas growth factors FGF fibroblast growth factor receptor 1 FLT2 "fms-related tyrosine kinase 2" KAL2 HUGO:FGFR1 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR1"/> <bbox w="86.0" h="56.0" x="2969.0" y="6036.5"/> <glyph class="unit of information" id="_e7a9e85a-c063-4f78-b0ef-5730921db18b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3002.0" y="6031.5"/> </glyph> <glyph class="unit of information" id="_5f4fe7e1-4944-4826-894b-e3053d74e864"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2989.5" y="6031.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4661_emtc_emtc_sa2452" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor 2 "bacteria-expressed kinase" BEK CFD1 "craniofacial dysostosis 1" "Jackson-Weiss syndrome" JWS "keratinocyte growth factor receptor" KGFR HUGO:FGFR2 HGNC:3689 ENTREZ:2263 UNIPROT:P21802 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR2"/> <bbox w="86.0" h="56.0" x="3082.0" y="6039.5"/> <glyph class="unit of information" id="_febedbf9-e5e7-4b73-923c-8563754a4b8d"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3115.0" y="6034.5"/> </glyph> <glyph class="unit of information" id="_6c245654-201e-4234-9545-f4ca355ff7d1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3102.5" y="6034.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4662_emtc_emtc_sa2453" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor 3 ACH "achondroplasia thanatophoric dwarfism" HUGO:FGFR3 HGNC:3690 ENTREZ:2261 UNIPROT:P22607 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR3"/> <bbox w="86.0" h="56.0" x="3333.0" y="6041.5"/> <glyph class="unit of information" id="_e59063f7-6faf-491e-8499-422b09ec12f0"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3366.0" y="6036.5"/> </glyph> <glyph class="unit of information" id="_162e403f-b33c-4b3c-9d96-5dcb9d018540"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3353.5" y="6036.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="emtc_emtc_s4663_emtc_emtc_sa2454" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor 4 HUGO:FGFR4 HGNC:3691 ENTREZ:2264 UNIPROT:P22455 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGFR4"/> <bbox w="86.0" h="56.0" x="3444.0" y="6044.5"/> <glyph class="unit of information" id="_1b10ae42-c5c2-4bca-bb43-e876d01e218e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3477.0" y="6039.5"/> </glyph> <glyph class="unit of information" id="_a8809c91-6b17-47cb-8338-62c2fc54359d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3464.5" y="6039.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4664_emtc_emtc_sa2455" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phospholipase C, gamma 1 HUGO:PLCG1 HGNC:9065 ENTREZ:5335 UNIPROT:P19174 phospholipase C, gamma 2 (phosphatidylinositol-specific) HUGO:PLCG2, HGNC:9066, ENTREZ:5336, UNIPROT:P16885 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PLCγ*"/> <bbox w="49.0" h="18.0" x="3198.0" y="5916.5"/> <glyph class="state variable" id="_fe23ee0d-b722-428c-8729-1c7924919278"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3218.0095" y="5911.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4665_emtc_emtc_sa2456" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phospholipase C, gamma 1 HUGO:PLCG1 HGNC:9065 ENTREZ:5335 UNIPROT:P19174 phospholipase C, gamma 2 (phosphatidylinositol-specific) HUGO:PLCG2, HGNC:9066, ENTREZ:5336, UNIPROT:P16885 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PLCγ*"/> <bbox w="49.0" h="18.0" x="3363.5" y="5917.0"/> <glyph class="state variable" id="_90d22c4a-d90d-4536-8885-657b6aa8a262"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3381.0095" y="5912.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4666_emtc_emtc_sa2458" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor substrate 2 HUGO:FRS2, HGNC:16971, ENTREZ:10818, UNIPROT:Q8WU20 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FRS2"/> <bbox w="52.0" h="19.0" x="5395.5" y="3336.0"/> <glyph class="state variable" id="_78830ece-b0d7-4e68-8eb3-730cdfe7dc94"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5390.5" y="3340.4849"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4667_emtc_emtc_sa2457" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor receptor substrate 2 HUGO:FRS2, HGNC:16971, ENTREZ:10818, UNIPROT:Q8WU20 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17673906 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FRS2"/> <bbox w="51.0" h="19.0" x="5526.0" y="3337.5"/> <glyph class="state variable" id="_00c90572-f038-4fe6-a469-5221bb93948b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5518.5" y="3341.9849"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4682_emtc_emtc_sa2467" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor alpha polypeptide HUGO:PDGFA HGNC:8799 ENTREZ:5154 UNIPROT:P04085 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFA"/> <bbox w="49.0" h="17.0" x="2092.0" y="4542.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4687_emtc_emtc_sa1138" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine phosphatase, non-receptor type 11 "Noonan syndrome 1", NS1 HUGO:PTPN11 HGNC:9644 ENTREZ:5781 UNIPROT:Q06124 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTPN11"/> <bbox w="51.0" h="16.0" x="880.0" y="3741.5"/> <glyph class="state variable" id="_a5c8d685-3985-4aca-b57d-d0e7900315c6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="898.5304" y="3736.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4691_emtc_emtc_sa2475" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lectin, galactoside-binding, soluble, 3 HUGO:LGALS3 HGNC:6563 ENTREZ:3958 UNIPROT:P17931 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Galectin 3*"/> <bbox w="74.0" h="19.0" x="3286.0" y="6413.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4692_emtc_emtc_sa2477" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lectin, galactoside-binding, soluble, 3 HUGO:LGALS3 HGNC:6563 ENTREZ:3958 UNIPROT:P17931 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="truncated Galectin 3*"/> <bbox w="127.0" h="27.0" x="3260.0" y="6674.0"/> <glyph class="unit of information" id="_791af1fd-6b87-4fd4-bc2a-a4e78bfb9041"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3298.5" y="6669.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4693_emtc_emtc_sa2478" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Galectin 3 partners*"/> <bbox w="124.0" h="21.0" x="3531.0" y="6402.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4697_emtc_emtc_sa2481" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: elastin HUGO:ELN HGNC:3327 ENTREZ:2006 UNIPROT:P15502 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Elastin*"/> <bbox w="49.0" h="18.0" x="5685.0" y="6364.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4698_emtc_emtc_sa2482" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) HUGO:MMP9, HGNC:7176, ENTREZ:4318, UNIPROT:P14780, GENECARDS:GC20P044637 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP9*"/> <bbox w="60.0" h="19.0" x="1285.0" y="6321.0"/> <glyph class="unit of information" id="_e8ce51d4-c1eb-4a97-995e-4883a687e985"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1290.0" y="6316.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4699_emtc_emtc_sa2483" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP1*"/> <bbox w="54.0" h="18.0" x="1285.0" y="6217.0"/> <glyph class="unit of information" id="_45c5fb98-6021-41fa-85f3-36a6652e1d6d"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1287.0" y="6212.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4700_emtc_emtc_sa2484" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 2 HUGO:SERPINF2, HGNC:9075, ENTREZ:5345, GENECARDS:GC17P001593, UNIPROT:P08697 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plasmin*"/> <bbox w="56.0" h="19.0" x="1439.0" y="6275.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4701_emtc_emtc_sa2485" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:114518 Laminin-1: LAMA1, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Truncated Laminin1*"/> <bbox w="128.0" h="24.0" x="5773.0" y="6238.0"/> <glyph class="unit of information" id="_2263996b-fbea-4ac5-b60f-8037a73aeda3"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5812.0" y="6233.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4702_emtc_emtc_sa2486" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 fibulin 1 HUGO:FBLN1 HGNC:3600 ENTREZ:2192 UNIPROT:P23142 fibulin 2 HUGO:FBLN2 HGNC:3601 ENTREZ:2199 UNIPROT:P98095 elastin HUGO:ELN HGNC:3327 ENTREZ:2006 UNIPROT:P15502 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin 1 partners*"/> <bbox w="121.0" h="22.0" x="6077.0" y="6374.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4706_emtc_emtc_sa2489" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 fibulin 1 HUGO:FBLN1 HGNC:3600 ENTREZ:2192 UNIPROT:P23142 fibulin 2 HUGO:FBLN2 HGNC:3601 ENTREZ:2199 UNIPROT:P98095 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:114518 Laminin-1: LAMA1, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Elastin partners*"/> <bbox w="107.0" h="22.0" x="5837.0" y="6395.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4707_emtc_emtc_sa2490" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: elastin HUGO:ELN HGNC:3327 ENTREZ:2006 UNIPROT:P15502 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Truncated Elastin*"/> <bbox w="115.0" h="22.0" x="5652.0" y="6273.0"/> <glyph class="unit of information" id="_bacaa562-00c9-452b-a6bc-16085b3fe938"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5684.5" y="6268.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4712_emtc_emtc_sa2493" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: a1b1*_a2b1* NAME:a1b1* ITGA1/ITGB1 integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME: a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen1 partners*"/> <bbox w="132.0" h="20.0" x="4881.0" y="6362.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4716_emtc_emtc_sa2496" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: NAME: a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 NAME:a10b1* ITGA10/ITGB1 integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen2 partners*"/> <bbox w="120.0" h="20.0" x="5136.0" y="6356.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4720_emtc_emtc_sa2499" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Fibronectin partners NAME:a5b1* ITGA5/ITGB1 integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, UNIPROT:P08648, GENECARDS:GC12M054789 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) HUGO:ITGB1, HGNC:6153, ENTREZ:3688, UNIPROT:P05556, GENECARDS:GC10M033189 NAME:aVb3* ITGAV/ITGB3 integrin, alpha V "antigen identified by monoclonal antibody L230", "integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)", MSK8, "vitronectin receptor", VNRA, VTNR HUGO:ITGAV HGNC:6150 ENTREZ:3685 UNIPROT:P06756 GENECARDS:GC02P187418 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 GENECARDS:GC17P045331 integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 NAME:a2b1* ITGA2/ITGB1 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 NAME:a10b1* ITGA10/ITGB1 integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin partners*"/> <bbox w="135.0" h="19.0" x="5370.0" y="6353.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4724_emtc_emtc_sa2502" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FERMT1 HUGO:FERMT2 HUGO:FERMT3 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Talin partners*"/> <bbox w="97.0" h="19.0" x="4939.0" y="5780.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4728_emtc_emtc_sa2505" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 13 (membrane-inserted) HUGO:MMP13, HGNC:7159, ENTREZ:4322, GENECARDS:GC11M102847, UNIPROT:P45452 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 MMP13 activates TGFB by cleavage of LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP13*"/> <bbox w="64.0" h="17.0" x="1285.0" y="6409.0"/> <glyph class="unit of information" id="_580d67a0-262d-4000-8234-845ac2572063"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1292.0" y="6404.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4729_emtc_emtc_sa2506" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 14 (membrane-inserted) HUGO:MMP14, HGNC:7160, ENTREZ:4323, UNIPROT:P50281, GENECARDS:GC14P023305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP14*"/> <bbox w="63.0" h="16.0" x="1285.0" y="6434.0"/> <glyph class="unit of information" id="_c6c38d02-6f71-4832-aab1-f1243e165313"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1291.5" y="6429.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4730_emtc_emtc_sa2507" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) HUGO:MMP2, HGNC:7166, ENTREZ:4313, GENECARDS:GC16P055478, P08253 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP2*"/> <bbox w="53.0" h="17.0" x="1285.0" y="6259.0"/> <glyph class="unit of information" id="_14a3c4ef-48ff-4bf3-b4b7-f8ad6d58872e"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1286.5" y="6254.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4731_emtc_emtc_sa2508" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 15 (membrane-inserted) "matrix metalloproteinase 15 (membrane-inserted)" HUGO:MMP15 HGNC:7161 ENTREZ:4324 UNIPROT:P51511 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP15*"/> <bbox w="64.0" h="17.0" x="1285.0" y="6463.0"/> <glyph class="unit of information" id="_eb413aec-13cf-453c-bc62-ef064f5f61e7"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1292.0" y="6458.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4732_emtc_emtc_sa2509" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 16 (membrane-inserted) C8orf57, "chromosome 8 open reading frame 57", "matrix metalloproteinase 16 (membrane-inserted)" HUGO:MMP16 HGNC:7162 ENTREZ:4325 UNIPROT:P51512 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP16*"/> <bbox w="63.0" h="17.0" x="1285.0" y="6489.0"/> <glyph class="unit of information" id="_7d40f494-721e-47c0-8a7e-3012ae13f4a0"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1291.5" y="6484.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4733_emtc_emtc_sa2510" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP3 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP3*"/> <bbox w="54.0" h="18.0" x="1285.0" y="6289.0"/> <glyph class="unit of information" id="_2833735d-25a8-46ad-b368-c395c4ac54c8"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1287.0" y="6284.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4734_emtc_emtc_sa2512" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP10 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP10*"/> <bbox w="61.0" h="19.0" x="1285.0" y="6350.0"/> <glyph class="unit of information" id="_8791c772-decf-4eb4-bc5e-76d61fb05beb"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1290.5" y="6345.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4735_emtc_emtc_sa2513" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP12 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP12*"/> <bbox w="66.0" h="18.0" x="1285.0" y="6379.0"/> <glyph class="unit of information" id="_82ceecc7-2ac0-4c16-8823-ad6509c47579"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1293.0" y="6374.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4736_emtc_emtc_sa2514" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Collagen 1* collagen, type I, alpha 1 HUGO:COL1A1 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023, UNIPROT:P08123 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Truncated Collagen1*"/> <bbox w="140.0" h="22.0" x="4729.0" y="6596.0"/> <glyph class="unit of information" id="_599e3bfc-5395-4f5d-9ec7-40b337a4045e"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4774.0" y="6591.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4737_emtc_emtc_sa2515" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type III, alpha 1 HUGO:COL3A1 HGNC:2201 ENTREZ:1281 UNIPROT:P02461 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL3A1"/> <bbox w="59.0" h="19.0" x="4919.0" y="6083.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4738_emtc_emtc_sa2516" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type III, alpha 1 HUGO:COL3A1 HGNC:2201 ENTREZ:1281 UNIPROT:P02461 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen3*"/> <bbox w="76.0" h="21.0" x="4910.0" y="6596.0"/> <glyph class="unit of information" id="_75350ba9-5168-4741-ba53-197d8431f676"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4923.0" y="6591.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4739_emtc_emtc_sa2517" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type II, alpha 1 "collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital)", SEDC HUGO:COL2A1 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Collagen2*"/> <bbox w="76.0" h="21.0" x="5015.0" y="6596.0"/> <glyph class="unit of information" id="_d92bf91e-2bea-4ea1-8f9e-217bc4efda0b"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5028.0" y="6591.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4741_emtc_emtc_sa2518" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 1 "tissue inhibitor of metalloproteinase 1" HUGO:TIMP1 HGNC:11820 ENTREZ:7076 UNIPROT:P01033 TIMP metallopeptidase inhibitor 2 "tissue inhibitor of metalloproteinase 2" HUGO:TIMP2 HGNC:11821 ENTREZ:7077 UNIPROT:P16035 TIMP metallopeptidase inhibitor 3 SFD, "tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory)" HUGO:TIMP3 HGNC:11822 ENTREZ:7078 UNIPROT:P35625 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP family*"/> <bbox w="87.0" h="20.0" x="1308.0" y="6178.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4747_emtc_emtc_sa2523" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Laminin 5* laminin, alpha 3 "laminin, alpha 3 (nicein (150kD), kalinin (165kD), BM600 (150kD), epilegrin)", LAMNA HUGO:LAMA3 HGNC:6483 ENTREZ:3909 UNIPROT:Q16787 laminin, beta 3 "laminin, beta 3 (nicein (125kD), kalinin (140kD), BM600 (125kD))", LAMNB1 HUGO:LAMB3 HGNC:6490 ENTREZ:3914 UNIPROT:Q13751 laminin, gamma 2 EBR2, EBR2A, LAMB2T, "laminin, gamma 2 (nicein (100kD), kalinin (105kD), BM600 (100kD), Herlitz junctional epidermolysis bullosa))", LAMNB2 HUGO:LAMC2 HGNC:6493 ENTREZ:3918 UNIPROT:Q13753 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID: Laminin-5: LAMA3, LAMB3, LAMC2 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Truncated Laminin5*"/> <bbox w="134.0" h="21.0" x="5878.0" y="6269.0"/> <glyph class="unit of information" id="_af0ab2f7-4c2d-48af-a888-9b0641723666"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5920.0" y="6264.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4748_emtc_emtc_sa2524" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Collagen 4* collagen, type IV, alpha 1 HUGO:COL4A1 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 collagen, type IV, alpha 2 HUGO:COL4A2 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 collagen, type IV, alpha 3 (Goodpasture antigen) HUGO:COL4A3 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 collagen, type IV, alpha 4 HUGO:COL4A4 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 collagen, type IV, alpha 5 "Alport syndrome", ASLN, ATS HUGO:COL4A5 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 collagen, type IV, alpha 6 HUGO:COL4A6 HGNC:2208 ENTREZ:1288 UNIPROT:Q14031 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Truncated Collagen4*"/> <bbox w="134.0" h="20.0" x="5162.0" y="6154.0"/> <glyph class="unit of information" id="_2eb625ae-9bf6-473e-a0d2-641ec66d6b26"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5204.0" y="6149.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4749_emtc_emtc_sa2525" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, UNIPROT:P02751, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:2409071 Fibronectin is located on the apical and basal cell surfaces. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Truncated Fibronectin*"/> <bbox w="142.0" h="21.0" x="5190.0" y="6597.0"/> <glyph class="unit of information" id="_be51dad8-e854-49a6-9551-07fa941aefb0"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="5236.0" y="6592.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4751_emtc_emtc_sa2526" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: IGF family* insulin-like growth factor 1 (somatomedin C) HUGO:IGF1 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 insulin-like growth factor 2 (somatomedin A) HUGO:IGF2 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF family*"/> <bbox w="70.0" h="19.0" x="1862.0" y="6509.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4752_emtc_emtc_sa2527" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: insulin-like growth factor 2 (somatomedin A) HUGO:IGF2 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF2"/> <bbox w="36.0" h="19.0" x="1917.0" y="6619.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4753_emtc_emtc_sa2528" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: IGF binding partners* insulin-like growth factor binding protein 1 HUGO:IGFBP1 HGNC:5469 ENTREZ:3484 UNIPROT:P08833 insulin-like growth factor binding protein 2 HUGO:IGFBP2 HGNC:5471 ENTREZ:3485 UNIPROT:P18065 insulin-like growth factor binding protein 3 HUGO:IGFBP3 HGNC:5472 ENTREZ:3486 UNIPROT:P17936 insulin-like growth factor binding protein 4 HUGO:IGFBP4 HGNC:5473 ENTREZ:3487 UNIPROT:P22692 insulin-like growth factor binding protein 5 HUGO:IGFBP5 HGNC:5474 ENTREZ:3488 UNIPROT:P24593 insulin-like growth factor binding protein 6 HUGO:IGFBP6 HGNC:5475 ENTREZ:3489 UNIPROT:P24592 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IGF binding partners*"/> <bbox w="144.0" h="19.0" x="2006.0" y="6509.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4771_emtc_emtc_sa2537" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: insulin receptor substrate 1 HUGO:IRS1 HGNC:6125 ENTREZ:3667 UNIPROT:P35568 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Upon IGF stimulation, the activated IGF1R recruits and directly phosphorylates IRS1, leading to both PI3K and (GRB2/SOS/HRas) pathways activation PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IRS1"/> <bbox w="69.0" h="21.0" x="1956.0" y="5825.5"/> <glyph class="state variable" id="_ce94310b-e8e7-45cb-aefb-c6fab8110c47"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="2017.5" y="5831.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4773_emtc_emtc_sa2538" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: insulin receptor substrate 1 HUGO:IRS1 HGNC:6125 ENTREZ:3667 UNIPROT:P35568 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: Upon IGF stimulation, the activated IGF1R recruits and directly phosphorylates IRS1, leading to both PI3K and (GRB2/SOS/HRas) pathways activation PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IRS1"/> <bbox w="69.0" h="21.0" x="2088.25" y="5827.5"/> <glyph class="state variable" id="_4f23195f-d223-4bc9-b505-a407f2e4606b"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="2147.25" y="5833.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4778_emtc_emtc_sa2542" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2-associated agonist of cell death HUGO:BAD, HGNC:936, ENTREZ:572, UNIPROT:Q92934, GENECARDS:GC11M064037 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAD"/> <bbox w="38.0" h="20.0" x="4938.5" y="1265.5"/> <glyph class="state variable" id="_577d9aa7-4c9c-4f30-b64b-a2b962103acc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4952.895" y="1260.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4780_emtc_emtc_sa2543" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2-associated agonist of cell death HUGO:BAD, HGNC:936, ENTREZ:572, UNIPROT:Q92934, GENECARDS:GC11M064037 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAD"/> <bbox w="38.0" h="20.0" x="4938.5" y="1132.5"/> <glyph class="state variable" id="_7cdbe716-7100-4d4b-a8b1-3cf6b2403c08"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4950.395" y="1127.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4781_emtc_emtc_sa2544" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BAD_binding partner* B-cell CLL/lymphoma 2 HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763 BCL2-like 1 HUGO:BCL2L1, HGNC:992, ENTREZ:598, UNIPROT:Q07817, GENECARDS:GC20M030252 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:23064052 BCL2 and BCL2L1 are known to be overexpressed in several cancers. PMID:12175651 PMID:10826997 PMID:12767520 PMID:19030972 PMID:16931767 PMID:21540285 PMID:12444011 IGFfamily exhibits anti-apoptotic activity. Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAD_binding partners*"/> <bbox w="142.0" h="20.0" x="4434.0" y="1204.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4785_emtc_emtc_sa2547" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: 14-3-3* tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide HUGO:YWHAQ HGNC:12854 ENTREZ:10971 UNIPROT:P27348 GENECARDS:YWHAQ REACTOME:48915 KEGG:10971 ATLASONC:GC_YWHAQ WIKI:YWHAQ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide HUGO:YWHAZ HGNC:12855 ENTREZ:7534 UNIPROT:P63104 GENECARDS:YWHAZ REACTOME:48917 KEGG:7534 ATLASONC:GC_YWHAZ WIKI:YWHAZ tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide HUGO:YWHAE HGNC:12851 ENTREZ:7531 UNIPROT:P62258 GENECARDS:YWHAE REACTOME:48891 KEGG:7531 ATLASONC:GC_YWHAE WIKI:YWHAE tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide HUGO:YWHAB HGNC:12849 ENTREZ:7529 UNIPROT:P31946 GENECARDS:YWHAB REACTOME:48889 KEGG:7529 ATLASONC:GC_YWHAB WIKI:YWHAB stratifin HUGO:SFN HGNC:10773 ENTREZ:2810 UNIPROT:P31947 GENECARDS:SFN REACTOME:48913 KEGG:2810 ATLASONC:GC_SFN WIKI:SFN tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma polypeptide HUGO:YWHAG HGNC:12852 ENTREZ:7532 UNIPROT:P61981 GENECARDS:YWHAG REACTOME:48907 KEGG:7532 ATLASONC:GC_YWHAG WIKI:YWHAG tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide HUGO:YWHAH HGNC:12853 ENTREZ:7533 UNIPROT:Q04917 GENECARDS:YWHAH REACTOME:48905 KEGG:7533 ATLASONC:GC_YWHAH WIKI:YWHAH Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: YWHAB is so-called 14-3-3 alpha/beta PMID:9069260 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="14-3-3*"/> <bbox w="105.0" h="17.0" x="5315.0" y="1053.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4794_emtc_emtc_sa2554" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box O3 HUGO:FOXO3, HGNC:3821, ENTREZ:2309, GENECARDS:GC06P108881, UNIPROT:O43524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19564415 The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression. This explains the role of FOXO3 in promoting tumor invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXO3"/> <bbox w="45.0" h="19.0" x="5168.5" y="1290.5"/> <glyph class="state variable" id="_d3161d48-ef58-40dc-be22-d99b0e325000"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5163.5" y="1285.572"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4796_emtc_emtc_sa2555" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box O3 HUGO:FOXO3, HGNC:3821, ENTREZ:2309, GENECARDS:GC06P108881, UNIPROT:O43524 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19564415 The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression. This explains the role of FOXO3 in promoting tumor invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXO3"/> <bbox w="45.0" h="19.0" x="3075.5" y="2024.5"/> <glyph class="state variable" id="_d890e702-85a4-40f8-b27d-531b923cd454"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3068.0" y="2019.572"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4797_emtc_emtc_sa2556" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 5 MEKK5 HUGO:MAP3K5 HGNC:6857 ENTREZ:4217 UNIPROT:Q99683 GENECARDS:MAP3K5 KEGG:4217 ATLASONC:GC_MAP3K5 WIKI:MAP3K5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11274345 PMID:12655147 ASK1 is a MAP3K and can activate both JNK and P38 pathways. TNF-dependent production of ROS triggers the dissociation of Trx from ASK1 and the consequently liberalised ASK1 binds to TRAF2. Finally TRAF2 appears to activate ASK1 (by phosphorylation) by enhancing and stabilising the oligomerisation of ASK1. PMID:12556535 IGF1R signaling suppresses the ASK1-mediated stimulation of JNK/p38 thus supresses the induction of apoptosis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K5"/> <bbox w="67.0" h="21.0" x="1830.0" y="5747.5"/> <glyph class="state variable" id="_d8b18fc7-1a1a-439d-8599-05d744ce7f31"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1825.0" y="5752.9834"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4800_emtc_emtc_sa2558" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase kinase kinase 5 MEKK5 HUGO:MAP3K5 HGNC:6857 ENTREZ:4217 UNIPROT:Q99683 GENECARDS:MAP3K5 KEGG:4217 ATLASONC:GC_MAP3K5 WIKI:MAP3K5 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11274345 PMID:12655147 ASK1 is a MAP3K and can activate both JNK and P38 pathways. TNF-dependent production of ROS triggers the dissociation of Trx from ASK1 and the consequently liberalised ASK1 binds to TRAF2. Finally TRAF2 appears to activate ASK1 (by phosphorylation) by enhancing and stabilising the oligomerisation of ASK1. PMID:12556535 IGF1R signaling suppresses the ASK1-mediated stimulation of JNK/p38 thus supresses the induction of apoptosis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MAP3K5"/> <bbox w="67.0" h="21.0" x="1994.5" y="5747.5"/> <glyph class="state variable" id="_e9684d06-311e-4aa7-a7ae-fb544396a96a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1987.0" y="5752.9834"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4801_emtc_emtc_sa2564" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine phosphatase type IVA, member 3 HUGO:PTP4A3 HGNC:9636 ENTREZ:11156 UNIPROT:O75365 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:24376839 PTP4A3 is implicated in cell adhesion and the regulation of focal adhesion components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. http://d-scholarship.pitt.edu/18634/1/Zimmerman_ETD-2013.pdf c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3. Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTP4A3"/> <bbox w="54.0" h="18.0" x="2071.5" y="4601.5"/> <glyph class="state variable" id="_7d9b888d-732e-4667-b2b9-6dac909f9072"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2092.9814" y="4596.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4807_emtc_emtc_sa2559" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine phosphatase type IVA, member 3 HUGO:PTP4A3 HGNC:9636 ENTREZ:11156 UNIPROT:O75365 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:24376839 PTP4A3 is implicated in cell adhesion and the regulation of focal adhesion components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. http://d-scholarship.pitt.edu/18634/1/Zimmerman_ETD-2013.pdf c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3. Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTP4A3"/> <bbox w="54.0" h="18.0" x="1901.0" y="4802.5"/> <glyph class="state variable" id="_897f5ed7-b2cb-4696-9700-dc4bb06e6f9a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1919.9814" y="4797.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4812_emtc_emtc_sa2566" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="115.0" h="20.0" x="1023.5" y="1147.0"/> <glyph class="state variable" id="_573f8c23-84bf-421c-8cf6-c6b5d00b86e7"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="1013.5" y="1142.8398"/> </glyph> <glyph class="state variable" id="_5a5106db-83f3-4a29-b3ed-d4feccdbc5e1"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1131.0" y="1143.2294"/> </glyph> <glyph class="state variable" id="_9db41f7a-0896-49c7-b01b-0423bcec8079"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1130.1113" y="1162.0"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4815_emtc_emtc_sa2568" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hepatocyte growth factor (hepapoietin A; scatter factor) HUGO:HGF HGNC:4893 ENTREZ:3082 UNIPROT:P14210 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HGF"/> <bbox w="38.0" h="17.0" x="972.5" y="117.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4819_emtc_emtc_sa1139" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: c-src tyrosine kinase HUGO:CSK HGNC:2444 ENTREZ:1445 UNIPROT:P41240 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:18829532 PMID:9819392 PTK6 and CSK both can phosphorylate ARHGAP35 (p190) at Y1105 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-SRC*"/> <bbox w="57.0" h="22.0" x="1978.0" y="3158.5"/> <glyph class="state variable" id="_ebfbea0e-01ac-4715-9eb6-c1b5b203a5bb"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="2025.0" y="3154.456"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4820_emtc_emtc_sa2573" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: EPH receptor A1 "EphA1", EPHT, EPHT1 HUGO:EPHA1 HGNC:3385 ENTREZ:2041 UNIPROT:P21709 EPH receptor A2 "EphA2" HUGO:EPHA2 HGNC:3386 ENTREZ:1969 UNIPROT:P29317 EPH receptor B1 "EphB1" HUGO:EPHB1 HGNC:3392 ENTREZ:2047 UNIPROT:P54762 EPH receptor B2 "EphB2" HUGO:EPHB2 HGNC:3393 ENTREZ:2048 UNIPROT:P29323 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20179713 There are 9 EPHA receptors which bind to 5 Ephrin-A ligands and 5 EPHB receptors which bind to 3 transmembrane Ephrin-B ligands. E-cadherin promotes EPHA2– ephrin-A1 localization at epithelial cell junctions EPHA2 is upregulated in many cancers and its expression has been linked to increased malignancy and a poor clinical prognosis. EPHA2 seems to be preferentially expressed in malignant breast and prostate cancers with a basal phenotype. EPHA1 is downregulated in advanced human skin and colorectal cancers, EphB receptors are downregulated in advanced colorectal cancer and ephrin-A5 is downregulated in glioblastomas TNF-alpha, VEGFA and HIF2A upregulate ephrin-A1 in cultured endothelial cells. Endothelial ephrin-B2 is upregulated by VEGF through the Notch pathway. PMID:19074825 Eph receptors comprise the largest family of tyrosine kinase receptors, with 16 known members across many species, 14 of which are found in mammals. Ephs are divided into two distinct A and B classes based on sequence homology of the extracellular domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EPH family*"/> <bbox w="80.0" h="50.0" x="576.5" y="667.5"/> <glyph class="unit of information" id="_4edfdb8c-4707-4bc3-aa2d-f4a5a398ca6f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="594.0" y="662.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4821_emtc_emtc_sa2575" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ephrin-A1 EPLG1, TNFAIP4 HUGO:EFNA1 HGNC:3221 ENTREZ:1942 UNIPROT:P20827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:19074825 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Epherin-A1*"/> <bbox w="79.0" h="16.0" x="2409.5" y="130.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4822_emtc_emtc_sa2576" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ephrin-B1 EPLG2 HUGO:EFNB1 HGNC:3226 ENTREZ:1947 UNIPROT:P98172 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Ephrin-B1*"/> <bbox w="83.0" h="16.0" x="2593.5" y="132.5"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4823_emtc_emtc_sa2577" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: EPH receptor B2 "EphB2" HUGO:EPHB2 HGNC:3393 ENTREZ:2048 UNIPROT:P29323 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20179713 E-cadherin promotes EPHA2– ephrin-A1 localization at epithelial cell junctions EPHA2 is upregulated in many cancers and its expression has been linked to increased malignancy and a poor clinical prognosis. EPHA2 seems to be preferentially expressed in malignant breast and prostate cancers with a basal phenotype. EPHA1 is downregulated in advanced human skin and colorectal cancers, EphB receptors are downregulated in advanced colorectal cancer and ephrin-A5 is downregulated in glioblastomas TNF-alpha, VEGFA and HIF2A upregulate ephrin-A1 in cultured endothelial cells. Endothelial ephrin-B2 is upregulated by VEGF through the Notch pathway. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EPHB2"/> <bbox w="80.0" h="50.0" x="2507.5" y="157.5"/> <glyph class="state variable" id="_f7b52fe9-a6b3-4bc9-a93e-0fcd060bbef0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2582.5" y="173.46552"/> </glyph> <glyph class="unit of information" id="_5ad33ff6-26e4-4440-88d9-0be35b1f5cfe"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2525.0" y="152.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2224_sa1975" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:25234227 Nm23-h1(NME1) binds to gelsolin and inactivates its actin-severing capacity to promote tumor cell motility and metastasis. Dynamin 2 act on the actin cytoskeleton by Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) NPDK-A and dynamin associate during cytokinesis to promote chromosome stability. Loss of NDPK-A is linked to cytokinesis failure and tetraploidy PMID:18470881 Nm23-H1 binds Dbl-1(MCF2) and thus interferes with the ability of Dbl-1 to load GTP onto CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NME1"/> <bbox w="80.0" h="40.0" x="2031.0" y="522.0"/> </glyph> <glyph class="macromolecule" id="s2225_sa1976" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NME2"/> <bbox w="80.0" h="40.0" x="2030.0" y="455.0"/> </glyph> <glyph class="macromolecule" id="s2227_sa1978" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:12447393 Activation of (activated) ARF6 is required for dynamin-dependent endocytosis of E-cadherin. Nm23-H1 binds ARF6-GTP and mediates dynamin-dependent vesicle fission. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARF6"/> <clone/> <bbox w="80.0" h="40.0" x="1300.0" y="525.0"/> </glyph> <glyph class="macromolecule" id="s2227_sa1991" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:12447393 Activation of (activated) ARF6 is required for dynamin-dependent endocytosis of E-cadherin. Nm23-H1 binds ARF6-GTP and mediates dynamin-dependent vesicle fission. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ARF6"/> <clone/> <bbox w="80.0" h="40.0" x="1300.0" y="315.0"/> </glyph> <glyph class="macromolecule" id="s2235_sa1986" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:25234227 Nm23-h1(NME1) binds to gelsolin(GSN) and inactivates its actin-severing capacity to promote tumor cell motility (=migration) and metastasis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSN"/> <clone/> <bbox w="80.0" h="40.0" x="1884.0" y="529.0"/> </glyph> <glyph class="macromolecule" id="s2235_sa1992" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:CYTOSKELETON_POLARITY MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:25234227 Nm23-h1(NME1) binds to gelsolin(GSN) and inactivates its actin-severing capacity to promote tumor cell motility (=migration) and metastasis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSN"/> <clone/> <bbox w="80.0" h="40.0" x="1886.0" y="338.0"/> </glyph> <glyph class="macromolecule" id="s2291_sa2012" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. 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This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="20.0" x="959.0" y="1487.0"/> <glyph class="state variable" id="_06f20829-ae05-464e-8103-79a23d392ee3"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="951.5" y="1482.8398"/> </glyph> <glyph class="state variable" id="_0910790f-2583-4b1c-9516-234859ebf7dc"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1031.5" y="1483.2294"/> </glyph> <glyph class="state variable" id="_0957583f-ec79-42fc-b8b0-7990c571a98f"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1030.8818" y="1502.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2306_sa2027" compartmentRef="emtc_emtc_c21_emtc_emtc_ca21"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), delta 1 HUGO:CTNND1 HGNC:2515 ENTREZ:1500 UNIPROT:O60716 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p120*"/> <bbox w="52.0" h="16.0" x="843.0" y="1379.0"/> </glyph> <glyph class="macromolecule" id="s2304_sa2025" compartmentRef="emtc_emtc_c21_emtc_emtc_ca21"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), alpha 1, 102kDa HUGO:CTNNA1 HGNC:2509 ENTREZ:1495 UNIPROT:P35221 Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="α-Catenin*"/> <bbox w="69.0" h="18.0" x="914.5" y="1378.0"/> </glyph> <glyph class="macromolecule" id="s2305_sa2026" compartmentRef="emtc_emtc_c21_emtc_emtc_ca21"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: catenin (cadherin-associated protein), beta 1, 88kDa HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, UNIPROT:P35222, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has been shown that the GSK-3 dependent phosphorylation of b-catenin requires prior priming through phosphorylation of Ser45 GSK-3b was found to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and APC. There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I, alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="66.0" h="28.0" x="1016.0" y="1373.0"/> <glyph class="state variable" id="_d1e6c4f0-1f99-4819-a342-a9dcf2b5bba5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1011.0" y="1369.6815"/> </glyph> <glyph class="state variable" id="_d77bf29b-49fd-48e0-8362-ec18a8ddf312"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1044.0262" y="1368.0"/> </glyph> <glyph class="state variable" id="_fd78c8f6-2d1c-4df0-a88d-20c32df36e6f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1077.0" y="1368.0"/> </glyph> <glyph class="state variable" id="_8cdfa26c-7db1-4ff5-a9d9-35a2f90d1e12"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1057.211" y="1368.0"/> </glyph> <glyph class="state variable" id="_feafc20f-9e2f-458d-8907-7373fe4be7ab"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1030.0787" y="1368.0"/> </glyph> <glyph class="state variable" id="_1289890d-37a7-42d4-952d-b36961ccc54e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1077.0" y="1394.358"/> </glyph> </glyph> <glyph class="macromolecule" id="s2309_sa2030" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="115.0" h="20.0" x="909.5" y="416.0"/> <glyph class="state variable" id="_11a3f18c-c2f3-4396-aef1-369c441d84e7"> <state value="P" variable="Y"/> <bbox w="20.0" h="10.0" x="899.5" y="411.83984"/> </glyph> <glyph class="state variable" id="_4898f273-12b5-4bb2-927e-29cf0ed193c2"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1017.0" y="412.2293"/> </glyph> <glyph class="state variable" id="_2242cffe-e705-42e0-9064-7806b9fd3b06"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="1016.1113" y="431.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2310_sa2031" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="20.0" x="924.0" y="834.0"/> <glyph class="state variable" id="_addfafd5-b261-440d-88dd-02cb104edbcd"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="916.5" y="829.83984"/> </glyph> <glyph class="state variable" id="_f861072a-d612-486c-8460-21a36496e16c"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="996.5" y="830.2293"/> </glyph> <glyph class="state variable" id="_83470199-2045-4cb7-93d0-9d5ea4e219ea"> <state value="" variable="S"/> <bbox w="15.0" h="10.0" x="995.8818" y="849.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2313_sa2034" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:EMT_REGULATORS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:15263019 Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IQGAP1"/> <bbox w="80.0" h="40.0" x="1858.0" y="1643.0"/> </glyph> <glyph class="macromolecule" id="s2327_sa2041" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR family*"/> <bbox w="90.0" h="55.0" x="671.0" y="1122.0"/> <glyph class="state variable" id="_b3c73de3-4ed0-4832-a826-7493f930cb0d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="710.13574" y="1117.0"/> </glyph> <glyph class="unit of information" id="_3f614cab-b76e-4b91-82e7-3415ad5bf050"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="693.5" y="1117.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2328_sa2042" compartmentRef="emtc_emtc_c24_emtc_emtc_ca24"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:22674073 E-cadherin does not travel directly from the Golgi complex to the cell surface, but transits first through Rab11-positive recycling endosomes. Rab11 is involved in E-cadherin localization to the surface of the cell . In addition to acting as way stations for newly synthesized cadherin on its way to the plasma membrane, Rab11-positive recycling endosomes can also sort internalized cadherin for recycling back to the cell surface. Desclozeaux and colleagues also found that cadherin recycling is necessary for maintaining adherens junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Rab11"/> <bbox w="70.0" h="40.0" x="1636.0" y="1172.0"/> </glyph> <glyph class="macromolecule" id="s2332_sa2046" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TAB1"/> <bbox w="50.0" h="20.0" x="5507.0" y="2439.0"/> </glyph> <glyph class="macromolecule" id="s2357_sa2055" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transcription factor 4 HUGO:TCF4, HGNC:11634, ENTREZ:6925, UNIPROT:P15884, GENECARDS:GC18M052889 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TCF4"/> <bbox w="40.0" h="20.0" x="2182.0" y="3509.0"/> <glyph class="state variable" id="_5b94262c-7bd8-413b-8374-7e18fe6473c9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2174.5" y="3514.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2356_sa2053" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NLK"/> <clone/> <bbox w="60.0" h="20.0" x="4532.0" y="2609.0"/> </glyph> <glyph class="macromolecule" id="s2356_sa2060" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="NLK"/> <clone/> <bbox w="60.0" h="20.0" x="4672.0" y="2609.0"/> </glyph> <glyph class="macromolecule" id="s2358_sa2057" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIPK2"/> <clone/> <bbox w="50.0" h="20.0" x="4537.0" y="2699.0"/> </glyph> <glyph class="macromolecule" id="s2358_sa2058" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIPK2"/> <clone/> <bbox w="50.0" h="20.0" x="4687.0" y="2699.0"/> </glyph> <glyph class="macromolecule" id="s2366_sa2064" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. PMID:22439866 c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. PMID:7706314 Members of the nuclear factor kappa B family transactivate the murine c-myb gene. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYB"/> <bbox w="70.0" h="30.0" x="4897.0" y="2624.0"/> </glyph> <glyph class="macromolecule" id="s2370_sa2068" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22439866 Several components of ECM, such as fibronectin, proteoglycans, and collagens, are substrates for CTSD(cathepsin D) References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTSD"/> <bbox w="50.0" h="30.0" x="4877.0" y="3434.0"/> </glyph> <glyph class="macromolecule" id="s2375_sa2073" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:18209571 Roles of MAPK and NF-_kappa_B in interleukin-6 induction by lipopolysaccharide in vascular smooth muscle cells. PMID:18555778 In response to oncogenic stress, both IL6 and IL8 genes were activatedbythe transcription factorC/EBPb,upon its recruitment to either promoter.PMID:18555778 PMID:18555777 There is a positive feedback loop between IL6 and CEBP that help maintain the senescence state References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="IL6"/> <bbox w="40.0" h="20.0" x="3931.0" y="104.0"/> </glyph> <glyph class="macromolecule" id="s2377_sa2075" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:19215923 The activity of MCP-1 is up-regulated through NF-_kappa_B_ References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MCP1*"/> <bbox w="50.0" h="20.0" x="4080.0" y="103.0"/> </glyph> <glyph class="macromolecule" id="s2378_sa2076" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:16940415 PMID:9759866 TCDD regulates Fas and FasL promoters through DRE and/or NF-kappaB motifs via AhR. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FAS"/> <bbox w="80.0" h="50.0" x="3093.0" y="156.0"/> <glyph class="unit of information" id="_f492b8ee-6394-432b-b3b1-ca3dee5ac78f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3110.5" y="151.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2379_sa2077" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:17435549 Bile salts induce resistance to apoptosis through NF-kappaB-mediated XIAP expression. PMID:22733138 XIAP (X-linked IAP, BIRC4) is a critical barrier to apoptosis induction in cancer cells because of its robust affinity to bind and inhibit initiator caspase-9 and effector caspases -3 and -7 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="XIAP"/> <bbox w="50.0" h="20.0" x="3583.0" y="932.0"/> </glyph> <glyph class="macromolecule" id="s2380_sa2078" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BCL2L11 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:18281283 production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIM*"/> <bbox w="40.0" h="30.0" x="4240.0" y="1336.0"/> </glyph> <glyph class="macromolecule" id="s2385_sa2083" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:18555777 CXCR2 (IL8RB), binds IL8 and induces a self-amplifying secretory network in which CXCR2-binding chemokines reinforce senescence_induced growth arrest PMID:17533374 HIF-1 and NF-kappaB upregulates CXCR1 and CXCR2 expression PMID:23869868 Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CXCR2"/> <bbox w="80.0" h="50.0" x="3316.0" y="154.0"/> <glyph class="unit of information" id="_f474b4c8-bd23-4d96-aff5-8999648d47cb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3333.5" y="149.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2387_sa2085" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:RB1 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="pRB*"/> <bbox w="80.0" h="40.0" x="2606.0" y="1562.0"/> <glyph class="state variable" id="_d1dd40e4-7fb8-478d-acfa-30e40d118476"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2657.0134" y="1557.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2391_sa2089" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP7"/> <bbox w="50.0" h="23.0" x="2071.0" y="4912.0"/> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s18_emtc_emtc_sa19" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, GENECARDS:GC20P048599 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI1"/> <bbox w="60.0" h="20.0" x="3287.5" y="3694.0"/> <glyph class="unit of information" id="_d118444a-8679-4104-912a-cd032c897a75"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3307.5" y="3689.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s19_emtc_emtc_sa20" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: snail homolog 2 HUGO:SNAI2, HGNC:11094, ENTREZ:6591, GENECARDS:GC08M049830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SNAI2"/> <bbox w="60.0" h="20.0" x="3287.5" y="4044.0"/> <glyph class="unit of information" id="_33e91b6a-fb34-407a-8f7e-bae7110a2652"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3307.5" y="4039.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s21_emtc_emtc_sa22" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 ZEB1 inhibits MIR200 PMID:21224848 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1"/> <bbox w="60.0" h="20.0" x="3639.0" y="3872.5"/> <glyph class="unit of information" id="_66f1495d-e78c-4d0b-a9fa-dfaad32c7c89"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3659.0" y="3867.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s22_emtc_emtc_sa23" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19839049 Feedback loops PMID:225147423 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB2"/> <bbox w="60.0" h="20.0" x="2981.5" y="4024.0"/> <glyph class="unit of information" id="_ed356200-8272-4260-b8ab-cba1836adb06"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3001.5" y="4019.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s23_emtc_emtc_sa24" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: itwist homolog 1 (Drosophila) HUGO:TWIST1 HGNC:12428, ENTREZ:7291, GENECARDS:GC07M019121 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TWIST1"/> <bbox w="60.0" h="20.0" x="3054.5" y="3765.5"/> <glyph class="unit of information" id="_98b651d9-0e76-4f8e-9ba5-3b3d11795094"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3074.5" y="3760.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s24_emtc_emtc_sa25" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: itwist homolog 2 (Drosophila) HUGO:TWIST2, HGNC:20670, ENTREZ:117581, GENECARDS:GC02P239757 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TWIST2"/> <bbox w="60.0" h="20.0" x="3639.0" y="3772.5"/> <glyph class="unit of information" id="_281e8226-d1a9-45a3-ab22-feb3eaf011f5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3659.0" y="3767.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s65_emtc_emtc_sa62" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 1 (interstitial collagenase) HUGO:MMP1, HGNC:7155, ENTREZ:4312, GENECARDS:GC11M102660 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP1"/> <bbox w="60.0" h="20.0" x="2215.5" y="4800.562"/> <glyph class="unit of information" id="_d380344f-113b-47b9-b585-c0fdaf008188"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2235.5" y="4795.562"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s66_emtc_emtc_sa63" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:22349261 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA, HGNC:12680, ENTREZ:7422, GENECARDS:GC06P043737 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:11166270 VEGF stands for the vascular Endothelial Growth Factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults PMID:13678960 VEGFs belong to a family of homodimeric glycoproteins that containts five members (VEGF-A, B, C, D, and Placenta growth factor PLGF). VEGFs bind to 3 different VEGF-receptor tyrosine kinases (VEGFR-1, 2, 3). Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular functions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFA"/> <bbox w="60.0" h="20.0" x="4679.0" y="5030.125"/> <glyph class="unit of information" id="_ad542b39-f719-4de6-8f24-6a4a38aeb924"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4699.0" y="5025.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s69_emtc_emtc_sa66" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) HUGO:TCF3, HGNC:11633, ENTREZ:6929, GENECARDS:GC19M001609 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TCF3"/> <bbox w="60.0" h="20.0" x="3647.0" y="4266.5"/> <glyph class="unit of information" id="_8dcd9a83-bbf6-42a0-b9f1-fca55492df49"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3667.0" y="4261.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s72_emtc_emtc_sa69" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: Feedback loops References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="100.0" h="20.0" x="2191.0" y="3349.5"/> <glyph class="unit of information" id="_4d5f699a-066b-49b8-a09b-df93e2d9540d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2231.0" y="3344.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s74_emtc_emtc_sa71" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: crumbs homolog 3 (Drosophila) HUGO:CRB3, HGNC:20237, ENTREZ:92359, GENECARDS:GC19P006414 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CRB3"/> <bbox w="60.0" h="20.0" x="4677.0" y="2865.5"/> <glyph class="unit of information" id="_3fcc97b1-1e1e-4792-b931-4e5384f40a35"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4697.0" y="2860.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s78_emtc_emtc_sa75" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 PATJ* is target of and thus repressed by ZEB1 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: InaD-like (Drosophila) HUGO:INADL, HGNC:28881, ENTREZ:10207, GENECARDS:GC01P062208 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17486063 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PATJ*"/> <bbox w="60.0" h="20.0" x="4675.0" y="2795.25"/> <glyph class="unit of information" id="_ce9fb716-4432-4e28-8958-3b7e226c85d2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4695.0" y="2790.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s81_emtc_emtc_sa78" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="80.0" h="20.0" x="2190.5" y="2534.5"/> <glyph class="unit of information" id="_02aff3c5-a7e0-4713-bfd3-b0a10c29f7bd"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2220.5" y="2529.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s84_emtc_emtc_sa81" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 7 HUGO:CLDN7, HGNC:2049, ENTREZ:1366, GENECARDS:GC17M007163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin7*"/> <bbox w="80.0" h="20.0" x="2191.0" y="3114.582"/> <glyph class="unit of information" id="_71da8678-9478-40d7-92f3-e22501d7d5ab"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2221.0" y="3109.582"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s87_emtc_emtc_sa84" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: F11 receptor HUGO:F11R, HGNC:14685, ENTREZ:50848, GENECARDS:GC01M160965 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JAM1*"/> <bbox w="60.0" h="20.0" x="2203.5" y="2421.9"/> <glyph class="unit of information" id="_b18baf5a-8469-4a5a-a3d3-edc2406720e6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2223.5" y="2416.9"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s90_emtc_emtc_sa87" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 3 HUGO:TJP3, HGNC:11829, ENTREZ:27134, GENECARDS:GC19P003659 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO3*"/> <bbox w="60.0" h="20.0" x="2186.5" y="2638.36"/> <glyph class="unit of information" id="_32d4e237-1ab9-4990-bfbc-0a7eddbb3334"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2206.5" y="2633.36"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s94_emtc_emtc_sa90" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 2, 26kDa HUGO:GJB2, HGNC:4284, ENTREZ:2706, GENECARDS:GC13M020761 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB2"/> <bbox w="56.0" h="21.0" x="2211.0" y="4482.5"/> <glyph class="unit of information" id="_57ee8925-7cf6-4aef-b376-8e6a0ec3f237"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2229.0" y="4477.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s97_emtc_emtc_sa93" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: gap junction protein, beta 3, 31kDa HUGO:GJB3, HGNC:4285, ENTREZ:2707, GENECARDS:GC01P035246 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GJB3"/> <bbox w="51.0" h="20.0" x="2211.0" y="4510.5"/> <glyph class="unit of information" id="_03d58955-300d-4954-a327-48569555a88b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2226.5" y="4505.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s100_emtc_emtc_sa96" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 4 HUGO:CLDN4, HGNC:2046, ENTREZ:1364, GENECARDS:GC07P073213 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin4*"/> <bbox w="80.0" h="20.0" x="2193.5" y="3029.512"/> <glyph class="unit of information" id="_73d167ff-7ce3-427c-96f8-4af4d79c6a22"> <label text="RNA"/> <bbox w="20.0" h="10.0" 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id="_082ec7f6-fcce-42f5-b703-b6638e734a36"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2261.0" y="4452.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s106_emtc_emtc_sa102" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: plakophilin 3 HUGO:PKP3, HGNC:9025, ENTREZ:11187, GENECARDS:GC11P000394 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:DESMOSOMES Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakophilin3*"/> <bbox w="120.0" h="20.0" x="2211.0" y="4419.5"/> <glyph class="unit of information" id="_eb1ca961-d8f1-4680-8649-af9adfd874bd"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2261.0" y="4414.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s109_emtc_emtc_sa105" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 2, type 1, N-cadherin (neuronal) HUGO:CDH2, HGNC:1759, ENTREZ:1000, GENECARDS:GC18M025465 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="N-Cadherin*"/> <bbox w="100.0" h="20.0" x="2234.5" y="3842.5"/> <glyph class="unit of information" id="_eb07b81e-7225-4951-99e2-78a52817e4e3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2274.5" y="3837.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s112_emtc_emtc_sa108" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 3, type 1, P-cadherin (placental) HUGO:CDH3, HGNC:1762, ENTREZ:1001, GENECARDS:GC16P068679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="P-Cadherin*"/> <bbox w="100.0" h="20.0" x="2234.5" y="3922.5"/> <glyph class="unit of information" id="_4629d53e-d397-4cf0-8f4b-72ee4b15e903"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2274.5" y="3917.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s115_emtc_emtc_sa111" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: vimentin HUGO:VIM, HGNC:12692, ENTREZ:7431, GENECARDS:GC10P017310 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Vimentin is a putative direct HIF1 target gene http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Vimentin*"/> <bbox w="80.0" h="20.0" x="4656.0" y="2929.5"/> <glyph class="unit of information" id="_f9b40039-cbfc-41d2-99eb-61307f820a52"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4686.0" y="2924.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s118_emtc_emtc_sa114" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 4, type 1, R-cadherin (retinal) HUGO:CDH4, HGNC:1763, ENTREZ:1002, GENECARDS:GC20P059827 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="R-Cadherin*"/> <bbox w="100.0" h="20.0" x="2234.5" y="4002.5"/> <glyph class="unit of information" id="_43588e31-8edf-4959-b22a-cecb7be20515"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2274.5" y="3997.5"/> </glyph> </glyph> <glyph 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Confidence_end</body> </html> </notes> <label text="MMP3"/> <bbox w="60.0" h="20.0" x="2215.5" y="4879.688"/> <glyph class="unit of information" id="_94ea4943-5f0e-4bc7-8ae9-876fd070204f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2235.5" y="4874.688"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s128_emtc_emtc_sa124" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) HUGO:MMP9, HGNC:7176, ENTREZ:4318, GENECARDS:GC20P044637 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP9"/> <bbox w="60.0" h="20.0" x="2212.5" y="4945.25"/> <glyph class="unit of information" id="_7061b948-dd5e-47ce-8bb1-abca2b8f8fc5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2232.5" y="4940.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s132_emtc_emtc_sa128" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 14 (membrane-inserted) HUGO:MMP14, HGNC:7160, ENTREZ:4323, GENECARDS:GC14P023305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP14"/> <bbox w="60.0" h="20.0" x="2212.5" y="5056.375"/> <glyph class="unit of information" id="_6747f22d-b5d9-4aa9-9b17-2c8c11c5822f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2232.5" y="5051.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s134_emtc_emtc_sa130" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibronectin 1 HUGO:FN1, HGNC:3778, ENTREZ:2335, GENECARDS:GC02M216225 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="86.875" h="20.0" x="2212.5" y="5095.938"/> <glyph class="unit of information" id="_437980e9-c568-4d63-8338-c91d60c7e4f2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2245.9375" y="5090.938"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s145_emtc_emtc_sa141" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: membrane protein, palmitoylated 5 (MAGUK p55 subfamily member 5) HUGO:MPP5, HGNC:18669, ENTREZ:64398, GENECARDS:GC14P067708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PALS1*"/> <bbox w="80.0" h="20.0" x="2208.5" y="2314.5"/> <glyph class="unit of information" id="_9a7217dd-1dd5-49b1-b333-571ea217f94c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2238.5" y="2309.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s180_emtc_emtc_sa167" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: calcium/calmodulin-dependent serine protein kinase (MAGUK family) HUGO:CASK, HGNC:1497, ENTREZ:8573, GENECARDS:GC0XM041374 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN2*"/> <bbox w="60.0" h="20.0" x="4679.0" y="3285.5"/> <glyph class="unit of information" id="_bd2e0541-6212-4b13-a03a-538dea27b690"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4699.0" y="3280.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s183_emtc_emtc_sa170" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: lin-7 homolog C (C. elegans) HUGO:LIN7C, HGNC:17789, ENTREZ:55327, GENECARDS:GC11M027472 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation PMID:10871881 LIN2(CASK) contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate Kinase domain LIN7 contains one L27 domain, 1 PDZ domain Interaction LIN2-LIN7 via L27 domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN7C"/> <bbox w="60.0" h="17.5" x="4679.0" y="3346.75"/> <glyph class="unit of information" id="_56aa34ac-db7e-46ea-b71a-ca8aa3ba8b4b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4699.0" y="3341.75"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s186_emtc_emtc_sa173" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: chromosome 16 open reading frame 70 HUGO:C16orf70, HGNC:29564, ENTREZ:80262, GENECARDS:GC16P067143 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="LIN10*"/> <bbox w="60.0" h="20.0" x="4679.0" y="3239.5"/> <glyph class="unit of information" id="_accec7fa-e980-4650-b82c-bb16efe8387a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4699.0" y="3234.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s311_emtc_emtc_sa269" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 1 HUGO:ITGA1 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA1"/> <bbox w="60.0" h="20.0" x="3505.5" y="5272.5"/> <glyph class="unit of information" id="_3bb6380d-2895-4b20-8af4-5610d43696c1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3525.5" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s312_emtc_emtc_sa270" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) CD49B HUGO:ITGA2 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2"/> <bbox w="60.0" h="20.0" x="3552.799" y="5272.5"/> <glyph class="unit of information" id="_21387a38-25f2-4947-943c-17f565e4e0ae"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3572.799" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s313_emtc_emtc_sa271" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) GP2B, "integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)" HUGO:ITGA2B HGNC:6138 ENTREZ:3674 UNIPROT:P08514 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA2B"/> <bbox w="60.0" h="20.0" x="3600.096" y="5272.5"/> <glyph class="unit of information" id="_81326913-9ac8-427e-81f8-92be7bedf47a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3620.096" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s314_emtc_emtc_sa272" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) "antigen identified by monoclonal antibody J143", MSK18 HUGO:ITGA3 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA3"/> <bbox w="60.0" h="20.0" x="3647.395" y="5272.5"/> <glyph class="unit of information" id="_9044600b-6846-47c3-974d-03780ffa6e66"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3667.395" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s315_emtc_emtc_sa273" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) CD49D HUGO:ITGA4 HGNC:6140 ENTREZ:3676 UNIPROT:P13612 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="60.0" h="20.0" x="3694.691" y="5272.5"/> <glyph class="unit of information" id="_90e79afd-d45e-4b04-8c44-d5c252406d4f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3714.691" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s316_emtc_emtc_sa274" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 5 (fibronectin receptor, alpha polypeptide) HUGO:ITGA5, HGNC:6141, ENTREZ:3678, GENECARDS:GC12M054789 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:19487819 During gastrulation, type 1 EMT is associated with de novo expression of a5b1, which is a receptor for fibronectin. Type 2 EMT in experimental kidney fibrosis is associated with increased a5 integrin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="60.0" h="20.0" x="3741.99" y="5272.5"/> <glyph class="unit of information" id="_2b80bddf-aa18-4948-ae1d-ebce614b8277"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3761.99" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s317_emtc_emtc_sa275" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 6 HUGO:ITGA6 HGNC:6142 ENTREZ:3655 UNIPROT:P23229 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA6"/> <bbox w="60.0" h="20.0" x="3789.29" y="5272.5"/> <glyph class="unit of information" id="_95b456de-645e-4bf8-a8f1-8bf86d8918f8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3809.29" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s318_emtc_emtc_sa276" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 7 HUGO:ITGA7 HGNC:6143 ENTREZ:3679 UNIPROT:Q13683 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA7"/> <bbox w="60.0" h="20.0" x="3836.586" y="5272.5"/> <glyph class="unit of information" id="_7f394bae-780c-41c0-94fb-e65a6b6c64b3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3856.586" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s319_emtc_emtc_sa277" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 8 HUGO:ITGA8 HGNC:6144 ENTREZ:8516 UNIPROT:P53708 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA8"/> <bbox w="60.0" h="20.0" x="3883.885" y="5272.5"/> <glyph class="unit of information" id="_3b9f1034-c058-401e-bc4c-9381cf86212a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3903.885" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s320_emtc_emtc_sa278" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 9 HUGO:ITGA9 HGNC:6145 ENTREZ:3680 UNIPROT:Q13797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGA9"/> <bbox w="60.0" h="20.0" x="3931.184" y="5272.5"/> <glyph class="unit of information" id="_7ecc47e7-83ad-42f7-a736-9c7e07c5838e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3951.184" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s321_emtc_emtc_sa279" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha 10 HUGO:ITGA10 HGNC:6135 ENTREZ:8515 UNIPROT:O75578 Identifiers_end 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UNIPROT:Q13349 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGAD"/> <bbox w="60.0" h="20.0" x="4073.076" y="5272.5"/> <glyph class="unit of information" id="_523ddd20-b3fb-4362-a02d-8f146c68d835"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4093.076" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s324_emtc_emtc_sa282" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, alpha E (antigen CD103, 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Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="60.0" h="20.0" x="4356.865" y="5272.5"/> <glyph class="unit of information" id="_1c5aecb5-a1cb-4269-ad59-4d08ae537f8e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4376.865" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s330_emtc_emtc_sa288" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) CD18, "integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit)", MFI7 HUGO:ITGB2 HGNC:6155 ENTREZ:3689 UNIPROT:P05107 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB2"/> <bbox w="60.0" h="20.0" x="4404.164" y="5272.5"/> <glyph class="unit of information" id="_e321b5c0-65d5-4dcf-8e98-739a3f6ea7d0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4424.164" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s331_emtc_emtc_sa289" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) GP3A HUGO:ITGB3 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB3"/> <bbox w="60.0" h="20.0" x="4451.46" y="5272.5"/> <glyph class="unit of information" id="_0ddaf9ea-fd53-4aca-bdaf-b16c026d7feb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4471.46" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s332_emtc_emtc_sa290" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 4 HUGO:ITGB4 HGNC:6158 ENTREZ:3691 UNIPROT:P16144 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB4"/> <bbox w="60.0" h="20.0" x="4498.76" y="5272.5"/> <glyph class="unit of information" id="_5e462be4-35f9-4bb6-8941-6129765a10bb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4518.76" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s333_emtc_emtc_sa291" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 5 HUGO:ITGB5 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB5"/> <bbox w="60.0" h="20.0" x="4546.059" y="5272.5"/> <glyph class="unit of information" id="_9357bc19-f358-4f6a-b56a-fc57417b786d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4566.059" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s334_emtc_emtc_sa292" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 6 HUGO:ITGB6 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB6"/> <bbox w="60.0" h="20.0" x="4593.355" y="5272.5"/> <glyph class="unit of information" id="_31768c61-e98c-4c62-9885-2044b8cf7fb9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4613.355" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s335_emtc_emtc_sa293" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 7 HUGO:ITGB7 HGNC:6162 ENTREZ:3695 UNIPROT:P26010 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB7"/> <bbox w="60.0" h="20.0" x="4640.654" y="5272.5"/> <glyph class="unit of information" id="_d2e7ddb1-1323-4acd-88c5-9e111ee1f9d8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4660.654" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s336_emtc_emtc_sa294" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: integrin, beta 8 HUGO:ITGB8 HGNC:6163 ENTREZ:3696 UNIPROT:P26012 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ITGB8"/> <bbox w="60.0" h="20.0" x="4687.953" y="5272.5"/> <glyph class="unit of information" id="_086d5d86-2f6b-4f28-855e-5362d37fab32"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4707.953" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s453_emtc_emtc_sa366" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 1 "MAD, mothers against decapentaplegic homolog 1 (Drosophila)", MADH1, "SMAD, mothers against DPP homolog 1 (Drosophila)" HUGO:SMAD1 HGNC:6767 ENTREZ:4086 UNIPROT:Q15797 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD1"/> <bbox w="80.0" h="20.0" x="4704.0" y="4139.625"/> <glyph class="unit of information" id="_c55587c0-aedf-4241-8c1c-f3ab03097f18"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4734.0" y="4134.625"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s455_emtc_emtc_sa368" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" 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<html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 3 "MAD, mothers against decapentaplegic homolog 3 (Drosophila)", MADH3, "SMAD, mothers against DPP homolog 3 (Drosophila)" HUGO:SMAD3 HGNC:6769 ENTREZ:4088 UNIPROT:P84022 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="20.0" x="4704.0" y="3946.5"/> <glyph class="unit of information" id="_bc31e356-0993-40ff-9eb1-4558f660a998"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4734.0" y="3941.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s459_emtc_emtc_sa372" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 4 "MAD, mothers against decapentaplegic homolog 4 (Drosophila)", MADH4, "SMAD, mothers against DPP homolog 4 (Drosophila)" HUGO:SMAD4 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="77.0" h="19.0" x="4709.0" y="4514.75"/> <glyph class="unit of information" id="_fafb4f07-688a-4944-8fce-29a2cacc76a1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4737.5" y="4509.75"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s462_emtc_emtc_sa375" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 5 "MAD, mothers against decapentaplegic homolog 5 (Drosophila)", MADH5, "SMAD, mothers against DPP homolog 5 (Drosophila)" HUGO:SMAD5 HGNC:6771 ENTREZ:4090 UNIPROT:Q99717 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD5"/> <bbox w="80.0" h="20.0" x="4704.0" y="4086.5"/> <glyph class="unit of information" id="_72fe4459-84d7-45a5-a1a0-33723ea6d3fb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4734.0" y="4081.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s465_emtc_emtc_sa378" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 6 "MAD, mothers against decapentaplegic homolog 6 (Drosophila)", MADH6, MADH7, "SMAD, mothers against DPP homolog 6 (Drosophila)" HUGO:SMAD6 HGNC:6772 ENTREZ:4091 UNIPROT:O43541 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD6"/> <bbox w="79.0" h="19.0" x="4705.0" y="4258.5"/> <glyph class="unit of information" id="_cf7a2da5-79d2-42d8-9bad-21fdb88ba41e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4734.5" y="4253.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s468_emtc_emtc_sa381" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 7 "MAD, mothers against decapentaplegic homolog 7 (Drosophila)", MADH7, MADH8, "SMAD, mothers against DPP homolog 7 (Drosophila)" HUGO:SMAD7 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD7"/> <bbox w="82.0" h="20.0" x="4702.0" y="4291.25"/> <glyph class="unit of information" id="_8359eb67-8ae2-423d-b01d-601d9f3c8522"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4733.0" y="4286.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s471_emtc_emtc_sa384" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD family member 9 "MAD, mothers against decapentaplegic homolog 9 (Drosophila)", MADH9, "SMAD, mothers against DPP homolog 9 (Drosophila)" HUGO:SMAD9 HGNC:6774 ENTREZ:4093 UNIPROT:O15198 GENECARDS:GC13M037418 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD9"/> <bbox w="80.0" h="20.0" x="4704.0" y="4113.5"/> <glyph class="unit of information" id="_adfdea9d-0aaa-4121-ad4e-555a03765899"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4734.0" y="4108.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s580_emtc_emtc_sa441" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:19597490 CAR: a tight-junction-associated cell adhesion molecule CAR is downregulated in human cancer and in TGF-b-induced EMT PMID:15820557 CAR: a virus receptor within the tight junction CAR: a transmembrane protein PMID:12727824 CAR: down-stream target of Rag-MEK-ERK pathway PMID:16542650 In epithelial cell, CAR localizes with ZO1 and Occludin References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: coxsackie virus and adenovirus receptor HUGO:CXADR, HGNC:2559, ENTREZ:1525, GENECARDS:GC21P018884 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:19597490 CAR: a tight-junction-associated cell adhesion molecule CAR is downregulated in human cancer and in TGF-b-induced EMT PMID:15820557 CAR: a virus receptor within the tight junction CAR: a transmembrane protein PMID:12727824 CAR: down-stream target of Rag-MEK-ERK pathway PMID:16542650 In epithelial cell, CAR localizes with ZO1 and Occludin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CAR*"/> <bbox w="65.0" h="20.0" x="2187.0" y="2498.5"/> <glyph class="unit of information" id="_b3d3e6fe-0356-4af1-91cd-6cf9e245c9fc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2209.5" y="2493.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s585_emtc_emtc_sa447" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 1 HUGO:TJP1, HGNC:11827, ENTREZ:7082, GENECARDS:GC15M029991 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO1*"/> <bbox w="60.0" h="17.0" x="2186.5" y="2567.277"/> <glyph class="unit of information" id="_9f3482a3-92e0-4919-b1c9-74c4502819da"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2206.5" y="2562.277"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s588_emtc_emtc_sa450" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: tight junction protein 1 HUGO:TJP2, HGNC:11828, ENTREZ:9414, GENECARDS:GC09P071766 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZO2*"/> <bbox w="60.0" h="20.0" x="2186.5" y="2602.818"/> <glyph class="unit of information" id="_0e6f31e1-7e23-4c88-9584-2114c2faec12"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2206.5" y="2597.818"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s591_emtc_emtc_sa453" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:20519943 SNAIL1 is cofactor of SMAD3/SMAD4 complex. Target genes of this complex are CAR, E-Cadherin, Occludin, Claudin3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="80.0" h="20.0" x="2187.5" y="2843.25"/> <glyph class="unit of information" id="_b5a8c18d-a7a5-4173-9c47-7d5b6ed8663d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2217.5" y="2838.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s612_emtc_emtc_sa466" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) HUGO:CDKN2B, HGNC:1788, ENTREZ:1030, GENECARDS:GC09M021992 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11013220 Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene This interaction provides a mechanism underlying the TGFB-induced growth arrest PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:8078588 p15INK4B is a potential effector of TGFB-induced cell cycle arrest PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p15INK4B*"/> <bbox w="89.0" h="20.0" x="3526.666" y="2031.5"/> <glyph class="unit of information" id="_6292447a-4339-4a02-aee1-42852f55f42d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3561.166" y="2026.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s629_emtc_emtc_sa762" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Kruppel-like factor 4 (gut) HUGO:KLF4, HGNC:6348, ENTREZ:9314, GENECARDS:GC09M110247 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KLF4"/> <bbox w="60.0" h="20.0" x="4204.5" y="4696.445"/> <glyph class="unit of information" id="_c17c3279-af8c-4a0a-9739-a3bca08d3c2e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4224.5" y="4691.445"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s632_emtc_emtc_sa760" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SOX2"/> <bbox w="60.0" h="20.0" x="4212.5" y="4625.084"/> <glyph class="unit of information" id="_7cf1745d-b885-494c-aa35-b831a27e3c5a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4232.5" y="4620.084"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s651_emtc_emtc_sa493" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D1 HUGO:CCND1, HGNC:1582, ENTREZ:595, GENECARDS:GC11P069455 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:19238148 CDK activity requires binding of regulatory subunits known as cyclins. Cyclins are synthesized and destroyed at specific times during the cell cycle, thus regulating kinase activity in a timely manner. Human cells contain multiple loci encoding CDKs and cyclins (13 and 25 loci, respectively). A subset of CDK–cyclin complexes is directly involved in driving the cell cycle: -3 interphase CDKs (CDK2, CDK4 and CDK6), 1 mitotic CDK (CDK1) -10 cyclins that belong to 4 different classes (the A-, B-, D- and E-type cyclins). PMID:9832503 D-type cyclins are labile proteins guarantees Phosphorylation of cyclin D1 on T286 by GSK3B leads to the rapid ubiquitination and proteasomal degradation of cyclin D1 cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase GSK3B is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. Phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK3B. PMID:10331086 CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3) The vast majority of INK4 proteins are not found in complexes containing cyclins D. PMID:22943793 TGFB induces expression of p15INK4B and represses expression of c-Myc p15INK4B is able to prevent cyclin D-CDK4/6 complex formation p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD1*"/> <bbox w="80.0" h="20.0" x="2799.0" y="2262.5"/> <glyph class="unit of information" id="_b6b9eafd-7118-496e-a920-d91250470f60"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2829.0" y="2257.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s653_emtc_emtc_sa495" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: glycogen synthase kinase 3 beta HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:15465828 GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-κB (NF-κB) p65 subunit, leading to NF-κB transactivation in hepatocytes This phosphorylation negatively regulates basal p65 NF-kappaB activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="GSK3β*"/> <bbox w="71.0" h="20.0" x="2774.0" y="1935.5"/> <glyph class="unit of information" id="_2477094f-0a1d-42b7-8d0a-d521fd7f4653"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2799.5" y="1930.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s664_emtc_emtc_sa507" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1A (p21, Cip1) HUGO:CDKN1A, HGNC:1784, ENTREZ:1026, GENECARDS:GC06P036649 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p21CIP1*"/> <bbox w="80.0" h="20.0" x="3428.334" y="2030.5"/> <glyph class="unit of information" id="_69f0e7d5-c50c-467c-9774-714c4551fef1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3458.334" y="2025.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s668_emtc_emtc_sa509" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin E1 HUGO:CCNE1, HGNC:1589, ENTREZ:898, GENECARDS:GC19P030302 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinE1*"/> <bbox w="82.5" h="20.0" x="2878.75" y="2263.5"/> <glyph class="unit of information" id="_ea2a3079-a482-4e52-84c7-5e79caf85c48"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2910.0" y="2258.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s696_emtc_emtc_sa526" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: collagen, type I, alpha 2 HUGO:COL1A2, HGNC:2198, ENTREZ:1278, GENECARDS:GC07P094023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL1A2"/> <bbox w="80.0" h="20.0" x="4735.25" y="5272.5"/> <glyph class="unit of information" id="_41db4099-ff32-4bb3-ba18-363812c618c4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4765.25" y="5267.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s787_emtc_emtc_sa589" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: matrix metallopeptidase 13 (membrane-inserted) HUGO:MMP13, HGNC:7159, ENTREZ:4322, GENECARDS:GC11M102847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP13"/> <bbox w="60.0" h="20.0" x="2212.5" y="5016.812"/> <glyph class="unit of information" id="_3f40334a-6109-4d9d-abea-a872ab25ab94"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2232.5" y="5011.812"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s916_emtc_emtc_sa663" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-6 partitioning defective 6 homolog alpha (C. elegans) HUGO:PARD6A, HGNC:15943, ENTREZ:50855, GENECARDS:GC16P067696 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761148 PARD6A is a regulator of epithelial cell polarity and tight-junction assembly TGFBRI is localized to tight junctions where PARD6A is also found. TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="79.0" h="20.0" x="2212.5" y="2346.5"/> <glyph class="unit of information" id="_3eba492a-2e50-42b7-a4dc-2144866ff7d3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2242.0" y="2341.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1329_emtc_emtc_sa696" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) HUGO:ETS1, HGNC:3488, ENTREZ:2113, GENECARDS:GC11M128328 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16391805 Ets-1 is a transcription factor Ets-1 involves in inducing MMP2 expression by EMT in human squamous carcinoma cells PMID:21081489 miR-200b targets Ets-1 and is down-regulated by Hypoxia to induce Angiogenic response of Endothelial cells References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ETS1"/> <bbox w="60.0" h="20.0" x="2211.0" y="4761.0"/> <glyph class="unit of information" id="_593c3ef7-5500-43a7-80e5-f37d8fd5b875"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2231.0" y="4756.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1383_emtc_emtc_sa781" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: baculoviral IAP repeat containing 5 HUGO:BIRC5, HGNC:593, ENTREZ:332, GENECARDS:GC17P076210 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIRC5"/> <bbox w="60.0" h="20.0" x="4211.5" y="4553.723"/> <glyph class="unit of information" id="_dada3606-a937-42a7-9b2f-129f66c31694"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4231.5" y="4548.723"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1389_emtc_emtc_sa758" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:21224848 PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1"/> <bbox w="60.0" h="20.0" x="2281.5" y="4100.805"/> <glyph class="unit of information" id="_321ba2a4-531e-4602-b91a-cea944aac89c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2301.5" y="4095.8052"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1429_emtc_emtc_sa793" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FGF1"/> <bbox w="60.0" h="20.0" x="4679.0" y="5082.0"/> <glyph class="unit of information" id="_61616283-5ae4-4a37-9d47-2233fc77f8d9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4699.0" y="5077.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1444_emtc_emtc_sa797" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: kinase insert domain receptor (a type III receptor tyrosine kinase) HUGO:KDR, HGNC:6307, ENTREZ:3791, GENECARDS:GC04M055944 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:11166270 VEGFR2 is highly specific towards VEGFA. PMID:11741095 PMID:13678960 However VEGFR2 also binds to processed forms of VEGF-C, D, E. VEGFR2 is expressed in both vascular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stemm cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR2*"/> <bbox w="79.5" h="20.0" x="4679.0" y="4985.84"/> <glyph class="unit of information" id="_bff8c484-574a-48ba-ac47-c9beb19984ef"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4708.75" y="4980.84"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1599_emtc_emtc_sa854" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) HUGO:HIF1A, HGNC:4910, ENTREZ:3091, GENECARDS:GC14P062162 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: http://www.omicsonline.org/1948-5956/JCST-03-035.php HIF-1 is the Commander of Gateways to Cancer PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF1A"/> <bbox w="60.0" h="20.0" x="3834.0" y="1963.5"/> <glyph class="unit of information" id="_5a3ad7fd-3a73-4e15-ab90-dfb5d48171ff"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3854.0" y="1958.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1601_emtc_emtc_sa856" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 14 HUGO:KRT14, HGNC:6416, ENTREZ:3861, GENECARDS:GC17M039738 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT14"/> <bbox w="85.0" h="20.0" x="4654.0" y="3125.5"/> <glyph class="unit of information" id="_d9f03374-b57a-49e2-88a9-ef0cb2f25d3b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4686.5" y="3120.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1604_emtc_emtc_sa859" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 18 HUGO:KRT18, HGNC:6430, ENTREZ:3875, GENECARDS:GC12P053343 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT18"/> <bbox w="80.0" h="20.0" x="4659.0" y="3085.5"/> <glyph class="unit of information" id="_487b6c28-7d50-4654-95be-0a658b1155f7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4689.0" y="3080.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1607_emtc_emtc_sa862" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: keratin 19 HUGO:KRT19, HGNC:6436, ENTREZ:3880, GENECARDS:GC17M039679 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19 are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KRT19"/> <bbox w="80.0" h="20.0" x="4659.0" y="3045.5"/> <glyph class="unit of information" id="_58a80cf3-479e-46f2-9c37-a0683ae956d6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4689.0" y="3040.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1609_emtc_emtc_sa864" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: aryl hydrocarbon receptor nuclear translocator HUGO:ARNT, HGNC:700, ENTREZ:405, GENECARDS:GC01M150782 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: http://www.omicsonline.org/1948-5956/JCST-03-035.php HIF-1 is the Commander of Gateways to Cancer PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HIF1B*"/> <bbox w="60.0" h="20.0" x="3936.0" y="1964.5"/> <glyph class="unit of information" id="_33c33530-7a9d-4b69-bf00-5a84d0aece26"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3956.0" y="1959.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1616_emtc_emtc_sa870" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta 3 HUGO:TGFB3, HGNC:11769, ENTREZ:7043, GENECARDS:GC14M076424 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:11790723 Whereas TGFB1 and 2 are proscarring growth factors, TGFB3 is antiscarring TGFB1, 2, and 3 are embryonically expressed in skin and up-regulated at adult wound sites Overlapping expression patterns of HIF1Aand TGFB3 in vivo TGFB1 mRNA expression was serum- but not hypoxia-inducible. In contrast, TGF-b3 mRNA expression was hypoxia-inducible, but not serum- inducible TGFB3 might be a HIF1A target gene References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFB3"/> <bbox w="65.0" h="20.0" x="4679.0" y="5139.5"/> <glyph class="unit of information" id="_d79fe0ff-82fe-44a2-9a01-cbd6ff94cdf4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4701.5" y="5134.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1618_emtc_emtc_sa872" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: fms-related tyrosine kinase 1 HUGO:FLT1, HGNC:3763, ENTREZ:2321, GENECARDS:GC13M028874 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11528470 VEGFR1 (FLT1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, EG-VEGF, and Erythoproietin. PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 PMID:1312256 PMID:7929268 PMID:9751730 VEGFR1 is a hight-affinnity receptor for VEGF-A, B and PLGF PMID:11166270 PMID:11312109 VEGFR1 is expressed in vascular endothelial and some non-endothelial cells including harmatopoietic stem cells, macrophages and monocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="VEGFR1*"/> <bbox w="80.0" h="20.0" x="4679.0" y="4932.5"/> <glyph class="unit of information" id="_648d6ae0-2218-4984-a61f-517ec5703c50"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4709.0" y="4927.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s1621_emtc_emtc_sa875" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: prokineticin 1 HUGO:PROK1, HGNC:18454, ENTREZ:84432, GENECARDS:GC01P110994 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11528470 EG-VEGF (Prokinecticin 1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, VEGFR1, and Erythoproietin PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EG-VEGF*"/> <bbox w="80.0" h="20.0" x="4679.0" y="4892.5"/> <glyph class="unit of information" id="_e1794d28-b15c-46eb-a1ba-b44be1013e2e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4709.0" y="4887.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2151_emtc_emtc_sa1016" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: par-3 partitioning defective 3 homolog (C. elegans) HUGO:PARD3, HGNC:16051, ENTREZ:56288, GENECARDS:GC10M034438 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PAR3*"/> <bbox w="64.0" h="18.0" x="2206.0" y="2394.5"/> <glyph class="unit of information" id="_c1c62093-220c-4157-81a7-7bb9add698da"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2228.0" y="2389.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2460_emtc_emtc_sa1291" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 1 HUGO:CLDN1, HGNC:2032, ENTREZ:9076, GENECARDS:GC03M190023 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin1*"/> <bbox w="81.0" h="17.0" x="2179.0" y="2714.0"/> <glyph class="unit of information" id="_400217ba-357f-435e-9a17-30816f0d3546"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2209.5" y="2709.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2462_emtc_emtc_sa1293" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: claudin 2 HUGO:CLDN2, HGNC:2041, ENTREZ:9075, UNIPROT:P57739, GENECARDS:GC0XP106163 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin2*"/> <bbox w="78.0" h="17.0" x="2181.0" y="2778.0"/> <glyph class="unit of information" id="_0595a521-c4f8-4315-a600-a0b76f4a24cf"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2210.0" y="2773.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2879_emtc_emtc_sa1400" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin D3 HUGO:CCND3, HGNC:1585, ENTREZ:896, GENECARDS:GC06M041949 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21777377 Further studies are required to investigate the mechanism by which Cx31.1 repress cyclin D3 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CyclinD3*"/> <bbox w="86.0" h="20.0" x="2632.0" y="2261.5"/> <glyph class="unit of information" id="_78c31334-2e47-47f9-928d-903f31c11a0d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2665.0" y="2256.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s2936_emtc_emtc_sa1441" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN HUGO:PTEN, HGNC:9588, ENTREZ:5728, UNIPROT:P60484, GENECARDS:GC10P089613 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTEN"/> <bbox w="62.0" h="18.0" x="4030.0" y="1963.5"/> <glyph class="unit of information" id="_4b99c0c8-cc52-4f1c-a8ce-cf59369e12b7"> <label text="RNA"/> <bbox 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h="10.0" x="2748.0" y="2257.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3690_emtc_emtc_sa1826" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: beta catenin HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, GENECARDS:GC03P041236 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*"/> <bbox w="102.0" h="20.0" x="2230.5" y="3898.5"/> <glyph class="unit of information" id="_5d106dff-95fa-48c8-bf21-54d7701c4e7b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2271.5" y="3893.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3702_emtc_emtc_sa1835" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYC"/> <bbox w="60.0" h="20.0" x="3236.5" y="2303.25"/> <glyph class="unit of information" id="_fcd57c3e-d26b-4c23-9ba2-59771e42ea6d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3256.5" y="2298.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3707_emtc_emtc_sa1839" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: _beta_-Catenin*_ZEB1_ZEB2* beta catenin HUGO:CTNNB1, HGNC:2514, ENTREZ:1499, GENECARDS:GC03P041236 zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22024162 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="β-Catenin*_ZEB1_ZEB2*"/> <bbox w="214.0" h="19.0" x="3677.0" y="4411.0"/> <glyph class="unit of information" id="_07124674-57cb-450d-a0dc-206368eec8c3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3774.0" y="4406.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3710_emtc_emtc_sa1841" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1_BIRC5_KLF4_SOX2_SNAI1_ZEB2* BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 baculoviral IAP repeat containing 5 HUGO:BIRC5, HGNC:593, ENTREZ:332, GENECARDS:GC17P076210 Kruppel-like factor 4 (gut) HUGO:KLF4, HGNC:6348, ENTREZ:9314, GENECARDS:GC09M110247 SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 snail homolog 1 HUGO:SNAI1, HGNC:11128, ENTREZ:6615, GENECARDS:GC20P048599 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BMI1_BIRC5_KLF4_SOX2_SNAI1_ZEB2*"/> <bbox w="281.0" h="19.0" x="3677.0" y="4696.445"/> <glyph class="unit of information" id="_a4edd6e8-b773-467f-9bc7-79480d28cfe2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3807.5" y="4691.445"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3716_emtc_emtc_sa1846" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BMI1_KLF4_SOX2* BMI1 polycomb ring finger oncogene HUGO:BMI1, HGNC:1066, ENTREZ:648, GENECARDS:GC10P022605 Kruppel-like factor 4 (gut) HUGO:KLF4, HGNC:6348, ENTREZ:9314, GENECARDS:GC09M110247 SRY (sex determining region Y)-box 2 HUGO:SOX2, HGNC:11195, ENTREZ:6657, GENECARDS:GC03P181429 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIM1_KLF4_SOX2*"/> <bbox w="135.0" h="21.0" x="3677.0" y="4767.805"/> <glyph class="unit of information" id="_fcf5cd31-17c2-4cca-bf5d-f275edbb8180"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3734.5" y="4762.805"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3720_emtc_emtc_sa1849" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZEB1_ZEB2* zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20706219 ZEB1 and ZEB2 are targeted by all MIR200 family members. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ZEB1_ZEB2*"/> <bbox w="108.0" h="20.0" x="3677.0" y="4839.166"/> <glyph class="unit of information" id="_a3dd098c-7560-4a3e-9fac-ca46db4d86bb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3721.0" y="4834.166"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3725_emtc_emtc_sa1851" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: EST1_WASF3_WAVE3* v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) HUGO:ETS1, HGNC:3488, ENTREZ:2113, GENECARDS:GC11M128328 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:20706219 ETS1, WASF3 and WAVE3 are targeted by MIR-200B References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ETS1_WASF3_WAVE3*"/> <bbox w="163.0" h="19.0" x="3677.0" y="4482.361"/> <glyph class="unit of information" id="_ec3c9073-9c96-4c25-9868-6c0529c62b99"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3748.5" y="4477.361"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3728_emtc_emtc_sa1854" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SMAD2_TGFB2* SMAD family member 2 "MAD, mothers against decapentaplegic homolog 2 (Drosophila)", MADH2, "SMAD, mothers against DPP homolog 2 (Drosophila)" HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 transforming growth factor, beta 2 HUGO:TGFB2, HGNC:11768, ENTREZ:7042, UNIPROT:P61812, GENECARDS:GC01P218519 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21224848 PMID:20706219 BIM1 and TGFB2 are targeted by MIR200C PMID:22753312 direct regulation of SMAD2 by miR-141/200c/30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_TGFB2*"/> <bbox w="152.0" h="20.0" x="3677.0" y="4553.723"/> <glyph class="unit of information" id="_48f7c85c-628c-47d2-a4a2-f530914f68d4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3743.0" y="4548.723"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3734_emtc_emtc_sa1857" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TGFBR1_SMAD2* transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 SMAD family member 2 "MAD, mothers against decapentaplegic homolog 2 (Drosophila)", MADH2, "SMAD, mothers against DPP homolog 2 (Drosophila)" HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20498632 PMID:22753312 direct regulation of TGFBR1 by miR-141 direct regulation of SMAD2 by miR-141/200c/30e direct regulation of ZEB2 by miR-30e References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SMAD2_TGFBR1*"/> <bbox w="130.0" h="20.0" x="3677.0" y="4625.084"/> <glyph class="unit of information" id="_1ba47e75-8628-46ac-92a5-cdfce4483304"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3732.0" y="4620.084"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3738_emtc_emtc_sa1860" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor, beta receptor 1 HUGO:TGFBR1, HGNC:11772, ENTREZ:7046, UNIPROT:P36897, GENECARDS:GC09P101867 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="77.0" h="20.0" x="4710.0" y="3792.791"/> <glyph class="unit of information" id="_d0185df4-faa2-49da-bf2c-656f78dc5be9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4738.5" y="3787.791"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3794_emtc_emtc_sa1879" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein kinase C, epsilon HUGO:PRKCE, HGNC:9401, ENTREZ:5581, UNIPROT:Q02156, GENECARDS:GC02P045790 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:GAP_JUNCTIONS Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCE"/> <bbox w="70.0" h="18.0" x="2283.0" y="5134.0"/> <glyph class="unit of information" id="_f11ef86f-1023-4b1f-8897-5284b48c63a4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2308.0" y="5129.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3795_emtc_emtc_sa1880" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZEB1_ZEB2* zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 protein kinase C, epsilon HUGO:PRKCE, HGNC:9401, ENTREZ:5581, UNIPROT:Q02156, GENECARDS:GC02P045790 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 PMID:22753312 PMID:21209780 PMID:18376396 ZEB1 and ZEB2 contain one and two sites, respectively that are targeted by miRNA-205 PMID:19244118 miR-205 targets N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase C-epsilon. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCE_ZEB1_ZEB2*"/> <bbox w="154.0" h="22.0" x="3678.0" y="4909.0"/> <glyph class="unit of information" id="_765afcac-be6b-48ed-8727-656aa3c89507"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3745.0" y="4904.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3796_emtc_emtc_sa1881" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: ZEB1_ZEB2* zinc finger E-box binding homeobox 1 HUGO:ZEB1, HGNC:11642, ENTREZ:6935, GENECARDS:GC10P031648 zinc finger E-box binding homeobox 2 HUGO:ZEB2, HGNC:14881, ENTREZ:9839, GENECARDS:GC02M145145 protein kinase C, epsilon HUGO:PRKCE, HGNC:9401, ENTREZ:5581, UNIPROT:Q02156, GENECARDS:GC02P045790 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:21518799 PMID:22753312 PMID:21209780 PMID:18376396 ZEB1 and ZEB2 contain one and two sites, respectively that are targeted by miRNA-205 PMID:19244118 miR-205 targets N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase C-epsilon. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PRKCE_ZEB1_ZEB2*"/> <bbox w="154.0" h="22.0" x="2758.5" y="5556.5"/> <glyph class="unit of information" id="_959e8388-d2e8-4297-a20f-f51e87fed9e1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2825.5" y="5551.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3845_emtc_emtc_sa1929" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 2A HUGO:CDKN2A, HGNC:1787, ENTREZ:1029, GENECARDS:GC09M021957, UNIPROT:P42771 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:20818389 Physical interaction between BMI1 and TWIST1 E-Cadherin repression by cooperative BMI1 and TWIST1 p16INK4A repression by cooperative BMI1 and TWIST1 PMID:23140366 p16INK4A expression induced by ROS PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF PMID:24954210 RAS activates p16 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p16INK4A*"/> <bbox w="91.0" h="21.0" x="3634.0" y="2028.5"/> <glyph class="unit of information" id="_6f0fcf6c-6f07-48fc-91db-a2f85859d40a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3669.5" y="2023.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3867_emtc_emtc_sa1949" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: forkhead box C2 (MFH-1, mesenchyme forkhead 1) HUGO:FOXC2, HGNC:3801, ENTREZ:2303 , UNIPROT:Q99958 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17537911 Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FOXC2"/> <bbox w="68.0" h="21.0" x="3639.0" y="4342.0"/> <glyph class="unit of information" id="_c85dd64e-14c5-4c62-afa9-3cb0ce5480a9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3663.0" y="4337.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3871_emtc_emtc_sa1953" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 1, dominant negative helix-loop-helix protein HUGO:ID1, HGNC:5360, ENTREZ:3397 , UNIPROT:P41134 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17490644 Snai1 and TCF3 (E47) upregulate both mRNA and protein level of ID1 This upregulation depends on SP1 or AP1 co-transcription factors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID1"/> <bbox w="51.0" h="19.0" x="4089.0" y="4337.0"/> <glyph class="unit of information" id="_cdd33efb-daa1-43b2-ae67-e7a25e16c9c7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4104.5" y="4332.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3874_emtc_emtc_sa1956" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RAC1"/> <bbox w="64.0" h="20.0" x="2296.0" y="5201.0"/> <glyph class="unit of information" id="_786585c8-538e-433f-8d36-19b97c073591"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2318.0" y="5196.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3886_emtc_emtc_sa1969" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: endothelin 1 HUGO:EDN1, HGNC:3176, ENTREZ:1906, GENECARDS:GC06P012290, UNIPROT:P05305 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9588211 Endothelin1 is target gene of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Endothelin1*"/> <bbox w="93.0" h="17.0" x="4679.0" y="4806.5"/> <glyph class="unit of information" id="_1e8adb21-fe3f-4dba-b125-8d0ccf704c8c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4715.5" y="4801.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3889_emtc_emtc_sa1972" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: inhibitor of DNA binding 2, dominant negative helix-loop-helix protein HUGO:ID2, HGNC:5361, ENTREZ:3398, UNIPROT:Q02363, GENECARDS:GC02P008818 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11708773 PMID:15252039 ID2 is target of HIF1 upon hypoxic conditions References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID2"/> <bbox w="52.0" h="20.0" x="4088.0" y="4385.5"/> <glyph class="unit of information" id="_7a2f183e-8e94-4b48-aaa0-efe22cfc18cc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4104.0" y="4380.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3907_emtc_emtc_sa1991" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: activating transcription factor 3 HUGO:ATF3, HGNC:785, ENTREZ:467, GENECARDS:GC01P212738, UNIPROT:P18847 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ATF3"/> <bbox w="53.0" h="17.0" x="4087.0" y="4291.0"/> <glyph class="unit of information" id="_c16c0f83-0399-46f7-9e76-490d98644648"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4103.5" y="4286.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3929_emtc_emtc_sa2010" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: jun B proto-oncogene HUGO:JUNB, HGNC:6205, ENTREZ:3726, GENECARDS:GC19P012902 UNIPROT:P17275 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CELL_MATRIX_ADHESIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="JUNB"/> <bbox w="55.0" h="19.0" x="3652.0" y="4208.25"/> <glyph class="unit of information" id="_fe06b876-2b5b-4859-8379-625f6dbd79de"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3669.5" y="4203.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3985_emtc_emtc_sa2057" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Mdm2 p53 binding protein homolog (mouse) HUGO:MDM2, HGNC:6973, ENTREZ:4193, UNIPROT:Q00987 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: MDM2 = ubiquitin-ligase, regulates p53 stability: induce its degradation via the proteasome. PMID:15024084 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MDM2"/> <bbox w="90.0" h="25.0" x="3639.0" y="2219.0"/> <glyph class="unit of information" id="_b52a4565-4928-4033-af0d-986978965ce1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3674.0" y="2214.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3987_emtc_emtc_sa2059" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 1 RPD3L1 HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC1"/> <bbox w="90.0" h="25.0" x="2942.0" y="3566.0"/> <glyph class="unit of information" id="_b137a8d2-9b65-4508-b21b-3fe8c536b603"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2977.0" y="3561.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3989_emtc_emtc_sa2061" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: histone deacetylase 2 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HDAC2"/> <bbox w="90.0" h="25.0" x="2589.0" y="3507.0"/> <glyph class="unit of information" id="_382cac13-98dd-4589-99c6-d0d4723d1e15"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2624.0" y="3502.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3991_emtc_emtc_sa2063" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: SIN3 transcription regulator homolog A (yeast) SIN3A HUGO:SIN3A HGNC:19353 ENTREZ:25942 UNIPROT:Q96ST3 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="SIN3A"/> <bbox w="90.0" h="25.0" x="2583.0" y="3561.0"/> <glyph class="unit of information" id="_e332de65-a592-435b-96c6-c886630e4201"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2618.0" y="3556.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s3993_emtc_emtc_sa2066" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-akt murine thymoma viral oncogene homolog 2 HUGO:AKT2 HGNC:392 ENTREZ:208 UNIPROT:P31751 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="AKT2"/> <bbox w="61.0" h="20.0" x="3259.0" y="1942.5"/> <glyph class="unit of information" id="_b4954568-f930-40c3-a627-654e516d3419"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3279.5" y="1937.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4289_emtc_emtc_sa2075" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cyclin-dependent kinase inhibitor 1B (p27, Kip1) HUGO:CDKN1B, HGNC:1785, ENTREZ:1027, GENECARDS:GC12P012867, UNIPROT:P46527 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="p27KIP1*"/> <bbox w="83.0" h="20.0" x="3327.0" y="2030.5"/> <glyph class="unit of information" id="_030ae830-f214-46a7-832c-e029c2bdc6c5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3358.5" y="2025.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4347_emtc_emtc_sa2160" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="ID3"/> <bbox w="55.0" h="20.0" x="4093.0" y="4428.5"/> <glyph class="unit of information" id="_570eb027-bd61-4af5-b00a-55916a2d91e3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4110.5" y="4423.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4378_emtc_emtc_sa2185" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 1 HUGO:HEY1, HGNC:4880, ENTREZ:23462, UNIPROT:Q9Y5J3, GENECARDS:GC08M080676 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY1"/> <bbox w="63.0" h="17.0" x="2341.0" y="2175.0"/> <glyph class="unit of information" id="_0aaced57-7622-4212-965d-819a1996e2a7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2362.5" y="2170.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4380_emtc_emtc_sa2187" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: hes-related family bHLH transcription factor with YRPW motif 2 HUGO:HEY2, HGNC:4881, ENTREZ:23493, UNIPROT:Q9UBP5, GENECARDS:GC06P126068 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="HEY2"/> <bbox w="60.0" h="17.0" x="2338.0" y="2211.0"/> <glyph class="unit of information" id="_eb94c899-2f66-443f-964a-2f2ea239f4a8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2358.0" y="2206.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4386_emtc_emtc_sa2193" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: runt-related transcription factor 2 HUGO:RUNX2, HGNC:10427, ENTREZ:860, UNIPROT:Q13950 , GENECARDS:GC06P045295 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:18497317 Notch1, Hey1, and Hey2 physically interact with and repress the function of the transcription factor RUNX2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RUNX2"/> <bbox w="70.0" h="18.0" x="2330.0" y="2248.5"/> <glyph class="unit of information" id="_70ef637c-1cb2-4695-af24-ec2ac6ff5fdb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2355.0" y="2243.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4394_emtc_emtc_sa2200" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP10"/> <bbox w="74.0" h="19.0" x="2212.5" y="4984.25"/> <glyph class="unit of information" id="_4884da7f-354a-402a-8573-dc1357636779"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2239.5" y="4979.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4398_emtc_emtc_sa2204" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 2 (Drosophila) "enhancer of zeste (Drosophila) homolog 2" HUGO:EZH2 HGNC:3527 ENTREZ:2146 UNIPROT:Q15910 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:22796940 The silencing of E-cadherin expression by hypermethylation is a common event in cancer. DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts such as colorectal cancer, gastric cancer and hepatocellular carcinomas. Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b. DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a. However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1. Cooperation between Polycomb proteins and EMT-inducing transcription factors. The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling. The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase. Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT. SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression. Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT. BMI-1 can also interact with TWIST to induce EMT. Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EZH2"/> <bbox w="62.0" h="19.0" x="2695.0" y="3331.0"/> <glyph class="unit of information" id="_fc65c2ad-7e8b-4549-8012-e334e3bd444c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2716.0" y="3326.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4400_emtc_emtc_sa2206" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: enhancer of zeste homolog 1 (Drosophila) "enhancer of zeste (Drosophila) homolog 1" HUGO:EZH1 HGNC:3526 ENTREZ:2145 UNIPROT:Q92800 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16567498 PMID:17587822 EZH1 and EZH2 are targets of HEYs-mediated transcriptional repression. 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Confidence_begin: Confidence_end</body> </html> </notes> <label text="AXIN2"/> <bbox w="60.0" h="20.0" x="2165.5" y="3685.0"/> <glyph class="unit of information" id="_6ad710a6-f720-4b78-98df-0b0c2eff00e1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2185.5" y="3680.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4613_emtc_emtc_sa2404" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 1 "tissue inhibitor of metalloproteinase 1" HUGO:TIMP1 HGNC:11820 ENTREZ:7076 UNIPROT:P01033 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP1"/> <bbox w="63.0" h="17.0" x="2211.0" y="4626.0"/> <glyph class="unit of information" id="_d46dffeb-7c6b-47c2-bc5d-3bbf654a8048"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2232.5" y="4621.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4615_emtc_emtc_sa2406" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: TIMP metallopeptidase inhibitor 2 "tissue inhibitor of metalloproteinase 2" HUGO:TIMP2 HGNC:11821 ENTREZ:7077 UNIPROT:P16035 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metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory)" HUGO:TIMP3 HGNC:11822 ENTREZ:7078 UNIPROT:P35625 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="TIMP3"/> <bbox w="59.0" h="17.0" x="2211.0" y="4694.0"/> <glyph class="unit of information" id="_55840f4c-d05e-48b5-b819-6c4a00290c9f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2230.5" y="4689.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4622_emtc_emtc_sa2413" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to 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HGNC:8799 ENTREZ:5154 UNIPROT:P04085 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFA"/> <bbox w="72.0" h="16.0" x="2211.0" y="4545.0"/> <glyph class="unit of information" id="_c326e864-2d1d-4703-83bd-36f4fdca31f1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2237.0" y="4540.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4684_emtc_emtc_sa2469" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: platelet-derived growth factor receptor alpha polypeptide HUGO:PDGFRA HGNC:8803 ENTREZ:5156 UNIPROT:P16234 platelet-derived growth factor receptor beta polypeptide HUGO:PDGFRB HGNC:8804 ENTREZ:5159 UNIPROT:P09619 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PDGFR family*"/> <bbox w="114.0" h="20.0" x="2211.0" y="4571.0"/> <glyph class="unit of information" id="_8d6a1f7d-d7b5-4af0-a801-15de997d398b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2258.0" y="4566.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4802_emtc_emtc_sa2560" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: protein tyrosine phosphatase type IVA, member 3 HUGO:PTP4A3 HGNC:9636 ENTREZ:11156 UNIPROT:O75365 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:24376839 PTP4A3 is implicated in cell adhesion and the regulation of focal adhesion components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. http://d-scholarship.pitt.edu/18634/1/Zimmerman_ETD-2013.pdf c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3. Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PTP4A3"/> <bbox w="76.0" h="17.0" x="2211.0" y="4602.0"/> <glyph class="unit of information" id="_0da0519d-d91b-499b-bd43-4cf5a6561a49"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2239.0" y="4597.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="emtc_emtc_s4804_emtc_emtc_sa2562" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUP Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Plakoglobin*"/> <bbox w="103.0" h="18.0" x="2215.0" y="4368.0"/> <glyph class="unit of information" id="_7805333d-6e65-4d6b-9a53-ccd2679912d1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2256.5" y="4363.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2365_sa2063" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MYB"/> <bbox w="90.0" h="25.0" x="4257.0" y="2646.5"/> <glyph class="unit of information" id="_5e815e30-e4e2-4add-aa36-9aeb6898bf96"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4292.0" y="2641.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2369_sa2067" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="CTSD"/> <bbox w="90.0" h="25.0" x="4627.0" y="3436.5"/> <glyph class="unit of information" id="_7cbb1ef3-404c-439f-b87f-75882968f665"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4662.0" y="3431.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2382_sa2080" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BCL2L11 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:18281283 production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BIM*"/> <bbox w="90.0" h="25.0" x="4237.0" y="1946.5"/> <glyph class="unit of information" id="_414b1a04-4b51-4f17-b03d-186e85121c38"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4272.0" y="1941.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2384_sa2082" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:11704864 Transcriptional regulation of bcl-2 by nuclear factor kappa B PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BCL2"/> <bbox w="90.0" h="25.0" x="4367.0" y="1946.5"/> <glyph class="unit of information" id="_e54f0560-b7ca-442e-8292-7d9a1e16539a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4402.0" y="1941.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2389_sa2087" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE Maps_Modules_end References_begin: p16INK4a activates the pRB tumor suppressor, which silences certain proproliferative genes by heterochromatinization, thereby instituting a stringent arrest of cell proliferation References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="RB1"/> <bbox w="65.0" h="22.0" x="2612.0" y="1936.5"/> <glyph class="unit of information" id="_c6728731-82cf-4b6c-bc6d-f68329978268"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2634.5" y="1931.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2392_sa2090" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="MMP7"/> <bbox w="72.0" h="18.0" x="2207.0" y="4913.5"/> <glyph class="unit of information" id="_39cbb0f6-5f6b-495e-9bcf-80baa1b3dc7a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2233.0" y="4908.5"/> </glyph> </glyph> <glyph class="simple chemical" id="emtc_emtc_s413_emtc_emtc_sa1961" compartmentRef="emtc_emtc_c2_emtc_emtc_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CHEBI:26523 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:16001073 RAC1B increases the cellular level of ROS, causing an upregulation of Snail and induction of EMT References_end Confidence_begin: Confidence_end</body> </html> </notes> <label 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<body>Identifiers_begin: 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate CAS:N/A PUBCHEM:7726, CHEBI:18348, KEGGCOMPOUND:C04637 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI(4,5)P2"/> <bbox w="70.0" h="25.0" x="4867.0" y="1139.0"/> </glyph> <glyph class="simple chemical" id="emtc_emtc_s4497_emtc_emtc_sa2317" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: phosphatidylinositol-3,4,5-triphosphate CAS:N/A PUBCHEM:8260 CHEBI:16618 KEGGCOMPOUND:C05981 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PI(3,4,5)P3"/> <bbox w="70.0" h="25.0" 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<head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog (avian) HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748, UNIPROT:P01106 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. 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------ Identifiers_begin: v-myc myelocytomatosis viral oncogene homolog (avian) HUGO:MYC, HGNC:7553, ENTREZ:4609, GENECARDS:GC08P128748, UNIPROT:P01106 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:SENESCENCE MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. 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References_begin: PMID:18375391 Type I procollagen is a heterotrimer composed of 2 proalpha1(I) chains (encoded by COL1A1) and 1 proalpha2(I) chain (encoded by COL1A2 genes) proalpha2(I) C-propeptide and proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. PMID:17217948 Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGFB2 in human retinal pigment epithelial cells PMID:11114293 Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGFB1-induced 2(I) collagen expression in human mesangial cells. Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="COL1A2"/> <bbox w="53.0" h="19.0" x="4739.75" y="6085.5"/> </glyph> <glyph class="macromolecule" id="s2492_emtc_emtc_sa2045" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog HUGO:KIT HGNC:6342 ENTREZ:3815 UNIPROT:P10721 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:15337769 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KIT"/> <clone/> <bbox w="80.0" h="50.0" x="726.5" y="159.5"/> <glyph class="unit of information" id="_f4bc0359-2dcf-462d-86f4-6488e5dc2df1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="744.0" y="154.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2492_emtc_emtc_sa2370" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog HUGO:KIT HGNC:6342 ENTREZ:3815 UNIPROT:P10721 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:15337769 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="KIT"/> <clone/> <bbox w="80.0" h="50.0" x="637.0" y="161.0"/> <glyph class="unit of information" id="_9f794d21-5c8d-4925-8afd-ba8210f5cd2e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="654.5" y="156.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2493_emtc_emtc_sa2567" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: met proto-oncogene synonym "hepatocyte growth factor receptor", HGFR HUGO:MET HGNC:7029 ENTREZ:4233 UNIPROT:P08581 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:22128289 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-MET*"/> <clone/> <bbox w="80.0" h="50.0" x="953.5" y="157.5"/> <glyph class="unit of information" id="_b748131a-7417-4bb1-a83e-1211d3e087f0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="971.0" y="152.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2493_emtc_emtc_sa2570" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: met proto-oncogene synonym "hepatocyte growth factor receptor", HGFR HUGO:MET HGNC:7029 ENTREZ:4233 UNIPROT:P08581 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:22128289 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="c-MET*"/> <clone/> <bbox w="80.0" h="50.0" x="1037.5" y="157.5"/> <glyph class="unit of information" id="_f9b8829b-648a-4f2e-a0fe-c3828158e89a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1055.0" y="152.5"/> </glyph> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4511_emtc_emtc_sa934" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: BCL2-associated X protein HUGO:BAX, HGNC:959, ENTREZ:581, UNIPROT:Q07812, GENECARDS:GC19P049458 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS MODULE:SENESCENCE Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:8358790 Bax homodimerizes and forms heterodimers with BCL2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of BCL2. These data suggest a model in which the ratio of BCL2 to Bax determines survival or death following an apoptotic stimulus. PMID:7644501 The susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner. Multiple BCL2 family members demonstrate selective dimerizations with Bax PMID:21641962 The pro-apoptototic protein Bax plays a central role in the mitochondria- dependent apoptotic pathway. In healthy mammalian cells, Bax is essentially cytosolic and inactive. Following a death signal, the protein is translocated to the outer mitochondrial membrane, where it promotes a permeabilization that favors the release of different apoptogenic factors, such as cytochrome c. PMID:23064052 Inactive Bax can be directly converted into an active conformation following the interaction with activator Bid , Bim (BCL2L11) or Puma (BBC3) The interaction of Bax with BCL2 or BCL2L1 drives the translocation of Bax to the outer mitochondrial membrane Under this condition, active Bax can be liberated from its interaction with BCL2L1 by a derepressor BH3-only protein, such as Bad. Other experiments have shown that Bax can be translocated to the outer mitochondrial membrane and further activated by different proteins such as Myc or p38MapK References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="BAX"/> <bbox w="28.0" h="19.0" x="4119.0" y="1332.0"/> </glyph> <glyph class="macromolecule" id="emtc_emtc_s4789_emtc_emtc_sa2550" compartmentRef="emtc_emtc_c39_emtc_emtc_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: v-raf-1 murine leukemia viral oncogene homolog 1 HUGO:RAF1, HGNC:9829, ENTREZ:5894 , GENECARDS:GC03M012625, UNIPROT:P04049 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:MITOCHONDRIA_OXIDATIVE_STRESS Maps_Modules_end References_begin: PMID:9069260 Inactive RAF1 is associated in the cytoplasm with YWHAB. YWHAB binds to RAF1 via the Ser259 phosphorylation site. This interaction stabilises the inactive conformation of RAF1, in which the RAS-binding Cysteine-rich doomain (CRD) is obscured. RAF1 contains an additional RAS-binding domain (RBD). 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TGFBR1 binds to PARD6A and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for binding to TGFBR1 TGFB stimulation induces redistribution of TGFBRII into tight junctions. PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="PARD6A"/> <bbox w="63.0" h="38.0" x="1136.8677" y="1950.8235"/> <glyph class="state variable" id="_f967be97-a730-4097-8af7-c99284dcb06f"> <state value="P" variable="S345"/> <bbox w="35.0" h="10.0" x="1144.1799" y="1945.8235"/> </glyph> </glyph> <glyph class="complex" id="s2500_csa323" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:L1CAM Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="s2500"/> <bbox w="77.0" h="56.0" x="577.0" y="3675.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s1643_emtc_emtc_sa894"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: L1 cell adhesion molecule HUGO:L1CAM, HGNC:6470, ENTREZ:3897, GENECARDS:GC0XM153126, UNIPROT:P32004 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: ISBN:978-953-51-0410-0 PMID:8893017 PMID:20044598 The adhesion molecule L1CAM (CD171) is a 220 kD transmembrane glyocoprotein and belongs to the immunoglobulin superfamily. The extracellular part of the molecule comprises six Ig-like domains followed by 5 fibronectin type III repeats. The transmembrane domain is followed by a short cytoplasmic tail of 32kD PMID:10413675 L1CAM can be expressed and mediate its effects as a membrane-bound form. L1CAM can also be proteolytically cleaved by different proteases releasing a soluble ectodomain that is likewise functionally active. PMID:16199880 PMID:11706054 The metalloproteases ADAM 10 and 17 as well as plasmin have been described to cleave L1CAM generating a soluble 200 kD and 150 kD form, respectively After ADAM-mediated cleavage, the membrane-bound intracellular C-terminal fragment of L1CAM can be further processed by the presenilin/gamma-secretase complex giving rise of a 28 kD fragment. PMID:19260824 This small intracellular fragment translocates into the nucleus where it is thought to contribute to L1CAM-dependent gene regulation. L1CAM can bind to different substrates/molecules in a cell and context dependent manner. PMID:10469653 LACAM can undergo homophilic binding to itself as a membrane-bound or shedded form. PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. PMID:8898967 PMID:8636223 PMID:11553709 PMID:10455125 PMID:16377081 PMID:7613634 PMID:1720120 L1CAM can interact with a plethora of other proteins, e.g. integrins aVb1, aVb3, aVb5, a5b1, neuropilin-1, CD24, neurocan, and axonin-1/TAX-1. PMID:6368220 L1CAM was originally identified in cells of the nervous system PMID:9127006 L1CAM expression has been also found in certain populations of hematopoietic cells. PMID:19273627 Potential role for L1CAM in transendothelial migration and trafficking of murine dendritic cells. PMID:9864376 Furthermore, L1CAM is expressed by renal tubular epithelial cells under physiological conditions being involved in branching of renal tubes in the kidney However, distribution of L1CAM in adults is quite restricted so that its elevated expression in cancerous tissues which is discussed in the next paragraph favours its suitability as therapeutic target in anti-cancer therapy. PMID:19356150 PMID:21195665 L1CAM expression in tumors can be associated with the activation of several signalling pathways that are known to play a pivotal role in tumor progression e.g. the MAPK/ERK and AKT pathway or FAK-mediated signalling PMID:15716380 PMID:17699774 PMID:20501702 L1CAM is a target gene of b-catenin-TCF signaling in colorectal cancer cells. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis The transmembrane localization and shedding of L1CAM by metalloproteases, including ADAM10 could be useful for detection and as target for colon cancer therapy. Expression of L1CAM and ADAM10 in human colon cancer cells induces metastasis. NFkB signaling and ezrin are essential for L1CAM-mediated metastasis of colon cancer cells. PMID:21123622 Gavert and al. showed that L1CAM-mediated colon cancer cell metastasis does not require changes in EMT and cancer stem cell markers. BUT in other context, PMID:19435915 PMID:21109948 Geismann and al. showed that upregulation of L1CAM in pancreatic duct cells is TGFB1- and SNAI2-dependent. Binding of SNAI2 to the L1CAM promoter is essential for TGFB1-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. TGFB1–mediated L1CAM expression is SMAD independent but requires JNK activation. In the context of the human PDAC (pancreatic ductal epithelial cell) line H6c7 which mimics the early steps in PDAC tumorigenesis,TGFB1 induces SNAI2 expression in H6c7 cells through JNK activation. THUS, the impact of L1CAM on EMT might be either tumor specific and/or tumor stage dependent. Further studies are required to elaborate whether upregulation of L1CAM is part of the EMT or even the inducing event. If it is the case, elevated cell migration and apoptosis resistance could be abolished by interfering wih TGFB1 signaling or by supression of SNAI2 or L1CAM. PMID:16506207 PMID:17952127 PMID:21373966 Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated. A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes. Besides its ability to induce Erk1/2 and FAK signalling pathways, L1CAM can also lead to the activation of NF-kB, so that inhibition of NF-kB reduced L1CAM-mediated metastasis of colon cancer cells. PMID:17145883 Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases B-catenin transcriptional activity, thus increases scattering and motility of MCF7 breast carcinoma cells. 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 5, type 2 (vascular endothelium) HUGO:CDH5, HGNC:1764, ENTREZ:1003, UNIPROT:P33151, GENECARDS:GC16P066400 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. 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<notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin14* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="s2508"/> <bbox w="98.0" h="48.0" x="527.0" y="3247.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s2352_emtc_emtc_sa1218"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 14 HUGO:CLDN14, HGNC:2035, ENTREZ:23562, UNIPROT:O95500, GENECARDS:GC21M037832 Identifiers_end 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id="s2520_emtc_emtc_sa1782"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:11413131 E-cadherin dimerization is essential for adhesion to the integrin aEb7 PMID:17325197 Interaction between E-cadherin and aEb7 integrin plays major role in effective tumor cell lysis, during cytolytic granule polarization and subsequent exocytosis References_end Identifiers_begin: Identifiers_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: cadherin 1, type 1, E-cadherin (epithelial) HUGO:CDH1, HGNC:1748, ENTREZ:999, GENECARDS:GC16P068771, UNIPROT:P12830 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS MODULE:LYSOSOME_ENDOSOME Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. PMID:16371504 N-cadherin is phosphorylated by c-Src at Tyr-820, Tyr-853, Tyr-860, Tyr-884, and Tyr-886. Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="86.0" h="26.0" x="543.5" y="3484.75"/> <glyph class="unit of information" id="_b71fb266-2577-48eb-99f0-ac1e9ec5ef5b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="576.5" y="3479.75"/> </glyph> <glyph class="state variable" id="_1b1f2bdd-828d-4d05-ade4-a4807a8a40d4"> <state value="" variable="Y"/> <bbox w="15.0" h="10.0" x="536.0" y="3480.8418"/> </glyph> <glyph class="state variable" 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HGNC:4041 ENTREZ:7976 UNIPROT:Q9NPG1 frizzled family receptor 4 HUGO:FZD4 HGNC:4042 ENTREZ:8322 UNIPROT:Q9ULV1 frizzled family receptor 5 HUGO:FZD5 HGNC:4043 ENTREZ:7855 UNIPROT:Q13467 frizzled family receptor 6 HUGO:FZD6 HGNC:4044 ENTREZ:8323 UNIPROT:O60353 frizzled family receptor 7 HUGO:FZD7 HGNC:4045 ENTREZ:8324 UNIPROT:O75084 frizzled family receptor 8 HUGO:FZD8 HGNC:4046 ENTREZ:8325 UNIPROT:Q9H461 frizzled family receptor 9 HUGO:FZD9 HGNC:4047 ENTREZ:8326 UNIPROT:O00144 frizzled family receptor 10 HUGOFZD10 HGNC:4039 ENTREZ:11211 UNIPROT:Q9ULW2 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:17884187 Activators: Fz1 Fz4 PMID:19020754 PMID:14704854 PMID:17127310 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="FZD*"/> <bbox w="80.0" h="50.0" x="1085.9231" y="6037.846"/> <glyph class="unit of information" id="_5ea86c3d-6048-459d-96e6-9aefdc4ad4db"> <label text="receptor"/> <bbox w="45.0" h="10.0" 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id="_f44254c2-b0d0-4678-82d0-1f328c07745d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1644.2976" y="6022.421"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s2531_sa2193" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Receptor tyrosine kinase epidermal growth factor receptor "epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)" ERBB HUGO:EGFR HGNC:3236 ENTREZ:1956 UNIPROT:P00533 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian) NGL "v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog)" HUGO:ERBB2 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) LCCS2 "lethal congenital contracture syndrome 2" HUGO:ERBB3 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) "v-erb-a avian erythroblastic leukemia viral oncogene homolog-like 4" HUGO:ERBB4 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: RTKs exist as inactive monomers; after binding to their ligands they form dimers and their intracellular domains are activated. PMID:17496910 PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="EGFR family*"/> <bbox w="86.0" h="56.0" x="2178.5264" y="6035.3945"/> <glyph class="unit of information" id="_c1cc5edf-d561-4a63-878c-52184d6b0ad4"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2211.5264" y="6030.3945"/> </glyph> <glyph class="state variable" id="_dbc69ba6-1770-4320-8fed-deaebf5b2691"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2215.7004" y="6030.3945"/> </glyph> <glyph class="unit of information" id="_0e5fe39c-b7da-48bd-8768-df6bc8aeb2ef"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2199.0264" y="6030.3945"/> </glyph> </glyph> <glyph class="complex" id="s2532_csa336" compartmentRef="c14_ca14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Claudin3* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="s2532"/> <bbox w="93.0" h="42.0" x="534.0" y="2873.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s2347_emtc_emtc_sa1213"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Claudin 3 HUGO:CLDN3, HGNC:2045, ENTREZ:1365, GENECARDS:GC07M073183, UNIPROT:O15551 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Claudin3*"/> <bbox w="66.0" h="22.0" x="550.0" y="2876.5"/> <glyph class="unit of information" id="_948b5190-c365-4904-afec-e4075fb4c197"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="573.0" y="2871.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2533_csa337" compartmentRef="emtc_emtc_c6_emtc_emtc_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:Occludin* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="s2533"/> <bbox w="88.0" h="46.0" x="538.0" y="2546.0"/> <glyph class="macromolecule multimer" id="emtc_emtc_s2354_emtc_emtc_sa1220"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: occludin HUGO:OCLN, HGNC:8104, ENTREZ:100506658, UNIPROT:Q16625, GENECARDS:GC05P068788 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y 474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Occludin*"/> <bbox w="65.0" h="22.0" x="549.5" y="2550.5"/> <glyph class="unit of information" id="_a3e5e791-cfd9-4007-ae3f-12b2cd350dcc"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="572.0" y="2545.5"/> </glyph> <glyph class="state variable" id="_812f0b56-dc83-4c3a-b0d4-cd33ce5e7900"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="609.5" y="2556.5352"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s2534_sa2194" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Laminin 1* laminin, alpha 1 HUGO:LAMA1 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:114518 Laminin-1: LAMA1, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin1*"/> <bbox w="74.0" h="18.0" x="5867.3687" y="6111.8945"/> </glyph> <glyph class="macromolecule" id="s2535_sa2195" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Laminin 8* laminin, alpha 4 HUGO:LAMA4 HGNC:6484 ENTREZ:3910 UNIPROT:Q16363 laminin, beta 1 CLM, "cutis laxa with marfanoid phenotype" HUGO:LAMB1 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin, gamma 1 HUGO:LAMC1 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_MATRIX_ADHESIONS MODULE:ECM Maps_Modules_end References_begin: PMID:10809728 Laminin-8 contains LAMA4, LAMB1, LAMC1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin8*"/> <bbox w="72.0" h="20.0" x="6087.8423" y="6109.421"/> </glyph> <glyph class="macromolecule" id="s2536_sa2196" compartmentRef="emtc_emtc_c40_emtc_emtc_ca40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LAMA5 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <label text="Laminin5*"/> <bbox w="76.0" h="20.0" x="5972.0" y="6112.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_172e083a-d865-4cc2-b098-851e580292e3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20731704 PMID:21317430 In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h. Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation PMID:22406545 TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways PMID:16617148 Negative feedback by SNAI1 itself PMID:17671186 KLF8 directly bound to the promotor of Snail and repressed Snail expression PMID:17563753 Snail promoter is regulated positively by NFkB_p65 PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3252.5" y="3699.0"/> <port id="pr_172e083a-d865-4cc2-b098-851e580292e3_p1" x="3242.5" y="3704.0"/> <port id="pr_172e083a-d865-4cc2-b098-851e580292e3_p2" x="3272.5" y="3704.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_f06d4c54-9a2a-4bb9-829f-0a86379f20dd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20731704 PMID:21317430 In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h. Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation PMID:22406545 TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways PMID:14623871 Activation of Slug (SNAI2) by two mechanisms: -transcriptional activation of Slug by the CTNNB1and TCF/LEF complex -activation of the ERK pathway. When adherens junctions are established in dense cultures, ErbB1/2 and the ERK pathway become inactive, CTNNB1 is localized at adherens junctions, Slug expression is reduced, and E-cadherin transcription is induced. Antibody-mediated disruption of adherens junctions led to nuclear CTNNB1 localization and enhanced beta-catenin signaling, induction of Slug and inhibition of E-cadherin expression. PMID:17093497 PMID:12490555 Snail1 induces Snail2 transcription. Snail is able to induce the expression of Slug and all other neural crest markers (Zic5, FoxD3, Twist and Ets1) PMID:16510505 Snail2 activates the Snail2 promoter PMID:21199805 Twist1 binds to an E-box on the proximate Snail2 promoter to induce its transcription. PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression PMID:17550342 Activation of KIT by binding to KITLG induces SNAI2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3241.369" y="4049.0"/> <port id="pr_f06d4c54-9a2a-4bb9-829f-0a86379f20dd_p1" x="3231.369" y="4054.0"/> <port id="pr_f06d4c54-9a2a-4bb9-829f-0a86379f20dd_p2" x="3261.369" y="4054.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0bd47f27-5aad-4841-8374-6482f145767a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20731704 PMID:19208835 TCF8 (ZEB1) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator. PMID:21317430 In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h. Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3729.0" y="3877.5"/> <port id="pr_0bd47f27-5aad-4841-8374-6482f145767a_p1" x="3749.0" y="3882.5"/> <port id="pr_0bd47f27-5aad-4841-8374-6482f145767a_p2" x="3719.0" y="3882.5"/> </glyph> <glyph class="and" orientation="horizontal" id="logicglyph_e25f2517-d648-4262-9686-1e33b2a7bcf6"> <bbox w="20.0" h="20.0" x="3578.496" y="3785.652"/> <port id="logicglyph_e25f2517-d648-4262-9686-1e33b2a7bcf6_p1" x="3568.496" y="3795.652"/> <port id="logicglyph_e25f2517-d648-4262-9686-1e33b2a7bcf6_p2" x="3608.496" y="3795.652"/> </glyph> <glyph class="process" orientation="vertical" id="pr_412158a8-8fd9-444f-aa21-fa2a176e4f75"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3006.5" y="3979.5"/> <port id="pr_412158a8-8fd9-444f-aa21-fa2a176e4f75_p1" x="3011.5" y="3969.5"/> <port id="pr_412158a8-8fd9-444f-aa21-fa2a176e4f75_p2" x="3011.5" y="3999.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4c63cff2-061a-422c-8977-addc6ba335cf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21883379 PMID:18297062 TWIST is a downstream target of HIF-1 Hypoxia or HIF-1 induces EMT through the direct activation of TWIST expression PMID:19412634 Twist is a target of Snail1 PMID:22945800 PMID:21317430 Expression of Twist1 and Snail1 are mutually dependent Knock-down of Snail1 downregulates Twist1 protein and mRNA Knock- down of Twist1 interferes with TGFb-mediated induction of Snail1. PMID:22006115 Alternatively, it has also been reported that Snail1 transcriptionally represses Twist1 PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1 HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression PMID:17403902 Twist1 is a direct downstream target of NKFB. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3079.5" y="3734.75"/> <port id="pr_4c63cff2-061a-422c-8977-addc6ba335cf_p1" x="3084.5" y="3724.75"/> <port id="pr_4c63cff2-061a-422c-8977-addc6ba335cf_p2" x="3084.5" y="3754.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9759d0b7-38b0-4ec1-8117-16cdd2001267"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3664.0" y="3737.5"/> <port id="pr_9759d0b7-38b0-4ec1-8117-16cdd2001267_p1" x="3669.0" y="3727.5"/> <port id="pr_9759d0b7-38b0-4ec1-8117-16cdd2001267_p2" x="3669.0" y="3757.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_5dd8df9b-71e3-4e67-864e-1a49b2282ba2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16001073 RAC1B increases the cellular level of ROS, causing an upregulation of Snail rexpression and induction of EMT PMID:17563753 Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3375.0" y="3699.0"/> <port id="pr_5dd8df9b-71e3-4e67-864e-1a49b2282ba2_p1" x="3365.0" y="3704.0"/> <port id="pr_5dd8df9b-71e3-4e67-864e-1a49b2282ba2_p2" x="3395.0" y="3704.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_58342e72-d92c-4cf1-baee-246a0921c061"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19448627 Wild-type p53 inhibits Slug protein expression. Slug protein levels were significantly decreased in parallel with increased wtp53 accumulation. Slug mRNA levels did not change indicating that Slug is not transcriptionally regulated by wtp53 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3374.0" y="4049.0"/> <port id="pr_58342e72-d92c-4cf1-baee-246a0921c061_p1" x="3364.0" y="4054.0"/> <port id="pr_58342e72-d92c-4cf1-baee-246a0921c061_p2" x="3394.0" y="4054.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e289f1cf-11d4-4630-a631-d107e38c1ea6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:28212565 Double negative feedback loop between ZEB1 and miR200 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3664.0" y="3927.5"/> <port id="pr_e289f1cf-11d4-4630-a631-d107e38c1ea6_p1" x="3669.0" y="3917.5"/> <port id="pr_e289f1cf-11d4-4630-a631-d107e38c1ea6_p2" x="3669.0" y="3947.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2e7c00f0-37d5-447d-88c6-c3dd715d1d33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2864.5" y="4029.0"/> <port id="pr_2e7c00f0-37d5-447d-88c6-c3dd715d1d33_p1" x="2884.5" y="4034.0"/> <port id="pr_2e7c00f0-37d5-447d-88c6-c3dd715d1d33_p2" x="2854.5" y="4034.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b25a579b-b311-4c6a-a1ec-6950a6d1d6cc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:18297062 TWIST is a downstream target of HIF-1 Hypoxia or HIF-1 induces EMT through the direct activation of TWIST expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3028.0" y="3770.7046"/> <port id="pr_b25a579b-b311-4c6a-a1ec-6950a6d1d6cc_p1" x="3048.0" y="3775.7046"/> <port id="pr_b25a579b-b311-4c6a-a1ec-6950a6d1d6cc_p2" x="3018.0" y="3775.7046"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_029d2e0b-1dd2-4feb-b522-dc6763006f6f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3719.0" y="3777.5"/> <port id="pr_029d2e0b-1dd2-4feb-b522-dc6763006f6f_p1" x="3709.0" y="3782.5"/> <port id="pr_029d2e0b-1dd2-4feb-b522-dc6763006f6f_p2" x="3739.0" y="3782.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0d61a548-baf5-43c2-9f25-259b5b56b603"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3864.1816" y="4015.3003"/> <port id="pr_0d61a548-baf5-43c2-9f25-259b5b56b603_p1" x="3869.1816" y="4005.3003"/> <port id="pr_0d61a548-baf5-43c2-9f25-259b5b56b603_p2" x="3869.1816" y="4035.3003"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_ecd876bb-5a38-4c26-95a1-b250ae314958"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10048576 The gene expressions of MMP-1, MMP-3, and MMP-9 and gelatinolytic activity of MMP-9 were significantly increased in high ETS-1 expression cells. Low ETS-1 expression cells could not spread on a vitronectin substratum, and the phosphorylation of focal adhesion kinase was markedly impaired because of the reduced expression of integrin b3 PMID:19208835 TCF8 (ZEB1) regulates cell invasion and migration via MMP1 expression. TCF8 is likely to be dispensable for endothelial cell motility. One possible mechanism underlying the increased invasiveness and migration might be the up-regulated digestion of ECMs via TCF8-mediated transcriptional regulation of the gene encoding MMP1. MMP1 induction during tube formation was significantly enhanced in Matrigel when TCF8 was silenced PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. PMID:20589835 Our results indicate that MT1-MMP is a direct down-stream target in the Wnt signaling pathway, and that one of the ways accumulated beta-catenin contributes to colorectal carcinogenesis is by transactivating this gene. MT1-MMP is one target gene of Lef-1/Tcf-4 (Takahashi et al, 2002) PMID:22439866 c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. PMID:9811054 Nuclear factor kappaB/p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1beta-stimulated synovial fibroblasts. PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2413.25" y="4805.562"/> <port id="pr_ecd876bb-5a38-4c26-95a1-b250ae314958_p1" x="2433.25" y="4810.562"/> <port id="pr_ecd876bb-5a38-4c26-95a1-b250ae314958_p2" x="2403.25" y="4810.562"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dbc195af-b41c-48c9-9462-cbd59d414b41"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22439866 c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. 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<notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5450.75" y="2870.5"/> <port id="pr_cee2e5f9-279b-4415-8ca0-30172e3acb3f_p1" x="5440.75" y="2875.5"/> <port id="pr_cee2e5f9-279b-4415-8ca0-30172e3acb3f_p2" x="5470.75" y="2875.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_7be6b356-b14e-4618-a225-67f15127def0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17486063 ZEB1 represses PATJ* expression PMID:17012742 Knock down of LIN7 results in 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<html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 PMID:18403754 PMID:16607286 Keratin-14, 18, 19, Vimentin are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin: PMID:16077980 the NF-kappaB binding site is located in the human vimentin promoter. 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MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2413.5" y="4845.125"/> <port id="pr_ec2b59e7-197d-45a4-b950-8542e9bc430e_p1" x="2433.5" y="4850.125"/> <port id="pr_ec2b59e7-197d-45a4-b950-8542e9bc430e_p2" x="2403.5" y="4850.125"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_fc8984a3-bd85-4667-bbfc-83196f7e1ee8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2160.75" y="4845.3965"/> <port id="pr_fc8984a3-bd85-4667-bbfc-83196f7e1ee8_p1" x="2180.75" y="4850.3965"/> <port id="pr_fc8984a3-bd85-4667-bbfc-83196f7e1ee8_p2" x="2150.75" y="4850.3965"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b6abca4f-fc55-4531-ba0e-d903cdd5684e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10048576 The gene expressions of MMP-1, MMP-3, and MMP-9 and gelatinolytic activity of MMP-9 were significantly increased in high ETS-1 expression cells. Low ETS-1 expression cells could not spread on a vitronectin substratum, and the phosphorylation of focal adhesion kinase was markedly impaired because of the reduced expression of integrin b3 PMID:15003528 NF-kappaB binds to a polymorphic repressor element in the MMP-3 promoter. 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Low ETS-1 expression cells could not spread on a vitronectin substratum, and the phosphorylation of focal adhesion kinase was markedly impaired because of the reduced expression of integrin b3 PMID:16079281 MMP-9 transcription is activated in response to Snail expression Oncogenic H-Ras (RasV12) synergistically co-operates with Snail in the induction of MMP-9 transcription and expression. Phosphorylated Sp-1 is recruited to the MMP-9 promoter following activation of the Erk1/2 pathway PMID:19564415 The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression. This explains the role of FOXO3 in promoting tumor invasion. PMID:22439866 c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. PMID:8844971 Molecular mechanism of transcriptional activation of human gelatinase B (=MMP9) by proximal promoter. (NFKB) PMID:16556862 ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2410.5" y="4950.25"/> <port id="pr_0ecef322-03b8-43d7-8751-46ecbd40362d_p1" x="2430.5" y="4955.25"/> <port id="pr_0ecef322-03b8-43d7-8751-46ecbd40362d_p2" x="2400.5" y="4955.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_56ae69a9-0951-4f38-9ce6-19b9153e70e9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22439866 c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2157.75" y="4950.5264"/> <port id="pr_56ae69a9-0951-4f38-9ce6-19b9153e70e9_p1" x="2177.75" y="4955.5264"/> <port id="pr_56ae69a9-0951-4f38-9ce6-19b9153e70e9_p2" x="2147.75" y="4955.5264"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_927314a4-3e36-4912-9692-c533b5e61790"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15592504 PMID:16716598 SP1 and HIF1 complex (HIF2_alpha_ and HIF1_beta_) cooperatively induce MMP1 transcriptional expression PMID:20589835 Our results indicate that MT1-MMP is a direct down-stream target in the Wnt signaling pathway, and that one of the ways accumulated beta-catenin contributes to colorectal carcinogenesis is by transactivating this gene. MT1-MMP is one target gene of Lef-1/Tcf-4 (Takahashi et al, 2002) PMID:16556862 NF-κB is an important transcriptional factor of MT1-MMP expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2410.25" y="5061.375"/> <port id="pr_927314a4-3e36-4912-9692-c533b5e61790_p1" x="2430.25" y="5066.375"/> <port id="pr_927314a4-3e36-4912-9692-c533b5e61790_p2" x="2400.25" y="5066.375"/> </glyph> <glyph class="and" orientation="vertical" id="logicglyph_8904b41c-4d39-4926-ae4a-18b49ecb14e2"> <bbox w="20.0" h="20.0" x="2552.36" y="4684.934"/> <port id="logicglyph_8904b41c-4d39-4926-ae4a-18b49ecb14e2_p1" x="2562.36" y="4674.934"/> <port id="logicglyph_8904b41c-4d39-4926-ae4a-18b49ecb14e2_p2" x="2562.36" y="4714.934"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dd0f40db-476a-4c93-aec4-bd4c1bd2d0e5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2157.75" y="5061.6562"/> <port id="pr_dd0f40db-476a-4c93-aec4-bd4c1bd2d0e5_p1" x="2177.75" y="5066.6562"/> <port id="pr_dd0f40db-476a-4c93-aec4-bd4c1bd2d0e5_p2" x="2147.75" y="5066.6562"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_636e4c40-9a2a-4e5c-9a4c-379ad9e3768c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2410.6875" y="5101.0664"/> <port id="pr_636e4c40-9a2a-4e5c-9a4c-379ad9e3768c_p1" x="2430.6875" y="5106.0664"/> <port id="pr_636e4c40-9a2a-4e5c-9a4c-379ad9e3768c_p2" x="2400.6875" y="5106.0664"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dc7a69a7-1ffa-43bb-af34-f9e5a8cbe08e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2159.25" y="5101.4756"/> <port id="pr_dc7a69a7-1ffa-43bb-af34-f9e5a8cbe08e_p1" x="2179.25" y="5106.4756"/> <port id="pr_dc7a69a7-1ffa-43bb-af34-f9e5a8cbe08e_p2" x="2149.25" y="5106.4756"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c79920de-81a1-407b-b370-3f80f0b3bdb3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1424.0" y="5135.162"/> <port id="pr_c79920de-81a1-407b-b370-3f80f0b3bdb3_p1" x="1444.0" y="5140.162"/> <port id="pr_c79920de-81a1-407b-b370-3f80f0b3bdb3_p2" x="1414.0" y="5140.162"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_56abe578-4aa7-4bb5-af6c-37754c105017"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17012742 Knock down of LIN7 results in loss of expression of PATJ* References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2343.75" y="2318.9617"/> <port id="pr_56abe578-4aa7-4bb5-af6c-37754c105017_p1" x="2363.75" y="2323.9617"/> <port id="pr_56abe578-4aa7-4bb5-af6c-37754c105017_p2" x="2333.75" y="2323.9617"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c346e65f-b881-4d7f-a376-f60c20c592f1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17012742 Without LIN7, PALS1 is instable and degraded. Binding of LIN7 to PALS1 stabilizes the latter. Loss of Lin7 correlates with the lost of PALS1 expression (translation) but the level of mRNA-PALS1 is not changed (transcription). The effect is rescued by exogenous LIN7 containing L27 but not PGZ domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1422.5" y="2319.5"/> <port id="pr_c346e65f-b881-4d7f-a376-f60c20c592f1_p1" x="1442.5" y="2324.5"/> <port id="pr_c346e65f-b881-4d7f-a376-f60c20c592f1_p2" x="1412.5" y="2324.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_8c3ed18f-8d71-4396-ae5d-32c34377a8d7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:2288140 PMID:8365569 Without PALS1 (Sdt in Drosophila), CRB is delivered to the apical plasma membrane but rapidly endocytosed and degraded References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4932.0244" y="2129.6616"/> <port id="pr_8c3ed18f-8d71-4396-ae5d-32c34377a8d7_p1" x="4952.0244" y="2134.6616"/> <port id="pr_8c3ed18f-8d71-4396-ae5d-32c34377a8d7_p2" x="4922.0244" y="2134.6616"/> </glyph> <glyph class="process" orientation="vertical" id="pr_480cb1fe-403a-44a6-9278-69afe34aa72a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: CRB3/PALS1* Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:8365569 PMID:18005931 PMID:11740559 PMID:11740560 CRB3 and PALS1* in the same pathway PALS1* binds to CRB3 via its PDZ domain References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6217.0996" y="2965.0"/> <port id="pr_480cb1fe-403a-44a6-9278-69afe34aa72a_p1" x="6222.0996" y="2955.0"/> <port id="pr_480cb1fe-403a-44a6-9278-69afe34aa72a_p2" x="6222.0996" y="2985.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3916b3b7-bb23-4875-8b96-878fc2ac957d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: InaD-like (Drosophila) HUGO:INADL, HGNC:28881, ENTREZ:10207, UNIPROT:Q8NI35, GENECARDS:GC01P062208 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:10102271 PATJ* is a component of the Crb complex. The L27 domain of PATJ* binds to the L27 domain of PALS1* PMID:11927608 PALS1 contains two L27 domains, 1 PDZ domain, 1 SH3 domain, 1 inactive Guanylate kinase domain Interaction PALS1-LIN7 via the C-terminal L27 domain of PALS1 PMID:10871881 LIN7 contains one L27 domain, 1 PDZ domain PMID:18177979 Lin7 is a component of the Crumbs complex in Drosophila epithelia and photoreceptor cells PMID:2288140 Apical recuritment of PATJ* and LIN7 depends on the CRB3/PALS1* complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6241.1924" y="2742.0"/> <port id="pr_3916b3b7-bb23-4875-8b96-878fc2ac957d_p1" x="6246.1924" y="2762.0"/> <port id="pr_3916b3b7-bb23-4875-8b96-878fc2ac957d_p2" x="6246.1924" y="2732.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9bf0f9e5-9e2c-4e18-b23b-2d7a74738451"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" 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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4778.5" y="3350.2422"/> <port id="pr_a846061e-aac8-42d0-ac45-4a1344f57b1b_p1" x="4768.5" y="3355.2422"/> <port id="pr_a846061e-aac8-42d0-ac45-4a1344f57b1b_p2" x="4798.5" y="3355.2422"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dcbd9ee2-89d0-4fba-8914-ada5bbacbbe0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4517.25" y="3244.5"/> <port id="pr_dcbd9ee2-89d0-4fba-8914-ada5bbacbbe0_p1" x="4507.25" y="3249.5"/> <port id="pr_dcbd9ee2-89d0-4fba-8914-ada5bbacbbe0_p2" x="4537.25" y="3249.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_13ecdf1f-d1cb-4c4f-8ffe-29dbd05cf881"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4781.75" y="3245.0083"/> <port id="pr_13ecdf1f-d1cb-4c4f-8ffe-29dbd05cf881_p1" x="4771.75" y="3250.0083"/> <port id="pr_13ecdf1f-d1cb-4c4f-8ffe-29dbd05cf881_p2" x="4801.75" y="3250.0083"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_fab87baa-0154-43a4-acaa-f396daf9a716"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:9753323 Heterotrimeric complex Lin2-Lin7-Lin10 (C. elegans) PMID:9822620 human lin10 contains 2 PDZ domains human lin10 interacts with mammalian lin2 (CASK) mammalian lin7 interacts with mammalian lin2 (CASK) heterotrimeric complex Lin2-lin7-Lin10 in mouse brain PMID:9753324 Trimeric complex Lin2-Lin7-Lin10 in brain. Each protein contains PDZ domains-not involved in complex formation References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4920.5625" y="3289.5725"/> <port id="pr_fab87baa-0154-43a4-acaa-f396daf9a716_p1" x="4910.5625" y="3294.5725"/> <port id="pr_fab87baa-0154-43a4-acaa-f396daf9a716_p2" x="4940.5625" y="3294.5725"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_0e896458-1f1f-4a2e-bcdd-7c2f98a31cbe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS MODULE:CYTOSKELETON_POLARITY Maps_Modules_end References_begin: PMID:17012742 Without LIN7, PALS1 is instable and degraded Binidng of LIN7 to PALS1 stabilizes the latter References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2116.125" y="1791.614"/> <port id="pr_0e896458-1f1f-4a2e-bcdd-7c2f98a31cbe_p1" x="2106.125" y="1796.614"/> <port id="pr_0e896458-1f1f-4a2e-bcdd-7c2f98a31cbe_p2" x="2136.125" y="1796.614"/> </glyph> <glyph class="process" orientation="vertical" id="pr_27cb2ecc-ac1d-4035-954f-45262f57114d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: transforming growth factor, beta receptor II (70/80kDa) HUGO:TGFBR2, HGNC:11773, ENTREZ:7048, UNIPROT:P37173, GENECARDS:GC03P030623 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:16474430 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6196.716" y="4478.625"/> <port id="pr_27cb2ecc-ac1d-4035-954f-45262f57114d_p1" x="6201.716" y="4498.625"/> <port id="pr_27cb2ecc-ac1d-4035-954f-45262f57114d_p2" x="6201.716" y="4468.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_daaa1f74-b47c-4b9a-9613-7eefbc05377e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6273.534" y="4438.6675"/> <port id="pr_daaa1f74-b47c-4b9a-9613-7eefbc05377e_p1" x="6278.534" y="4458.6675"/> <port id="pr_daaa1f74-b47c-4b9a-9613-7eefbc05377e_p2" x="6278.534" y="4428.6675"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e4c44b0a-100b-4aac-8d29-5c16b2cb24cc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:12809600 PMID:22710166 The active ligand–receptor complex is a heterotetrameric complex This complex consists of an active dimer of TGFB and homodimers of both TGFBRI and TGFBR2. Within the active receptor complex, TGFBR2 autophosphorylates itself and catalyzes transphosphorylation of the TGFBR1. Transphosphorylation of the TGFBRI activates its kinase activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6211.062" y="4065.125"/> <port id="pr_e4c44b0a-100b-4aac-8d29-5c16b2cb24cc_p1" x="6216.062" y="4085.125"/> <port id="pr_e4c44b0a-100b-4aac-8d29-5c16b2cb24cc_p2" x="6216.062" y="4055.125"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6632c3d5-3dc6-4cf5-941a-e1c87b248664"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. Each TGFB gene encodes a preproprotein sequence consisting of a signal peptide, a propeptide (LAP) and the mature TGFB After translocation into the endoplamic reticulum, TGFB proprotein monomers form homomdimers liked by disulfide bonds, forming pro-TGFB In the Golgi, the prodomains undergo glycosylation. Also in the Golgi, FURIN hydolyzes the leavage site from LAP, creating TGFB and LAP-derived homodimers The 2 homodimers remain noncovalently associated and are secreted. The LAP-derived homodimer prevents TGFB from binding TGFB receptors. 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gene expressions of MMP-1, MMP-3, and MMP-9 and gelatinolytic activity of MMP-9 were significantly increased in high ETS-1 expression cells. Low ETS-1 expression cells could not spread on a vitronectin substratum, and the phosphorylation of focal adhesion kinase was markedly impaired because of the reduced expression of integrin b3 PMID:7512751 PMID:7528107 Integrin aVb3 plays an important role in angiogenesis. Bblocking of the binding of endothelial integrin aVb3 inhibits angiogenesis and forces neovascular ECs into apoptosis (Brooks et al., 1994a,b). PMID:24376839 PTP4A3 is implicated in cell adhesion and the regulation of focal adhesion components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP contains an integrin-binding site called RBD Several RBD-binding integrins are able to activate latnet TGFB complex through binding this site. PMID:21909923 The previously mentionned integrins are: a8b1, aVb1, aVb5, aVb6, aVb8. In the complex Ingergin-large latent TGFB complex, I picked aVb6 as example. But a8b1, aVb1, aVb5, and aVb8 can active TGFB with the same mechanism. MMP13 activates TGFB by cleavage of LAP Plasmin activates TGFB by cleavage of LAP MMP9 activates TGFB by cleavage of LAP Integrin aVb6 activates the ECM-bound latent TGFB1 and TGFB3 by traction, without participation of MMPs, so no hydrolyse or clevage Integrin aVb8 and MMP14 (so-called MT1-MMP) cooperate to activate the ECM-bound latent TGFB1 and TGFB3: -Integrin aVb8 binds LAP from the large latent complex -MMP14 then is recruited to cleave LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1183.9998" y="6588.375"/> <port id="pr_7df73df3-9dd6-47d4-a876-b630985b39d6_p1" x="1188.9998" y="6578.375"/> <port id="pr_7df73df3-9dd6-47d4-a876-b630985b39d6_p2" x="1188.9998" y="6608.375"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_78eea690-9a02-43ef-9fc3-5df422807325"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 Integrin aVb6 activates the ECM-bound latent TGFB1 and TGFB3 by traction, without participation of MMPs, so no hydrolyse or clevage Integrin aVb8 and MMP14 (so-called MT1-MMP) cooperate to activate the ECM-bound latent TGFB1 and TGFB3: -Integrin aVb8 binds LAP from the large latent complex -MMP14 then is recruited to cleave LAP PMID:18342983 Two main models are proposed how integrins contribute to latent TGFB1 activation: (1) In a protease-dependent mechanism, integrins avb8and avb3 are suggested to simultaneously bind the latent TGFB1 complex and proteinases. This close vicinity at the cell surface improves enzymatic cleavage of the latent complex to release active TGFB1. (2) Integrins avb3, avb5, avb6, and avb8 appear to change the conformation of the latent TGFB1 complex by transmitting cell traction forces. PMID:19854168 Integrins are linked intracellularly to cytoskleletal elements and associated contractile machinery, and extracellularly to ECM. Thus contractility of a cell bound to a rigid ECM generates force between a matrix molecule and its receptor. Such forces may uncouple LLCs so as to free TGFb. PMID:16710477 The small GTPase RhoA has well established roles in contractility and has been shown to promote TGFb activation from LLCs. 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id="pr_ccd0e3ec-f8b6-43a9-945e-e5096cfdfba4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9335507 TGFB rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGFB responses. 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id="pr_5eeec1f6-a8cb-4391-ad48-f1069e209bbd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4819.375" y="4145.0913"/> <port id="pr_5eeec1f6-a8cb-4391-ad48-f1069e209bbd_p1" x="4809.375" y="4150.0913"/> <port id="pr_5eeec1f6-a8cb-4391-ad48-f1069e209bbd_p2" x="4839.375" y="4150.0913"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1f44de37-4929-44c1-b5ee-89c79335cc7e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 PMID:11792802 SARA is a cytoplasmic protein that specifically interacts withe no-activated Smad2 and the receptor complex SARA thus forms the bridge between the receptor and Smad2 and assisting in the specific phosphorylation of Smad2 by the TGFBR1 The stable interaction of SARA with non-phosphorylated Smad2 also inhibits nuclear import of Smad2 PMID:10934479 The nuclear import function of Smad2 is masked by SARA and unmasked by TGFB- dependent phosphorylation References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5949.7666" y="4016.25"/> <port id="pr_1f44de37-4929-44c1-b5ee-89c79335cc7e_p1" x="5954.7666" y="4006.25"/> <port id="pr_1f44de37-4929-44c1-b5ee-89c79335cc7e_p2" x="5954.7666" y="4036.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0afba367-8b75-4178-817b-a92fe426497a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9865696 Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/ Smad4 complexes and nuclear translocation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5955.75" y="4235.9717"/> <port id="pr_8f734f2f-0133-4577-af68-3f97d802e684_p1" x="5975.75" y="4240.9717"/> <port id="pr_8f734f2f-0133-4577-af68-3f97d802e684_p2" x="5945.75" y="4240.9717"/> </glyph> <glyph class="process" orientation="vertical" id="pr_850db348-f52b-42c3-8aca-3c57d7f5fe6b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5855.7285" y="4015.0"/> <port id="pr_850db348-f52b-42c3-8aca-3c57d7f5fe6b_p1" x="5860.7285" y="4005.0"/> <port id="pr_850db348-f52b-42c3-8aca-3c57d7f5fe6b_p2" x="5860.7285" y="4035.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_91dec835-806f-4200-8b55-aea3ce739130"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9311995 Smad2 and Smad3 interacted with TGFBR1 after it was phosphorylated by TGFBR2 TGFB1 induced phosphorylation of Smad2 and Smad3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5775.5" y="4200.0"/> <port id="pr_91dec835-806f-4200-8b55-aea3ce739130_p1" x="5780.5" y="4190.0"/> <port id="pr_91dec835-806f-4200-8b55-aea3ce739130_p2" x="5780.5" y="4220.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_05bf8e59-b07d-4926-9b23-f7086eee3f29"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9865696 Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/ Smad4 complexes and nuclear translocation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5850.5" y="4235.0386"/> <port id="pr_05bf8e59-b07d-4926-9b23-f7086eee3f29_p1" x="5840.5" y="4240.0386"/> <port id="pr_05bf8e59-b07d-4926-9b23-f7086eee3f29_p2" x="5870.5" y="4240.0386"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dfb74a64-09b8-4007-8963-7f2d25bd9351"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11792802 PMID:8893010 All mammalian R-Smads and Smad4 reside in the cytoplasm Phosphorylated R-Smads quickly form complexes with Smad4 and possibly prior to nuclear translocation PMID:9389648 Nuclear translocation of R-Smads is independent of Smad4 Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-Smad References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4344.25" y="3831.8984"/> <port id="pr_dfb74a64-09b8-4007-8963-7f2d25bd9351_p1" x="4364.25" y="3836.8984"/> <port id="pr_dfb74a64-09b8-4007-8963-7f2d25bd9351_p2" x="4334.25" y="3836.8984"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f58dc383-b9ac-49af-bf86-244bacd61e5a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:20519943 PMID:17934056 PMID:16474430 PMID:14557817 PMID:21900405 TGFB inhibits proliferation TGFB overproduction causes fibrosis. Each TGFB gene encodes a preproprotein sequence consisting of a signal peptide, a propeptide (LAP) and the mature TGFB After translocation into the endoplamic reticulum, TGFB proprotein monomers form homomdimers liked by disulfide bonds, forming pro-TGFB In the Golgi, the prodomains undergo glycosylation. Also in the Golgi, FURIN hydolyzes the leavage site from LAP, creating TGFB and LAP-derived homodimers The 2 homodimers remain noncovalently associated and are secreted. The LAP-derived homodimer prevents TGFB from binding TGFB receptors. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="524.2633" y="6379.5"/> <port id="pr_f58dc383-b9ac-49af-bf86-244bacd61e5a_p1" x="529.2633" y="6369.5"/> <port id="pr_f58dc383-b9ac-49af-bf86-244bacd61e5a_p2" x="529.2633" y="6399.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_694707a2-c5b6-4fb4-b413-7648007bb008"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6284.8936" y="4168.2"/> <port id="pr_694707a2-c5b6-4fb4-b413-7648007bb008_p1" x="6304.8936" y="4173.2"/> <port id="pr_694707a2-c5b6-4fb4-b413-7648007bb008_p2" x="6274.8936" y="4173.2"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1f30bee5-0253-4a3d-b964-10a54a72c01f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 MMP13 activates TGFB by cleavage of LAP Plasmin activates TGFB by cleavage of LAP MMP9 activates TGFB by cleavage of LAP Integrin aVb6 activates the ECM-bound latent TGFB1 and TGFB3 by traction Integrin aVb8 and MMP14 (so-called MT1-MMP) cooperate to activate the ECM-bound latent TGFB1 and TGFB3: -Integrin aVb8 binds LAP from the large latent complex -MMP14 then is recruited to cleave LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="793.3004" y="6741.6113"/> <port id="pr_1f30bee5-0253-4a3d-b964-10a54a72c01f_p1" x="798.3004" y="6731.6113"/> <port id="pr_1f30bee5-0253-4a3d-b964-10a54a72c01f_p2" x="798.3004" y="6761.6113"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0b39a04d-7adf-4b31-8fca-2bc02555822d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11792802 Following phosphorylation of R-Smads by TGFBR1, Smad oligomerization is thought to occur. PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5747.975" y="4441.0"/> <port id="pr_0b39a04d-7adf-4b31-8fca-2bc02555822d_p1" x="5767.975" y="4446.0"/> <port id="pr_0b39a04d-7adf-4b31-8fca-2bc02555822d_p2" x="5737.975" y="4446.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ae40c895-8df8-4456-a9a8-a1809857c40e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11792802 Following phosphorylation of R-Smads by TGFBR1, Smad oligomerization is thought to occur. PMID:9670020 Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1 This oligomerization does not require Smad4. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6042.3984" y="4441.383"/> <port id="pr_ae40c895-8df8-4456-a9a8-a1809857c40e_p1" x="6047.3984" y="4431.383"/> <port id="pr_ae40c895-8df8-4456-a9a8-a1809857c40e_p2" x="6047.3984" y="4461.383"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f484ce1f-0178-4fca-8f78-999a98b5875c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11224571 Phosphorylated Smad3 recruits Smad4 to form a heterotrimer containing 2 Smad3 and 1 Smad4. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5492.0" y="4372.3125"/> <port id="pr_f484ce1f-0178-4fca-8f78-999a98b5875c_p1" x="5497.0" y="4392.3125"/> <port id="pr_f484ce1f-0178-4fca-8f78-999a98b5875c_p2" x="5497.0" y="4362.3125"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7f9e74e1-ce40-4457-9c22-60f617b12d6d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:9865696 Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/ Smad4 complexes and nuclear translocation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5295.1133" y="4125.5"/> <port id="pr_7f9e74e1-ce40-4457-9c22-60f617b12d6d_p1" x="5300.1133" y="4145.5"/> <port id="pr_7f9e74e1-ce40-4457-9c22-60f617b12d6d_p2" x="5300.1133" y="4115.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3fffcdd8-f2ac-48d7-b51e-4b01e4ae61cc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:11792802 PMID:8893010 All mammalian R-Smads and Smad4 reside in the cytoplasm Phosphorylated R-Smads quickly form complexes with Smad4 and possibly prior to nuclear translocation PMID:9389648 Nuclear translocation of R-Smads is independent of Smad4 Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-Smad References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4690.0" y="3890.8145"/> <port id="pr_3fffcdd8-f2ac-48d7-b51e-4b01e4ae61cc_p1" x="4710.0" y="3895.8145"/> <port id="pr_3fffcdd8-f2ac-48d7-b51e-4b01e4ae61cc_p2" x="4680.0" y="3895.8145"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_73b320e2-a161-4a31-a8a0-58925a89903f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19597490 SMAD3 and SMAD4 interact and form a complex with SNAIL1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3248.5" y="3572.0068"/> <port id="pr_73b320e2-a161-4a31-a8a0-58925a89903f_p1" x="3268.5" y="3577.0068"/> <port 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1420.25" y="2848.25"/> <port id="pr_16c76082-9460-4a55-b733-37889655207a_p1" x="1440.25" y="2853.25"/> <port id="pr_16c76082-9460-4a55-b733-37889655207a_p2" x="1410.25" y="2853.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_938254f2-112d-4b51-a5b0-e2d5b018eef1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3507.75" y="3901.1497"/> <port id="pr_938254f2-112d-4b51-a5b0-e2d5b018eef1_p1" x="3527.75" y="3906.1497"/> <port id="pr_938254f2-112d-4b51-a5b0-e2d5b018eef1_p2" x="3497.75" y="3906.1497"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3d65624a-8968-4d33-9616-89078bf7e48e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: PMID:9865696 SARA interacts directly with Smad2 and Smad3 The C-ter of SARA interacts TGFBR1 and TGFBR2 SARA presents Smad2 to the TGFb receptor Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2-Smad4 complexes and nuclear translocation. PMID:12154066 Small GTPases such as Rab5 catalyse movement of activated receptor complexes to early endosomal compartments Here, the complex encounter SARA: a phospholipid-bound carrier SARA presents Smads to the TGFBR1 PMID:22710166 PMID:11013220 The ligand bound activated receptor complex is internalized via endocytosis PMID:19050695 2 pathways of receptor complex endocytosis: clathrin-mediated or caveolae-mediated Through the clathrin pathway, activated ligan-receptor complex are brought into early endosomes which are enriched with scaffold proteins such as SARA. PMID:12717440 PMID:12724770 Clathrin-dependent internalization into endosome, where the Smad2 anchor SARA is enriched, promotes TGFB signalling. Raft-caveolar internalization pathway contains the Smad7-Smurf2 bound receptor and is required for rapid receptor turnover. Thus, segregation of TGF-b receptors into distinct endocytic compartments regulates Smad activation and receptor turnover References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6055.9546" y="3890.174"/> <port id="pr_3d65624a-8968-4d33-9616-89078bf7e48e_p1" x="6060.9546" y="3880.174"/> <port id="pr_3d65624a-8968-4d33-9616-89078bf7e48e_p2" x="6060.9546" y="3910.174"/> </glyph> <glyph class="process" orientation="vertical" id="pr_86b9fd46-a49c-4f81-89f4-b4da987221cc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11283613 Miz-1 regulates expression of p15INK4b The Myc/Miz1 complex binds to the p15 promoter Myc inhibits binding of p300 to Miz-1 Myc inhibits expression of p15INK4B by binding to Miz-1 (Myc represses p15INK4B by interacting with Miz1) PMID:11283614 Disruption of the Myc-Miz1 interaction prevents repression of p15INK4B by Myc. TGFB relieves Myc-mediated repression of p15INK4B by downregulating Myc bound to the p15INK4B transcriptional initiator region. At the same time TGFB induces the formation of a Smad transcriptional complex that recognizes the p15INK4B promoter. Is is proposed that by relieving the Myc-mediated repression of p15INK4B, TGFB allows this gene to be activated by the Smad complex. TGFB signaling controls p15INK4B activation by 2 coupled events: transactivation and relief of repression. PMID:10454538 Myc prevents inhibition of G1 CDKs by TGFB. Inhibition of the p15 promoter by c-Myc. Enforced expression of Myc abrogates p15INK4B induction and CDK inhibition by TGFB Myc downregulation by TGFB is required for Activation of the p15Ink4b G1 Arrest Pathway 3 populations of endogenous CDK4: Latent pools (400 kDa, source of CDK4 for Cyclin D), Active CDK4-CyclinD complex, Inactive monomeric CDK4 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3569.75" y="2082.0"/> <port id="pr_86b9fd46-a49c-4f81-89f4-b4da987221cc_p1" x="3574.75" y="2102.0"/> <port id="pr_86b9fd46-a49c-4f81-89f4-b4da987221cc_p2" x="3574.75" y="2072.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_088c5c2f-5518-4bd2-b3ed-1c50aa129e1e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3566.416" y="1960.5"/> <port id="pr_088c5c2f-5518-4bd2-b3ed-1c50aa129e1e_p1" x="3571.416" y="1980.5"/> <port id="pr_088c5c2f-5518-4bd2-b3ed-1c50aa129e1e_p2" x="3571.416" y="1950.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_21105894-e0b7-40be-a807-895d02663445"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. The inhibition of CDK4 and CDK6 ability to phosphorylate Rb, maintains Rb-family protein in a hypophosphorylated state which promotes G1 cell cycle arrest References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3467.5" y="1755.6182"/> <port id="pr_21105894-e0b7-40be-a807-895d02663445_p1" x="3457.5" y="1760.6182"/> <port id="pr_21105894-e0b7-40be-a807-895d02663445_p2" x="3487.5" y="1760.6182"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_4b13d1be-a675-4ec0-b07b-105e62fa0052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23140366 PMID:17055429 p16 and p15 activates the pRB tumor supressor by inhibiting the cyclin dependent kinase CDK4 and CDK6, which promotes proliferation. 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PMID:19020303 When Wnt binds its receptor, Frizzled, beta-catenin is released to translocate from the cytoplasm to the nucleus, where it forms a complex with TCF and/or LEF transcription factors and stimulates cyclin D1 gene transcription (Beta-catenin/TCF)- mediated cyclin D1 gene transcription is further regulated by active Rac signaling, phosphorylation by protein kinase A (PKA) PMID:10318916 The cyclin D1 gene is a direct target for transactivation by the beta-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. PMID:10201372 beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation PMID:14712077 PMID:12663502 Cyclin D1 over-expression correlates with beta-catenin activation PMID:15377999 Rac1-GTP augments nuclear accumulation of b-catenin and physical association of Rac1 with b-catenin and/or TCF-4 may facilitate this process. This culminates in the amplification of b-catenin signaling activity, resulting in enhanced transcriptional activation of perhaps a specific subset of Wnt target genes important in cancer progression. 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PMID:14663202 GSK3B is highly activated in nuclei and mitochondria. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2867.1787" y="1953.0"/> <port id="pr_752511e4-51b1-4f6c-a08c-9800f4b63539_p1" x="2872.1787" y="1943.0"/> <port id="pr_752511e4-51b1-4f6c-a08c-9800f4b63539_p2" x="2872.1787" y="1973.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_4a5e56c8-de55-4587-938a-4ddec87e2abf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15082531 Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 cell cycle arrest. PMID:23140366 p16INK4a activates the pRB tumor suppressor, which silences certain proproliferative genes(E2F) by heterochromatinization, thereby instituting a stringent arrest of cell proliferation PMID:19440234 p21 suppresses E2F1-dependent Wnt4 expression, thereby controlling cellular growth. 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Snail represses Cyclin D2 transcription and increases p21/Cip1 transcription. PMID:17550342 SNAI2 induces p21CIP1 (CDKN1A) expression PMID:23869868 PMID:23140366 p53 transactivate p21 PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3464.5063" y="2082.0"/> <port id="pr_ee13c00e-a377-48d9-9223-07986e221ffc_p1" x="3469.5063" y="2102.0"/> <port id="pr_ee13c00e-a377-48d9-9223-07986e221ffc_p2" x="3469.5063" y="2072.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3de26f8a-aa85-45ef-96f5-91d3c93c5741"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3463.4678" y="1960.0"/> <port id="pr_3de26f8a-aa85-45ef-96f5-91d3c93c5741_p1" x="3468.4678" y="1980.0"/> <port id="pr_3de26f8a-aa85-45ef-96f5-91d3c93c5741_p2" x="3468.4678" y="1950.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_84979dda-1ac5-4028-91f9-234d3aa9fdfa"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2915.5205" y="2396.5"/> <port id="pr_84979dda-1ac5-4028-91f9-234d3aa9fdfa_p1" x="2920.5205" y="2416.5"/> <port id="pr_84979dda-1ac5-4028-91f9-234d3aa9fdfa_p2" x="2920.5205" y="2386.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d5404e63-8c5c-48ee-9844-5a9f1b35f744"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2996.25" y="1965.0"/> <port id="pr_d5404e63-8c5c-48ee-9844-5a9f1b35f744_p1" x="3001.25" y="1985.0"/> <port id="pr_d5404e63-8c5c-48ee-9844-5a9f1b35f744_p2" x="3001.25" y="1955.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_65994995-cf49-46e2-a9d2-ab7a668ff03d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11283613 Miz-1 regulates expression of p15INK4b A Myc–Miz-1 complex binds to the p15 promoter Myc inhibits binding of p300 to Miz-1 Myc inhibits expression of p15INK4B by binding to Miz-1 (Myc represses p15INK4B by interacting with Miz1) PMID:11283614 Miz1: a Myc-interacting Zinc-finger protein that recognizes certain transcriptional initiator elements One of this transcriptional initiator element contains the sequence 5'-CCCACTCTGC corresponding to the p15INK4B transcriptional intiator References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3445.25" y="2205.812"/> <port id="pr_65994995-cf49-46e2-a9d2-ab7a668ff03d_p1" x="3435.25" y="2210.812"/> <port id="pr_65994995-cf49-46e2-a9d2-ab7a668ff03d_p2" x="3465.25" y="2210.812"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_8cbdecdf-7b13-4625-84f4-7cb6baa3244d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11283614 Miz1: a Myc-interacting Zinc-finger protein that recognizes certain transcriptional initiator elements One of this transcriptional initiator element contains the sequence 5'-CCCACTCTGC corresponding to the p15INK4B transcriptional intiator Physical interaction between Smad proteins and Miz-1: -Immunoprecipitation of endogenous Smad2 and Smad3 followed by anti-Miz western bloting provided evidence for an association -This association was stimulated by addition of TGFB -Interaction was observed between Miz1 and Smad3 and Smad4 but no clear interaction was observed between Miz1 and Smad2 -Smad3 and weakly Smad4 can directly and selectively bind to Miz1 through the MH1 domain -Although Sp1-Smad interactions have been reported, Sp1 does not directly bind to Miz1, even in the presence of TGFB. -The Smad-interaction region of Miz1 does not overlap with the Myc-interaction region. -Myc did not inhibit the Smad-Miz1 interaction -Miz1 can bridge Smad proteins and Myc when these proteins coexist. 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Involvement of Sp1 binding in Smad3-mediated TGFB1 induction of COL1A2 Sp1 and Smad proteins bind to the COL1A2 promoter TGFB1 increases association between Sp1 and Smad proteins Sp1 and Smad3 cooperate to regulate COL1A2 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4770.25" y="5240.0"/> <port id="pr_d3e6e74b-b7d4-4cb5-adbf-a832a7bd8597_p1" x="4775.25" y="5230.0"/> <port id="pr_d3e6e74b-b7d4-4cb5-adbf-a832a7bd8597_p2" x="4775.25" y="5260.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7c786321-74de-4869-9319-f3850bca1666"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4770.75" y="5511.0"/> 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Each TGFB gene encodes a preproprotein sequence consisting of a signal peptide, a propeptide (LAP) and the mature TGFB After translocation into the endoplamic reticulum, TGFB proprotein monomers form homomdimers liked by disulfide bonds, forming pro-TGFB In the Golgi, the prodomains undergo glycosylation. Also in the Golgi, FURIN hydolyzes the leavage site from LAP, creating TGFB and LAP-derived homodimers The 2 homodimers remain noncovalently associated and are secreted. The LAP-derived homodimer prevents TGFB from binding TGFB receptors. 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Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="751.9286" y="2301.2388"/> <port id="pr_ffe17ec1-4b33-42e0-9178-8afb272019b6_p1" x="771.9286" y="2306.2388"/> <port id="pr_ffe17ec1-4b33-42e0-9178-8afb272019b6_p2" x="741.9286" y="2306.2388"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_ff3e9445-e0d8-4a7a-8f07-eb9dcdceae39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761148 After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. Active TGFBR2 recruited to TIGHT_JUNCTIONS phosphorylates PARD6A on Serine residue S345 and it also phosphorylates TGFBR1 Once phosphorylated by TGFBR2, both TGFBR1 and PARD6A become active References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="840.0" y="2094.25"/> <port id="pr_ff3e9445-e0d8-4a7a-8f07-eb9dcdceae39_p1" x="830.0" y="2099.25"/> <port id="pr_ff3e9445-e0d8-4a7a-8f07-eb9dcdceae39_p2" x="860.0" y="2099.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dbe4d56a-71ce-4487-b2cb-f1833fc41f93"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:CELL_CELL_ADHESIONS MODULE:TIGHT_JUNCTIONS Maps_Modules_end References_begin: PMID:15761153 Occludin is a structural component of tight junctions that is associated with the cell polarity network. Occludin regulates TGFBR1 localization for efficient TGFB-dependent dissolution of tight junctions during EMT Interaction of endogenous OCLN with endogenous TGFBR1 was not modulated by TGFB but its association with the TGFBR2 increased in a TGFB-dependent manner PMID:15761148 TGFBR1 localizes with ZO-1 on the cellular apical aspect together with PARD6A and they are situated apically to endogenous E-cadherin After stimulation by TGFB, TGFBR2 is redistributed to the tight junctions, where it localizes with both TGFBR1 and ZO-1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1986.25" y="1514.6401"/> <port id="pr_dbe4d56a-71ce-4487-b2cb-f1833fc41f93_p1" x="2006.25" y="1519.6401"/> <port id="pr_dbe4d56a-71ce-4487-b2cb-f1833fc41f93_p2" x="1976.25" y="1519.6401"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b34c7166-6563-4c64-a740-6b06e3d7bcae"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21572392 SMURF1 is an homologous to E6AP C-ter (HECT)-type E3 ubiquitin ligase SMURF1 performs a crucial role in the regulation of the BMP signalling pathway in both embryonic development and bone remodelling. PMID:15761148 PARD6A interacts with TGFB receptors and is phsophorylated by TGFBRIII. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBRI binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBRII phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1184.0" y="2021.237"/> <port id="pr_b34c7166-6563-4c64-a740-6b06e3d7bcae_p1" x="1174.0" y="2026.237"/> <port id="pr_b34c7166-6563-4c64-a740-6b06e3d7bcae_p2" x="1204.0" y="2026.237"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6f9bce61-5196-4e69-b60d-acd9716ecdf8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21572392 SMURF1 is an homologous to E6AP C-ter (HECT)-type E3 ubiquitin ligase SMURF1 performs a crucial role in the regulation of the BMP signalling pathway in both embryonic development and bone remodelling. PMID:15761148 PARD6A interacts with and is phsophorylated by TGFBR2. Phosphorylation of Par6 is required for TGFB-dependent EMT in mammary gland epithelial cells This phosphorylation controls the interaction of PARD6A with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets GTPase RhoA for degradation, thereby leading to a loss of tight junctions. Ubiquitation of RHO1 by Smurf1 leads to disassembly of tight junctions, an important step in EMT. PMID:22949611 Signaling molecules act directly on polarity proteins, bypassing transcription factors such as Snail and Zeb1: TGFBR1 binds to the tight junction protein Occludin and locally assembles into a complex containing Par6. Activated TGFBR2 phosphorylates Par6, which binds to Smurf1 and causes RhoA ubiquitylation and the dissolution of junctions. PMID:14657501 SMURF1, but not SMURF2, decreases RHOA level, and this effect is proteasome dependent. PMID:16472676 Smurf1 could specifically target RhoA but not Cdc42 or Rac1 for degradation. Smurf1 interacts with the dominant inactive form of RhoA, RhoA N19, which binds constitutively to GEFs in vivo. Smurf1 also interacts directly with either nucleotide‐free or GDP‐bound RhoA in vitro; However, loading with GTPgS inhibits the interaction References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4867.0" y="1857.25"/> <port id="pr_6f9bce61-5196-4e69-b60d-acd9716ecdf8_p1" x="4872.0" y="1877.25"/> <port id="pr_6f9bce61-5196-4e69-b60d-acd9716ecdf8_p2" x="4872.0" y="1847.25"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_4b09d080-95dc-4227-bfd4-a91ad23b069b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14657501 SMURF1, but not SMURF2, decreases RHOA level, and this effect is proteasome dependent. PMID:16472676 Smurf1 could specifically target RhoA but not Cdc42 or Rac1 for degradation. Smurf1 interacts with the dominant inactive form of RhoA, RhoA N19, which binds constitutively to GEFs in vivo. Smurf1 also interacts directly with either nucleotide‐free or GDP‐bound RhoA in vitro; However, loading with GTPgS inhibits the interaction References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4211.5" y="1595.3035"/> <port id="pr_4b09d080-95dc-4227-bfd4-a91ad23b069b_p1" x="4231.5" y="1600.3035"/> <port id="pr_4b09d080-95dc-4227-bfd4-a91ad23b069b_p2" x="4201.5" y="1600.3035"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2b0b01c8-68f6-4187-ae79-ff2646a4cc72"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:21900405 LAP contains an integrin-binding site called RBD Several RBD-binding integrins are able to activate latnet TGFB complex through binding this site. PMID:21909923 The previously mentionned integrins are: a8b1, aVb1, aVb5, aVb6, aVb8. In the complex Ingergin-large latent TGFB complex, I picked aVb6 as example. But a8b1, aVb1, aVb5, and aVb8 can active TGFB with the same mechanism. MMP13 activates TGFB by cleavage of LAP Plasmin activates TGFB by cleavage of LAP MMP9 activates TGFB by cleavage of LAP Integrin aVb6 activates the ECM-bound latent TGFB1 and TGFB3 by traction, without participation of MMPs, so no hydrolyse or clevage Integrin aVb8 and MMP14 (so-called MT1-MMP) cooperate to activate the ECM-bound latent TGFB1 and TGFB3: -Integrin aVb8 binds LAP from the large latent complex -MMP14 then is recruited to cleave LAP References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="557.38086" y="6729.75"/> <port id="pr_2b0b01c8-68f6-4187-ae79-ff2646a4cc72_p1" x="562.38086" y="6719.75"/> <port id="pr_2b0b01c8-68f6-4187-ae79-ff2646a4cc72_p2" x="562.38086" y="6749.75"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_4f9f823f-5fd4-481f-99f2-cc3688c647a8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3249.1895" y="2584.0"/> <port id="pr_4f9f823f-5fd4-481f-99f2-cc3688c647a8_p1" x="3254.1895" y="2604.0"/> <port id="pr_4f9f823f-5fd4-481f-99f2-cc3688c647a8_p2" x="3254.1895" y="2574.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_f7eafdaa-d2db-4c4d-b52c-04429d8605b2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9157999 VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold. Protein levels were shown to increase concordantly. PMID:15111329 VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is PKC/ERK pathway-dependent. Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases PMID:12490555 Snail is able to induce the expression of Slug and all other neural crest markers (Zic5, FoxD3, Twist and Ets1) PMID:16716598 PMID:11708773 Endothelin1 is target gene of HIF1 PMID:21041997 In cells induced to undergo EMT, TGFB also activates the expresion of ZEB1 and ZEB2 through upregulation of ETS1 expression, which then may cooperate with the bHLH transcription factor E47 (TCF3) PMID:17615296 TGFB induces ETS1 transcriptional expression. TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457) ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1. Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3) References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2411.0" y="4766.0"/> <port id="pr_f7eafdaa-d2db-4c4d-b52c-04429d8605b2_p1" x="2431.0" y="4771.0"/> <port id="pr_f7eafdaa-d2db-4c4d-b52c-04429d8605b2_p2" x="2401.0" y="4771.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_d1970fe6-0d19-44c2-bd56-52c711a159a3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21081489 miR-200b interacts with the ETS1 to exert translational repression It is not clear yet whether miR-200b targets Ets1 for degradation, or it only inhibits translation of Ets1. PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) significantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2158.5" y="4765.7324"/> <port id="pr_d1970fe6-0d19-44c2-bd56-52c711a159a3_p1" x="2178.5" y="4770.7324"/> <port id="pr_d1970fe6-0d19-44c2-bd56-52c711a159a3_p2" x="2148.5" y="4770.7324"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0bc35a7b-bc90-464a-9acb-35cc01f33728"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21317430 Snail1 induces the nuclear translocation of Ets1, another factor required for Zeb1 expression. Both Twist and Ets1 bind to the ZEB1 promoter although to different elements: whereas Ets1 interacts with the proximal promoter, Twist does it with a 700-bp sequence upstream of the transcription start site. Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2214.5" y="4741.5"/> <port id="pr_0bc35a7b-bc90-464a-9acb-35cc01f33728_p1" x="2204.5" y="4746.5"/> <port id="pr_0bc35a7b-bc90-464a-9acb-35cc01f33728_p2" x="2234.5" y="4746.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_7bfe0d64-ad22-4f2b-a120-cd886ce76c14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22945800 PMID:22286765 Six1 induces ZEB1 and EMT through transcriptional repression of miR200. PMID:20706219 Feedback loop between ZEB1, ZEB2 and MIR200 family PMID:19935649 ZEB1 inhibits expression of MIR200 family PMID:22514743 SNAI1 represses expression of all MIR200 family members. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3111.1875" y="4415.0"/> <port id="pr_7bfe0d64-ad22-4f2b-a120-cd886ce76c14_p1" x="3101.1875" y="4420.0"/> <port id="pr_7bfe0d64-ad22-4f2b-a120-cd886ce76c14_p2" x="3131.1875" y="4420.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_dc4d3af0-86de-4a08-b9e4-45212b851001"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22024162 PMID:21909380 PMID:17823410 PMID:22134354 PMID:22160706 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="5149.0"/> <port id="pr_dc4d3af0-86de-4a08-b9e4-45212b851001_p1" x="3102.0" y="5154.0"/> <port id="pr_dc4d3af0-86de-4a08-b9e4-45212b851001_p2" x="3132.0" y="5154.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_ae94a4b4-78cb-447d-8c70-d53963bcfba7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21518799 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="4720.3994"/> <port id="pr_ae94a4b4-78cb-447d-8c70-d53963bcfba7_p1" x="3102.0" y="4725.3994"/> <port id="pr_ae94a4b4-78cb-447d-8c70-d53963bcfba7_p2" x="3132.0" y="4725.3994"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_ac4194e8-d35f-458e-937d-4da78799fa41"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="4598.2393"/> <port id="pr_ac4194e8-d35f-458e-937d-4da78799fa41_p1" x="3102.0" y="4603.2393"/> <port id="pr_ac4194e8-d35f-458e-937d-4da78799fa41_p2" x="3132.0" y="4603.2393"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_c3f6b2a8-ee37-4420-8fba-3e6cd1d4e14d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="5026.84"/> <port id="pr_c3f6b2a8-ee37-4420-8fba-3e6cd1d4e14d_p1" x="3102.0" y="5031.84"/> <port id="pr_c3f6b2a8-ee37-4420-8fba-3e6cd1d4e14d_p2" x="3132.0" y="5031.84"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_2c9acfea-387b-4062-ae0a-5790336d5a75"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="4904.6816"/> <port id="pr_2c9acfea-387b-4062-ae0a-5790336d5a75_p1" x="3102.0" y="4909.6816"/> <port id="pr_2c9acfea-387b-4062-ae0a-5790336d5a75_p2" x="3132.0" y="4909.6816"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_911a1e09-5b60-406e-bada-ad04d6203ba4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22945800 PMID:22286765 Six1 induces ZEB1 and EMT through transcriptional repression of miR200. PMID:22286770 miR-106b, miR-93 and miR-25 are overexpressed in Six1 transgenic mammary glands as compared with control mammary References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3107.0" y="4475.876"/> <port id="pr_911a1e09-5b60-406e-bada-ad04d6203ba4_p1" x="3097.0" y="4480.876"/> <port id="pr_911a1e09-5b60-406e-bada-ad04d6203ba4_p2" x="3127.0" y="4480.876"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_0285b6f6-15e4-4505-ae35-64f4a64fc166"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22370643 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="4965.7607"/> <port id="pr_0285b6f6-15e4-4505-ae35-64f4a64fc166_p1" x="3102.0" y="4970.7607"/> <port id="pr_0285b6f6-15e4-4505-ae35-64f4a64fc166_p2" x="3132.0" y="4970.7607"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_bf3faf53-4998-4f29-a424-bc9ce598d090"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="4844.079"/> <port id="pr_bf3faf53-4998-4f29-a424-bc9ce598d090_p1" x="3102.0" y="4849.079"/> <port id="pr_bf3faf53-4998-4f29-a424-bc9ce598d090_p2" x="3132.0" y="4849.079"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_eca92155-c06b-4522-9724-6a86fc98cd92"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20351093 PMID:17823410 PMID:22134354 PMID:22160706 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="5087.921"/> <port id="pr_eca92155-c06b-4522-9724-6a86fc98cd92_p1" x="3102.0" y="5092.921"/> <port id="pr_eca92155-c06b-4522-9724-6a86fc98cd92_p2" x="3132.0" y="5092.921"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_fc93b95b-da86-47d7-989d-37a6bcf2fa2d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19935649 SNAI1 inhibits miR-203 PMID:22514743 SNAI1 represses miR-203 and miR-200b expression PMID:21159887 p53 activates expression of miR-203 PMID:20702634 PMID:20706219 Feedback loop: ZEB1 inhibits expression of MIR203 and MIR183 ZEB1 directly controls transcription of the miR-203 and miR-183 and miR-200 family genes ZEB2 inhibits expression of MIR203 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3112.0" y="4537.16"/> <port id="pr_fc93b95b-da86-47d7-989d-37a6bcf2fa2d_p1" x="3102.0" y="4542.16"/> <port id="pr_fc93b95b-da86-47d7-989d-37a6bcf2fa2d_p2" x="3132.0" y="4542.16"/> </glyph> <glyph class="process" orientation="vertical" id="pr_fe700603-fc2b-4ef6-9490-dee472b55d7e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21081489 miR-200b interacts with the Ets-encoding RNA to exert translational repression PMID:20706219 ETS1, WASF3 and WAVE3 are targeted by MIR-200B References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2616.5" y="5311.75"/> <port id="pr_fe700603-fc2b-4ef6-9490-dee472b55d7e_p1" x="2621.5" y="5301.75"/> <port id="pr_fe700603-fc2b-4ef6-9490-dee472b55d7e_p2" x="2621.5" y="5331.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1c9c6350-a05e-4a3f-8f68-ce64af4857f7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4662.5" y="5087.0"/> <port id="pr_1c9c6350-a05e-4a3f-8f68-ce64af4857f7_p1" x="4652.5" y="5092.0"/> <port id="pr_1c9c6350-a05e-4a3f-8f68-ce64af4857f7_p2" x="4682.5" y="5092.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b2faa67f-e711-462e-9f6d-59dda6905650"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: fibroblast growth factor 1 (acidic) HUGO:FGF1, HGNC:3665, ENTREZ:2246, GENECARDS:GC05M141953 Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS MODULE:ECM Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4791.5" y="5087.0"/> <port id="pr_b2faa67f-e711-462e-9f6d-59dda6905650_p1" x="4781.5" y="5092.0"/> <port id="pr_b2faa67f-e711-462e-9f6d-59dda6905650_p2" x="4811.5" y="5092.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_81b429f2-9c6b-4e5e-ae9b-1cba82276645"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14517404 Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis. Eggs received secreted FGF1 showed a significant increase in vascularization when compared to eggs received vector alone plasmids. PMID:16272825 This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway. Blocked PI3K pathway via LY294002 in FGF1-transfected CAMs (chicken chorio- allantoic membrane) signifi cantly inhibited angiogenesis PMID:16682805 Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3907.0" y="5784.75"/> <port id="pr_81b429f2-9c6b-4e5e-ae9b-1cba82276645_p1" x="3927.0" y="5789.75"/> <port id="pr_81b429f2-9c6b-4e5e-ae9b-1cba82276645_p2" x="3897.0" y="5789.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b15e98f4-18c4-449d-a298-d8c60d8e8019"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21081489 MiR-200b Regulates Ets-1-associated Genes Suppression of endogenous miR-200b induced MMP-1 and VEGFR2 expressions Overexpression of Ets-1 did not completely reverse miR- 200b-associated MMP-1 and VEGFR2 down-regulation. It indicates that miR-200b, apart from targeting Ets-1, might silence other target proteins involved in transcription of the indicated genes. 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The resultant phosphotyrosines form docking sites for adaptator proteins (e.g. GRB2 via its SH2 domain). The SH3 domain of adaptator (e.g. GRB2) then binds to the proline-rich motifs in the GTP exchange factor (i.e. GEF) for RAS (e.g. SOS) Via this process that GEF (e.g. SOS) is recruited to the membrane where it colocalizes with and activates Ras. PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6057.1875" y="963.5"/> <port id="pr_dd528e50-4974-4ed2-884c-013594fc5c34_p1" x="6077.1875" y="968.5"/> <port id="pr_dd528e50-4974-4ed2-884c-013594fc5c34_p2" x="6047.1875" y="968.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_32c2dd08-447b-42a5-8d3a-21ecaff00807"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Negative feedback: MAPK1/ERK2 phosphorylates RAF1 on Ser 29, 43, 289, 296, 301, 642, generating an inactive kinase. PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6111.5" y="1396.75"/> <port id="pr_32c2dd08-447b-42a5-8d3a-21ecaff00807_p1" x="6116.5" y="1416.75"/> <port id="pr_32c2dd08-447b-42a5-8d3a-21ecaff00807_p2" x="6116.5" y="1386.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0d438aba-fe05-4697-b9b9-8dec0505be4b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5986.25" y="1085.0"/> <port id="pr_0d438aba-fe05-4697-b9b9-8dec0505be4b_p1" x="5976.25" y="1090.0"/> <port id="pr_0d438aba-fe05-4697-b9b9-8dec0505be4b_p2" x="6006.25" y="1090.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9adac4b3-34a1-4f3e-b3c9-efc6fa19329c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6086.8125" y="801.94745"/> <port id="pr_9adac4b3-34a1-4f3e-b3c9-efc6fa19329c_p1" x="6106.8125" y="806.94745"/> <port id="pr_9adac4b3-34a1-4f3e-b3c9-efc6fa19329c_p2" x="6076.8125" y="806.94745"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_deac9c3b-c4b9-42d1-b46c-1df773bcf404"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. YWHAB has been displaced from S259 may now bind its higher affinity S621 site. This stabilises an OPEN RAF1 conformation that is catalytically active. Active and open RAF1 binds to RAS via both CRD and RBD domains. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5892.0" y="830.4584"/> <port id="pr_deac9c3b-c4b9-42d1-b46c-1df773bcf404_p1" x="5912.0" y="835.4584"/> <port id="pr_deac9c3b-c4b9-42d1-b46c-1df773bcf404_p2" x="5882.0" y="835.4584"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0c02aba6-874a-473f-9d42-cb40593514d3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. YWHAB has been displaced from S259 may now bind its higher affinity S621 site. This stabilises an OPEN RAF1 conformation that is catalytically active. Active and open RAF1 binds to RAS via both CRD and RBD domains. An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341. This Tyrosine phosphorylation serves to further stabilise the active OPEN RAF1 conformation. While the kinase has not been definitively identified, SRC is a plausible candidate. RAF1 interacts with SRC and co-immunoprecipates with SRC-FYN. PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: S338, Y374 and T491 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5736.5" y="835.3"/> <port id="pr_0c02aba6-874a-473f-9d42-cb40593514d3_p1" x="5756.5" y="840.3"/> <port id="pr_0c02aba6-874a-473f-9d42-cb40593514d3_p2" x="5726.5" y="840.3"/> </glyph> <glyph class="process" orientation="vertical" id="pr_57c95462-8162-44d1-ac5b-36b29ea77e21"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7565670 Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5688.0" y="997.0"/> <port id="pr_57c95462-8162-44d1-ac5b-36b29ea77e21_p1" x="5693.0" y="987.0"/> <port id="pr_57c95462-8162-44d1-ac5b-36b29ea77e21_p2" x="5693.0" y="1017.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_07c15fa5-aacf-4ede-b75a-38452f5acdaa"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7565670 Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5808.0" y="997.0"/> <port id="pr_07c15fa5-aacf-4ede-b75a-38452f5acdaa_p1" x="5813.0" y="987.0"/> <port id="pr_07c15fa5-aacf-4ede-b75a-38452f5acdaa_p2" x="5813.0" y="1017.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_fdf62726-8390-4c84-a34d-5d7e4b2188e4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK1 phosphorylates the critical Tyr and Thr on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5642.5" y="1157.0"/> <port id="pr_fdf62726-8390-4c84-a34d-5d7e4b2188e4_p1" x="5662.5" y="1162.0"/> <port id="pr_fdf62726-8390-4c84-a34d-5d7e4b2188e4_p2" x="5632.5" y="1162.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_93a4e892-b7cd-4a0c-a275-f8160c9e3569"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8388392 PMID:8226933 In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). MEK1 phosphorylates the critical Tyr and Thr on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5853.5" y="1157.0"/> <port id="pr_93a4e892-b7cd-4a0c-a275-f8160c9e3569_p1" x="5843.5" y="1162.0"/> <port id="pr_93a4e892-b7cd-4a0c-a275-f8160c9e3569_p2" x="5873.5" y="1162.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_5386fe50-947c-430b-be43-cfd7758eda86"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4355.7344" y="2287.5"/> <port id="pr_5386fe50-947c-430b-be43-cfd7758eda86_p1" x="4375.7344" y="2292.5"/> <port id="pr_5386fe50-947c-430b-be43-cfd7758eda86_p2" x="4345.7344" y="2292.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d698bd99-8fd4-4086-a8f2-d05667f33e27"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. 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Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5919.0" y="1205.5"/> <port id="pr_a79bbca4-76fb-4540-aa6a-6b1496c727f8_p1" x="5924.0" y="1195.5"/> <port id="pr_a79bbca4-76fb-4540-aa6a-6b1496c727f8_p2" x="5924.0" y="1225.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_211a71be-042c-4864-bf33-521c1772e635"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. 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PMID:9155017 Mnk1 and Mnk2 bind to Erk1, Erk2 and p38 but not JNK Mnk1 and Mnk2 are in vitro substrates of Erk2 and p38 Mnk1 is a MAP kinase-activated eIF-4E kinase References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5708.0" y="1247.0"/> <port id="pr_211a71be-042c-4864-bf33-521c1772e635_p1" x="5713.0" y="1237.0"/> <port id="pr_211a71be-042c-4864-bf33-521c1772e635_p2" x="5713.0" y="1267.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_51a4f2d1-789a-4111-90e7-162bfa057731"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9604935 Phosphorylation of ERK-1/2 promotes its homodimerization PMID:18775330 Scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. PMID:9155017 Mnk1 and Mnk2 bind to Erk1, Erk2 and p38 but not JNK Mnk1 and Mnk2 are in vitro substrates of Erk2 and p38 Mnk1 is a MAP kinase-activated eIF-4E kinase References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5788.0" y="1247.0"/> <port id="pr_51a4f2d1-789a-4111-90e7-162bfa057731_p1" x="5793.0" y="1237.0"/> <port id="pr_51a4f2d1-789a-4111-90e7-162bfa057731_p2" x="5793.0" y="1267.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a5356ba3-03f1-4616-a43a-da6f059699a5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9878069 Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. PMID:9155017 In vitro, Mnk1 rapidly phosphorylates eIF-4E at the physiologically relevant site, Ser209 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5576.0" y="1344.0"/> <port id="pr_a5356ba3-03f1-4616-a43a-da6f059699a5_p1" x="5581.0" y="1334.0"/> <port id="pr_a5356ba3-03f1-4616-a43a-da6f059699a5_p2" x="5581.0" y="1364.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5249a9dd-ee55-4505-b4a6-fae4bc2dc9e5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Regulation of HIF-1a protein synthesis MNK phosphorylates eIF-4E and stimulates its activity directly. Active eIF-4E increases the rate of HIF1A-mRNA translation into HIF1A protein. PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3859.0" y="1915.0"/> <port id="pr_5249a9dd-ee55-4505-b4a6-fae4bc2dc9e5_p1" x="3864.0" y="1935.0"/> <port id="pr_5249a9dd-ee55-4505-b4a6-fae4bc2dc9e5_p2" x="3864.0" y="1905.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_34c6b036-9c89-408f-a3d0-a453e235f05a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19, Vimentin are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4509.25" y="3050.5"/> <port id="pr_34c6b036-9c89-408f-a3d0-a453e235f05a_p1" x="4499.25" y="3055.5"/> <port id="pr_34c6b036-9c89-408f-a3d0-a453e235f05a_p2" x="4529.25" y="3055.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_50fb0654-2652-4323-ba6f-e581257a69db"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4781.25" y="3051.0303"/> <port id="pr_50fb0654-2652-4323-ba6f-e581257a69db_p1" x="4771.25" y="3056.0303"/> <port id="pr_50fb0654-2652-4323-ba6f-e581257a69db_p2" x="4801.25" y="3056.0303"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9eb89269-d4ff-48c0-a929-47202c384d7e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19, Vimentin are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4509.75" y="3090.5"/> <port id="pr_9eb89269-d4ff-48c0-a929-47202c384d7e_p1" x="4499.75" y="3095.5"/> <port id="pr_9eb89269-d4ff-48c0-a929-47202c384d7e_p2" x="4529.75" y="3095.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_ef9e88fc-aebd-4e99-8e2d-35c946a1df04"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: GJB5 is so-called Connexin 31.1 PMID:21777377 Expression of Cx31.1 reduced mesenchymal marker vimentin level and increased epithelial marker cytokeratin 18 level, indicating that Cx31.1 may regulate molecular pathways leading to a reverse of the EMT process. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4781.25" y="3091.0303"/> <port id="pr_ef9e88fc-aebd-4e99-8e2d-35c946a1df04_p1" x="4771.25" y="3096.0303"/> <port id="pr_ef9e88fc-aebd-4e99-8e2d-35c946a1df04_p2" x="4801.25" y="3096.0303"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_00e0bd1c-acc3-4aa6-91be-63e80ca39a6e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Keratin-14, 18, 19, Vimentin are putative direct HIF1 target genes http://www.omicsonline.org/1948-5956/JCST-03-035.php Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4507.25" y="3130.5"/> <port id="pr_00e0bd1c-acc3-4aa6-91be-63e80ca39a6e_p1" x="4497.25" y="3135.5"/> <port id="pr_00e0bd1c-acc3-4aa6-91be-63e80ca39a6e_p2" x="4527.25" y="3135.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9598ec77-67db-46e3-b4ba-8741e02a3b7d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4781.25" y="3125.1257"/> <port id="pr_9598ec77-67db-46e3-b4ba-8741e02a3b7d_p1" x="4771.25" y="3130.1257"/> <port id="pr_9598ec77-67db-46e3-b4ba-8741e02a3b7d_p2" x="4801.25" y="3130.1257"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2743aa87-5971-41be-8af9-f44d82033a49"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Regulation of HIF-1a protein synthesis MNK phosphorylates eIF-4E and stimulates its activity directly. Active eIF-4E increases the rate of HIF1A-mRNA translation into HIF1A protein. PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3961.0" y="1915.0"/> <port id="pr_2743aa87-5971-41be-8af9-f44d82033a49_p1" x="3966.0" y="1935.0"/> <port id="pr_2743aa87-5971-41be-8af9-f44d82033a49_p2" x="3966.0" y="1905.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_43340f87-ff1d-45de-a1c5-32a36a218e43"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Regulation of HIF-1a protein synthesis MNK phosphorylates eIF-4E and stimulates its activity directly. Active eIF-4E increases the rate of HIF1A-mRNA translation into HIF1A protein. PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3909.0" y="2190.0"/> <port id="pr_43340f87-ff1d-45de-a1c5-32a36a218e43_p1" x="3914.0" y="2180.0"/> <port id="pr_43340f87-ff1d-45de-a1c5-32a36a218e43_p2" x="3914.0" y="2210.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_a4217254-44a6-45c4-8fa1-a4244f39e042"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:13130303 Regulation of HIF-1a protein synthesis MNK phosphorylates eIF-4E and stimulates its activity directly. Active eIF-4E increases the rate of HIF1A-mRNA translation into HIF1A protein. PMID:16887934 PMID:9159130 HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability PMID:9278421 HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen PMID:9746763 The transcription and synthesis of HIF-1A are constitutive and seem not to be affected by oxygen. PMID:7539918 In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein. PMID:8943284 During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active PMID:1823643 The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression. PMID:15451019 Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation The modification of HIF-1A occurs within several domains. PMID:10403805 PMID:11566883 PMID:12829734 In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001). PMID:12080085 pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome. In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a). References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3741.6514" y="1631.0"/> <port id="pr_a4217254-44a6-45c4-8fa1-a4244f39e042_p1" x="3746.6514" y="1651.0"/> <port id="pr_a4217254-44a6-45c4-8fa1-a4244f39e042_p2" x="3746.6514" y="1621.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c961fb8d-5623-47c1-b885-77761624c8a9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11790723 Whereas TGF-b1 and 2 are proscarring growth factors, TGF-b3 is antiscarring TGF-b1, 2, and 3 are embryonically expressed in skin and up-regulated at adult wound sites Overlapping expression patterns of HIF-1a and TGF-b3 in vivo TGF-b1 mRNA expression was serum- but not hypoxia-inducible. In contrast, TGF-b3 mRNA expression was hypoxia-inducible, but not serum- inducible Basal TGF-b3 levels were nearly undetectable in HIF-1a –/– MEFs, demonstrating that TGF-b3 might be a HIF-1a target gene PMID:9278421 PMID:10712429 HIF1 target genes include TGFB3 PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4646.0" y="5144.5"/> <port id="pr_c961fb8d-5623-47c1-b885-77761624c8a9_p1" x="4636.0" y="5149.5"/> <port id="pr_c961fb8d-5623-47c1-b885-77761624c8a9_p2" x="4666.0" y="5149.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_897b5e48-75d8-424f-84aa-308e9ee5c4d3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4794.0" y="5144.5"/> <port id="pr_897b5e48-75d8-424f-84aa-308e9ee5c4d3_p1" x="4784.0" y="5149.5"/> <port id="pr_897b5e48-75d8-424f-84aa-308e9ee5c4d3_p2" x="4814.0" y="5149.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0779f42f-730c-4f41-8af6-cfdd2800a771"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11528470 PMID:9295307 VEGFR1 (FLT1) is induced by hypoxia through a potential HIF1-dependent mechanis It indicates that this gene is in the same homeostatic cascade as VEGF, EG-VEGF, and Erythoproietin PMID:16887934 VEGF, EG-VEGF, TGFB3 are target genes of HIF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15501236 VEGFR2 and aVb3 were observed to co-associate after stimulation with either L1 (Ig6 domain) or VEGFA (isoform of 165 amino acids) VEGFR2 was tyrosine phosphorylated after stimulation with L1 (via Ig6 domain), even in the absence of exogenous VEGFA ( (isoform of 165 amino acids), indicating close cooperation between VEGFR2 and aVb3 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6081.0" y="4750.0913"/> <port id="pr_e5ec2f8d-4e10-4b1e-93dd-af926fe14432_p1" x="6071.0" y="4755.0913"/> <port id="pr_e5ec2f8d-4e10-4b1e-93dd-af926fe14432_p2" x="6101.0" y="4755.0913"/> </glyph> <glyph class="process" orientation="vertical" id="pr_780ce815-4a71-43cf-81f5-e68c1d4f6797"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="573.88403" y="3665.5"/> <port id="pr_780ce815-4a71-43cf-81f5-e68c1d4f6797_p1" x="578.88403" y="3655.5"/> <port id="pr_780ce815-4a71-43cf-81f5-e68c1d4f6797_p2" x="578.88403" y="3685.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f995b270-db66-40a6-852a-c799406efe4c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: NAME:(Integrin aVb3/L1CAM) Identifiers_end Maps_Modules_begin: MODULE:CELL_CELL_ADHESIONS MODULE:ADHERENS_JUNCTIONS Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. PMID:8636223 Integrin aVb3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. aVb3 can also interact with the neural cell adhesion molecule L1CAM; a member of the immunoglobulin superfamily (IgSF). In other words, aVb3 undergoes heterophilic binding with L1CAM M21 cells display some aVb3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and aVb3 was also observed to promote significant haptotactic cell migration. Significant aVb3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. aVb3 may recognize L1 in a cell-cell or cell-substrate interaction. PMID:11553709 Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin aVb3 has been associated with the metastatic potential of tumor cells. In the context of in vitro monolayer of human lung microvascular, L1CAM was shown to serve as a potential ligand for aVb3 during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and aVb3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin aVb3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells. Integrin aVb3 on melanoma cells, and not endothelial cells, is involved in the transmigration process. Because L1 is expressed in both melanoma and endothelial cells, it is possible that L1-L1 homophilic interactions at the heterotypic contacts might play a role in the transmigration of melanoma cells. The data thus indicate that transendothelial migration does not involve L1-L1 homophilic binding. These results led us to speculate that L1 on endothelial cells, and not melanoma cells, has a role during transendothelial migration of melanoma cells PMID:9003039 L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="638.1992" y="3704.4312"/> <port id="pr_f995b270-db66-40a6-852a-c799406efe4c_p1" x="643.1992" y="3694.4312"/> <port id="pr_f995b270-db66-40a6-852a-c799406efe4c_p2" x="643.1992" y="3724.4312"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_28a04f81-032b-4f03-aae7-d630a3591c80"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4260.859" y="1164.2439"/> <port id="pr_28a04f81-032b-4f03-aae7-d630a3591c80_p1" x="4280.859" y="1169.2439"/> <port id="pr_28a04f81-032b-4f03-aae7-d630a3591c80_p2" x="4250.859" y="1169.2439"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2736b529-fd3c-45f1-86e6-17205bdf9e3b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12667443 p53 induces apoptosis by target gene regulation and transcription-independent signaling. A fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Evidence that p53 translocation to the mitochondria occurs in vivo in irradiatedthymocytes was shown. Further, p53 can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1, resulting in cytochrome c release. p53 binds to BCL2L1 via its DNA binding domain. Tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BCL2L1 and promote cytochrome c release. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4581.0" y="1199.75"/> <port id="pr_2736b529-fd3c-45f1-86e6-17205bdf9e3b_p1" x="4586.0" y="1219.75"/> <port id="pr_2736b529-fd3c-45f1-86e6-17205bdf9e3b_p2" x="4586.0" y="1189.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2ece1e8b-896b-4340-84b1-90cb3b5e96c6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12667443 p53 induces apoptosis by target gene regulation and transcription-independent signaling. A fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Evidence that p53 translocation to the mitochondria occurs in vivo in irradiatedthymocytes was shown. Further, p53 can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1, resulting in cytochrome c release. p53 binds to BCL2L1 via its DNA binding domain. Tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BCL2L1 and promote cytochrome c release.References_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4231.5" y="1644.25"/> <port id="pr_2ece1e8b-896b-4340-84b1-90cb3b5e96c6_p1" x="4236.5" y="1664.25"/> <port id="pr_2ece1e8b-896b-4340-84b1-90cb3b5e96c6_p2" x="4236.5" y="1634.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_361de93d-dee0-4190-9a65-c1adc16c890f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic protines) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic protines)work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:22836101 BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro-survival family members such as BCL2L1 act to inhibit BAX activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4666.3677" y="1199.75"/> <port id="pr_361de93d-dee0-4190-9a65-c1adc16c890f_p1" x="4671.3677" y="1219.75"/> <port id="pr_361de93d-dee0-4190-9a65-c1adc16c890f_p2" x="4671.3677" y="1189.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_20f074ed-1142-47cd-9f0e-9f019da307b9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis PMID:9872359 A oncogene-derived protein, Bcl2, confers negative control in the pathway of cellular suicide machinery. A Bcl2-homologous protein, Bax, promotes cell death by competing with Bcl2. While Bax–Bax homodimers act as apoptosis inducers, Bcl2– Bax heterodimer formation evokes a survival signal for the cells. Both Bcl2 and Bax are transcriptional targets for the tumour suppressor protein, p53, which induces cell cycle arrest or apoptosis in response to DNA damage. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4654.073" y="1325.11"/> <port id="pr_20f074ed-1142-47cd-9f0e-9f019da307b9_p1" x="4644.073" y="1330.11"/> <port id="pr_20f074ed-1142-47cd-9f0e-9f019da307b9_p2" x="4674.073" y="1330.11"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f3373ee3-2e1d-4b92-bd3b-2b8bd76e3792"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic protines) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic protines)work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4918.1416" y="1290.75"/> <port id="pr_f3373ee3-2e1d-4b92-bd3b-2b8bd76e3792_p1" x="4923.1416" y="1280.75"/> <port id="pr_f3373ee3-2e1d-4b92-bd3b-2b8bd76e3792_p2" x="4923.1416" y="1310.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_e887762c-2c31-4fb4-9997-8ce5f80aea6e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22039431 The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates. The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family. Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic protines) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic protines)work against programmed cell death. The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function. Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4760.4062" y="1293.2148"/> <port id="pr_e887762c-2c31-4fb4-9997-8ce5f80aea6e_p1" x="4750.4062" y="1298.2148"/> <port id="pr_e887762c-2c31-4fb4-9997-8ce5f80aea6e_p2" x="4780.4062" y="1298.2148"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a3ba7add-6d2c-4cdc-8970-cda6738218c2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12667443 p53 induces apoptosis by target gene regulation and transcription-independent signaling. A fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Evidence that p53 translocation to the mitochondria occurs in vivo in irradiatedthymocytes was shown. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4425.213" y="1179.75"/> <port id="pr_a3ba7add-6d2c-4cdc-8970-cda6738218c2_p1" x="4430.213" y="1199.75"/> <port id="pr_a3ba7add-6d2c-4cdc-8970-cda6738218c2_p2" x="4430.213" y="1169.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dbb981b3-ffe6-4e6f-9f9f-223a07d149c1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14963330 Cytosolic localization of endogenous p53 was necessary and sufficient for apoptosis. p53 directly activated the pro-apoptotic BCL2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4256.5" y="1313.5684"/> <port id="pr_dbb981b3-ffe6-4e6f-9f9f-223a07d149c1_p1" x="4276.5" y="1318.5684"/> <port id="pr_dbb981b3-ffe6-4e6f-9f9f-223a07d149c1_p2" x="4246.5" y="1318.5684"/> </glyph> <glyph class="process" orientation="vertical" id="pr_fb7f979a-44d5-4594-8d82-81ab80bbb6e4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11463392 BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins that are induced in cells following p53 activation. BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway. PMID:11463391 PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain. It is via this binding to BBC3 (an apoptic inducer) that BCL2 and BCL2L1 exhibit their anti-apoptic effect. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4315.6562" y="1161.25"/> <port id="pr_fb7f979a-44d5-4594-8d82-81ab80bbb6e4_p1" x="4320.6562" y="1181.25"/> <port id="pr_fb7f979a-44d5-4594-8d82-81ab80bbb6e4_p2" x="4320.6562" y="1151.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_13bd34e1-97cd-422b-bb2c-2ed56ebb7ea8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15077116 p53 has a direct signalling role at mitochondria in the induction of apoptosis p53 interacts with the pro- apoptotic mitochondrial membrane protein Bak. Interaction of p53 with Bak causes oligomerization and thus activation of Bak and release of cytochrome c from mitochondria. Formation of the p53–Bak complex coincides with loss of an interaction between Bak and the anti-apoptotic Bcl2-family member Mcl1. These results are consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak.References_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4214.5" y="1243.6615"/> <port id="pr_13bd34e1-97cd-422b-bb2c-2ed56ebb7ea8_p1" x="4234.5" y="1248.6615"/> <port id="pr_13bd34e1-97cd-422b-bb2c-2ed56ebb7ea8_p2" x="4204.5" y="1248.6615"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_e2549508-97c8-4ca7-8c06-e8bf0b86669d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17464323 Translocation of p57Kip2 to mitochondria occurs within 20 min after staurosporine (apoptotic agent) application. In fact, p57Kip2 primarily promotes the intrinsic apoptotic pathways, favoring Bax activation and loss of mitochondrial transmembrane potential, consequent release of cytochrome-c into cytosol, caspase-9 and caspase-3 activation. In accordance, Bcl2 overexpression is able to inhibit p57Kip2 cell death promoting effect. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57Kip2 influences the mitochondrial apoptotic cell death pathway in cancer cells. 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="503.9474" y="3417.0"/> <port id="pr_c0f098f6-6ec8-4357-bb94-08b8388e1d42_p1" x="508.9474" y="3407.0"/> <port id="pr_c0f098f6-6ec8-4357-bb94-08b8388e1d42_p2" x="508.9474" y="3437.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_3c45d9e5-cc2d-441e-89b2-7871c5696b45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15459715 PMID:15448698 Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT. Snail is highly unstable, with a short half-life about 25 min. GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization. A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2915.404" y="2120.755"/> <port id="pr_3c45d9e5-cc2d-441e-89b2-7871c5696b45_p1" x="2935.404" y="2125.755"/> <port id="pr_3c45d9e5-cc2d-441e-89b2-7871c5696b45_p2" x="2905.404" y="2125.755"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_8aa32e98-5136-432e-b92d-e58f312e63a9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15459715 PMID:15448698 Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT. Snail is highly unstable, with a short half-life about 25 min. GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization. A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2710.25" y="1922.75"/> <port id="pr_8aa32e98-5136-432e-b92d-e58f312e63a9_p1" x="2715.25" y="1942.75"/> <port id="pr_8aa32e98-5136-432e-b92d-e58f312e63a9_p2" x="2715.25" y="1912.75"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_2cb44f47-e6bb-42e7-bcfc-7bb1dd6eee9f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19411070 TNFa dramatically enhanced the protein stabilization of Snail1 through NF-kB mediated CSN2 induction. CSN2 induces Snail stabilization by inhibiting its ubiquitination References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3096.5884" y="1524.9109"/> <port id="pr_2cb44f47-e6bb-42e7-bcfc-7bb1dd6eee9f_p1" x="3086.5884" y="1529.9109"/> <port id="pr_2cb44f47-e6bb-42e7-bcfc-7bb1dd6eee9f_p2" x="3116.5884" y="1529.9109"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_1ac713a7-60b9-4c54-9ad7-0fb3b4cfecfa"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2457.0" y="1854.9976"/> <port id="pr_1ac713a7-60b9-4c54-9ad7-0fb3b4cfecfa_p1" x="2477.0" y="1859.9976"/> <port id="pr_1ac713a7-60b9-4c54-9ad7-0fb3b4cfecfa_p2" x="2447.0" y="1859.9976"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_0ee8fb57-ce16-41ab-800e-0024f7cbd87e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7945242 PMID:8524413 AKT (PKB) phosphorylates GSK3B at Serine residue and inactivate GSK3B References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2865.0" y="1855.5"/> <port id="pr_0ee8fb57-ce16-41ab-800e-0024f7cbd87e_p1" x="2855.0" y="1860.5"/> <port id="pr_0ee8fb57-ce16-41ab-800e-0024f7cbd87e_p2" x="2885.0" y="1860.5"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_4c6103ec-0c46-49a1-b7f7-f59016a76a9d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3333.418" y="1692.0"/> <port id="pr_4c6103ec-0c46-49a1-b7f7-f59016a76a9d_p1" x="3338.418" y="1712.0"/> <port id="pr_4c6103ec-0c46-49a1-b7f7-f59016a76a9d_p2" x="3338.418" y="1682.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_23036e2d-5256-4ac3-bd50-480811b9908b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3321.9019" y="1666.5"/> <port id="pr_23036e2d-5256-4ac3-bd50-480811b9908b_p1" x="3326.9019" y="1686.5"/> <port id="pr_23036e2d-5256-4ac3-bd50-480811b9908b_p2" x="3326.9019" y="1656.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f93ba2ea-c8f5-4b23-9ff8-d6b5474bc133"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3109.25" y="1805.5"/> <port id="pr_f93ba2ea-c8f5-4b23-9ff8-d6b5474bc133_p1" x="3114.25" y="1795.5"/> <port id="pr_f93ba2ea-c8f5-4b23-9ff8-d6b5474bc133_p2" x="3114.25" y="1825.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_a6a3abe0-1ec0-4016-81bf-4afa4ce85906"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1582.2657" y="3794.0"/> <port id="pr_a6a3abe0-1ec0-4016-81bf-4afa4ce85906_p1" x="1572.2657" y="3799.0"/> <port id="pr_a6a3abe0-1ec0-4016-81bf-4afa4ce85906_p2" x="1602.2657" y="3799.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_326b3348-a5c7-4b89-a76e-4da7f5b1ede3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 in the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. Upon ligand binding (right panel), DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2630.5308" y="2567.5"/> <port id="pr_326b3348-a5c7-4b89-a76e-4da7f5b1ede3_p1" x="2635.5308" y="2587.5"/> <port id="pr_326b3348-a5c7-4b89-a76e-4da7f5b1ede3_p2" x="2635.5308" y="2557.5"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_e6a0a30d-31bb-422d-85c0-a463a22bf584"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CSNK1 (casein kinase 1) but not CSNK2 (casein kinase 2) phosphorylates CTNNB1 at S45. This priming phosphorylation results in subsequent phosphorylation by GSK3B at T41, S37, S33. CTNNB1 that is phosphorylated at S33 and S37 is ultimately recognized by E3-ligase and targeted for proteasomal destruction. PMID:7542250 Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes. The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction PMID:12051714 Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin. In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation. The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41. It has recently been shown that the GSK-3 dependent phosphorylation of b-catenin requiresprior priming through phosphorylation of Ser45 GSK-3b wasfound to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells. In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling. PMID:11955436 Wnt regulation of b-catenin degradation is essential for development and carcinogenesis. b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation. This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin. This priming kinase is casein kinase I -alpha (CSNK1A1). PMID:11967263 Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity. PMID:8666229 Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1440.6328" y="3707.25"/> <port id="pr_e6a0a30d-31bb-422d-85c0-a463a22bf584_p1" x="1445.6328" y="3697.25"/> <port id="pr_e6a0a30d-31bb-422d-85c0-a463a22bf584_p2" x="1445.6328" y="3727.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1ff799e8-64a1-4267-839b-67b0321e1b71"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10428961 PMID:8666229 Wnt transduces their signals through DVL1 to inhibit GSK3B, leading to the accumulation of cytosolic CTNNB1 and activation of TCF/LEF1 transcription factors. DVL1 interacts with AXIN1 and with Frat1. Binding of AXIN1 to DVL1 reduces formation of the destruction complex APC/AXIN1. 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PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. PMID:15866889 The ARP2_3 complex and Cofilin are involved in protrusion at the leading edge: the actin-severing activity of cofilin and the actin-branching activity of Arp2_3 act in synergy to drive the extension of lamellipodia. Cofilin is also required for the maintenance of a polarized cytoskeleton and thus for directional cell migration. Integrins control motile strategy through a Rho-cofilin pathway. Adhesion to fibronectin by a5b1 integrin leads to phosphorylation and thus inactivation of cofilin. Cells thus fail to polarize their cytoskeleton but extend thin protrusion with cell-matrix adhesions in multiple directions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4926.75" y="2819.5"/> <port id="pr_c8ded3a8-f017-495b-9a72-79ec27edfd18_p1" x="4946.75" y="2824.5"/> <port id="pr_c8ded3a8-f017-495b-9a72-79ec27edfd18_p2" x="4916.75" y="2824.5"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_0a893c11-ba57-4f29-af56-d0d3b4bf12eb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22154077, PMID:17522712 CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. PMID:11018042 LIMK1 is regulated by Pak1, References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4841.25" y="2573.75"/> <port id="pr_0a893c11-ba57-4f29-af56-d0d3b4bf12eb_p1" x="4846.25" y="2563.75"/> <port id="pr_0a893c11-ba57-4f29-af56-d0d3b4bf12eb_p2" x="4846.25" y="2593.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_11b27032-62d8-41d0-9084-c087555939de"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22315516 -Occludin is phosphorylated at S340 by PKC -Occludin is phosphorylated at T383 and S508 by ROCK -Occludin is phosphorylated at Y398, Y402 and Y474 by SRC -Occludin is phosphorylated at T400, T404 and S408 by CK2 -Occludin is phosphorylated at S403 and S404 by PKC-N -Occludin is phosphorylated at T424 and T438 by PKC-E -Occludin is phosphorylated at S490 by VEGF PMID:19017651 PMID:12604349 In mouse, phosphorylation of Occludin by SRC (at Y398, Y402) reduces TIGHT_JUNCTIONS assembly In mouse, phosphorylation of Occludin by SRC (at Y398, Y402) reduces interaction between Occludin and ZO1,2,3 PMID:20152177 In mouse, phosphorylation of Occludin by SRC (at Y474) increases interaction between Occludin and PI3K In mouse, phosphorylation of Occludin by SRC (at Y474) increases wound healing and migration PMID:12547828 Inactive Src delays the oxidative stress-induced disruption of tight junction and accelerates calcium- induced assembly of tight junction in Caco-2 cells. This demonstrates that oxidative stress-induced disruption of tight junction is mediated by the activation of Src. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="677.75" y="2538.6"/> <port id="pr_11b27032-62d8-41d0-9084-c087555939de_p1" x="667.75" y="2543.6"/> <port id="pr_11b27032-62d8-41d0-9084-c087555939de_p2" x="697.75" y="2543.6"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_cc5cb9c6-7849-4768-bf01-6c9302b8a1ae"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="583.975" y="2783.486"/> <port id="pr_cc5cb9c6-7849-4768-bf01-6c9302b8a1ae_p1" x="573.975" y="2788.486"/> <port id="pr_cc5cb9c6-7849-4768-bf01-6c9302b8a1ae_p2" x="603.975" y="2788.486"/> </glyph> <glyph class="process" orientation="vertical" id="pr_99caa6ad-d3ae-43f5-a893-1ed524f3d533"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="627.0" y="5607.5"/> <port id="pr_99caa6ad-d3ae-43f5-a893-1ed524f3d533_p1" x="632.0" y="5597.5"/> <port id="pr_99caa6ad-d3ae-43f5-a893-1ed524f3d533_p2" x="632.0" y="5627.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9b8332b1-7506-4d7e-b627-ba06b152f814"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="571.38116" y="2858.2139"/> <port id="pr_9b8332b1-7506-4d7e-b627-ba06b152f814_p1" x="576.38116" y="2848.2139"/> <port id="pr_9b8332b1-7506-4d7e-b627-ba06b152f814_p2" x="576.38116" y="2878.2139"/> </glyph> <glyph class="process" orientation="vertical" id="pr_14417b92-71e3-450c-a6c9-cbb68e899334"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="627.0" y="5167.5"/> <port id="pr_14417b92-71e3-450c-a6c9-cbb68e899334_p1" x="632.0" y="5157.5"/> <port id="pr_14417b92-71e3-450c-a6c9-cbb68e899334_p2" x="632.0" y="5187.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5a5ea5f3-a92e-4df9-9a98-11f67fc30448"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="577.00714" y="3076.1406"/> <port id="pr_5a5ea5f3-a92e-4df9-9a98-11f67fc30448_p1" x="582.00714" y="3066.1406"/> <port id="pr_5a5ea5f3-a92e-4df9-9a98-11f67fc30448_p2" x="582.00714" y="3096.1406"/> </glyph> <glyph class="process" orientation="vertical" id="pr_24eeec4b-6c79-467f-8e62-c25466e278ad"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: GJA1 is so-called Connexin 43 or Cx43 PMID:16492141 Binding partners proteins of Connexin 43 (GJA1): -Kinases: v-Src, c-Src, PKC, PKA, MAPK, Casein kinase 1, Cdc2 kinase -TIGHT_JUNCTIONS scaffold proteins: ZO1, ZO2, caveolin 1 -Cytoskeleton: b-catenin, a-tubulin, b-tubulin -Others: Drebrin, NOV, CIP85 PMID:10871288 Interaction between Connexin 43 (GJA1) and PKC (alpha, betat and gamma subunits) The 3 subunits phosphorylate GJA1 at Ser368 and reduce Gap junctions activity. PMID:10679481 Fibroblast growth factor-2 (FGF-2)decreases cardiomyocyte GJ permeability by stimulating phosphorylation of connexin-43 FGF-2 activates receptors linked to PKC and MAPK In immunoprecipitation experiments using specific anti-Cx43 antibodies, PKCE but not PKCA coprecipitated with Cx43. FGF-2 increased levels of coprecipitated PKCE, suggesting increased association between PKCE and Cx43 on stimulation. To conclude, PKC mediates the FGF-2–induced effects on cardiac GJs and that PKC likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact PMID:9278444 Reduction of gap junctional communication in v-src transformed cells is accompanied by tyrosine phosphorylation of the gap junction protein, connexin 43 SH3 and SH2 domains of v-Src bind to proline-rich motifs and a phosphorylated tyrosine residue in the C-terminal tail of Cx43 PMID:15534005 Phosphorylation of Cx43 on S368 has been shown to decrease gap junctional communication via a reduction in unitary channel conductance. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="627.0" y="5017.5"/> <port id="pr_24eeec4b-6c79-467f-8e62-c25466e278ad_p1" x="632.0" y="5007.5"/> <port id="pr_24eeec4b-6c79-467f-8e62-c25466e278ad_p2" x="632.0" y="5037.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5f1741ef-c23a-4c6e-abbb-f53a353e6fda"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="569.2046" y="3224.4478"/> <port id="pr_5f1741ef-c23a-4c6e-abbb-f53a353e6fda_p1" x="574.2046" y="3214.4478"/> <port id="pr_5f1741ef-c23a-4c6e-abbb-f53a353e6fda_p2" x="574.2046" y="3244.4478"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c03b3f27-4654-4626-8829-15563610f227"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15070779 WNK4 binds and phosphorylates claudins 1–4. Claudins 1–4 are known to be involved in the regulation of paracellular ion permeability. The increases in phosphorylation of claudins were greater in cells expressing the mutant WNK4 than in cells expressing wild-type protein. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. 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References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="529.5397" y="2451.4"/> <port id="pr_5e59c027-ca94-4349-a81f-1c2b81a4e4d5_p1" x="534.5397" y="2441.4"/> <port id="pr_5e59c027-ca94-4349-a81f-1c2b81a4e4d5_p2" x="534.5397" y="2471.4"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3907541c-f9cd-4264-b1ee-60418bf9115c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="992.0" y="2619.2842"/> <port id="pr_3907541c-f9cd-4264-b1ee-60418bf9115c_p1" x="997.0" y="2609.2842"/> <port id="pr_3907541c-f9cd-4264-b1ee-60418bf9115c_p2" x="997.0" y="2639.2842"/> </glyph> <glyph class="process" orientation="vertical" id="pr_12c810da-323b-4f04-b855-1e4913e56edc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1221.2649" y="2695.25"/> <port id="pr_12c810da-323b-4f04-b855-1e4913e56edc_p1" x="1226.2649" y="2685.25"/> <port id="pr_12c810da-323b-4f04-b855-1e4913e56edc_p2" x="1226.2649" y="2715.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_afe0d0c8-2c6f-4053-a12f-4419114a4603"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1045.4702" y="2322.0"/> <port id="pr_afe0d0c8-2c6f-4053-a12f-4419114a4603_p1" x="1050.4702" y="2342.0"/> <port id="pr_afe0d0c8-2c6f-4053-a12f-4419114a4603_p2" x="1050.4702" y="2312.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_440628fb-0b1e-4205-b5c6-9ac98b80310b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1261.49" y="2149.734"/> <port id="pr_440628fb-0b1e-4205-b5c6-9ac98b80310b_p1" x="1251.49" y="2154.734"/> <port id="pr_440628fb-0b1e-4205-b5c6-9ac98b80310b_p2" x="1281.49" y="2154.734"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_48c56dee-e1e1-49da-930a-004fce9eebd9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10613913 Cingulin is a functionally important component of TJ. It interacts with ZO-1, ZO-2, ZO-3, and myosin thus links the submembrane plaque domain of TJ to the actomyosin cytoskeleton References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1333.25" y="2234.2185"/> <port id="pr_48c56dee-e1e1-49da-930a-004fce9eebd9_p1" x="1353.25" y="2239.2185"/> <port id="pr_48c56dee-e1e1-49da-930a-004fce9eebd9_p2" x="1323.25" y="2239.2185"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1a3caa98-2bf6-4bd4-8762-a58ad72682de"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9334353 MLLT4 is so-called Afadin or AF-6 Afadin serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox 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h="10.0" x="1429.1829" y="2239.8066"/> <port id="pr_b041d37a-284f-4d8b-a341-1ab1ef3a7b48_p1" x="1419.1829" y="2244.8066"/> <port id="pr_b041d37a-284f-4d8b-a341-1ab1ef3a7b48_p2" x="1449.1829" y="2244.8066"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f741d228-60c3-4582-a049-7c96240ab434"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1643.4888" y="2177.5"/> <port id="pr_f741d228-60c3-4582-a049-7c96240ab434_p1" x="1648.4888" y="2197.5"/> <port id="pr_f741d228-60c3-4582-a049-7c96240ab434_p2" x="1648.4888" y="2167.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b22f20e4-9cbe-49fd-b57f-1c9e11530c0c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11689568 MPDZ accumulates at the TJ in epithelial cells through its binding to Claudins and JAMs. MPDZ is believed to function as a multivalent scaffold protein that recruits various proteins to TJ References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="799.5" y="2643.0"/> <port id="pr_b22f20e4-9cbe-49fd-b57f-1c9e11530c0c_p1" x="804.5" y="2663.0"/> <port id="pr_b22f20e4-9cbe-49fd-b57f-1c9e11530c0c_p2" x="804.5" y="2633.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b45d921f-f5ae-44e5-bd92-410d973fb730"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11689568 MPDZ accumulates at the TJ in epithelial cells through its binding to Claudins and JAMs. MPDZ is believed to function as a multivalent scaffold protein that recruits various proteins to TJ References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="970.0" y="2943.0"/> <port id="pr_b45d921f-f5ae-44e5-bd92-410d973fb730_p1" x="975.0" y="2933.0"/> <port id="pr_b45d921f-f5ae-44e5-bd92-410d973fb730_p2" x="975.0" y="2963.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6474477c-82c6-4b9b-b188-da0464c526f4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1533.25" y="2477.9268"/> <port id="pr_6474477c-82c6-4b9b-b188-da0464c526f4_p1" x="1523.25" y="2482.9268"/> <port id="pr_6474477c-82c6-4b9b-b188-da0464c526f4_p2" x="1553.25" y="2482.9268"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9fd72ed1-0199-4f83-a420-2d9a0289ff56"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1643.75" y="2285.5"/> <port id="pr_9fd72ed1-0199-4f83-a420-2d9a0289ff56_p1" x="1633.75" y="2290.5"/> <port id="pr_9fd72ed1-0199-4f83-a420-2d9a0289ff56_p2" x="1663.75" y="2290.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_096aee5f-5177-4140-ac1e-e821520a4cb1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15383321 MTDH is so-called LYRIC LYRIC colocalizes with ZO1 and Occludin in polarized epithelial cells. This protein is most likely not involved in the TJ formation as a structural component. However, it is required for the maturation of the TJ complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1380.5" y="2753.2593"/> <port id="pr_096aee5f-5177-4140-ac1e-e821520a4cb1_p1" x="1370.5" y="2758.2593"/> <port id="pr_096aee5f-5177-4140-ac1e-e821520a4cb1_p2" x="1400.5" y="2758.2593"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b80c83d1-46c4-4c74-a289-1870718ab2f8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15383321 MTDH is so-called LYRIC LYRIC colocalizes with ZO1 and Occludin in polarized epithelial cells. This protein is most likely not involved in the TJ formation as a structural component. However, it is required for the maturation of the TJ complex References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1380.5" y="2882.5"/> <port id="pr_b80c83d1-46c4-4c74-a289-1870718ab2f8_p1" x="1370.5" y="2887.5"/> <port id="pr_b80c83d1-46c4-4c74-a289-1870718ab2f8_p2" x="1400.5" y="2887.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b6f723df-956c-424f-bd2d-3c810b011ee4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1683.75" y="2071.4836"/> <port id="pr_b6f723df-956c-424f-bd2d-3c810b011ee4_p1" x="1673.75" y="2076.4836"/> <port id="pr_b6f723df-956c-424f-bd2d-3c810b011ee4_p2" x="1703.75" y="2076.4836"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dc20cfa7-44f6-4934-9790-ca75e68e9fbe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22671595 Caveolin-1 is an endocytic scaffolding protein It binds independently to claudin-2 and occludin (co-immunoprecipitation assays). The finding that caveolin-1 interacts with claudin-2 and occludin, but notwith claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1380.5" y="2934.2593"/> <port id="pr_dc20cfa7-44f6-4934-9790-ca75e68e9fbe_p1" x="1370.5" y="2939.2593"/> <port id="pr_dc20cfa7-44f6-4934-9790-ca75e68e9fbe_p2" x="1400.5" y="2939.2593"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dd7cd20d-6464-4d4e-9966-15581b474921"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22671595 Caveolin-1 is an endocytic scaffolding protein It binds independently to claudin-2 and occludin (co-immunoprecipitation assays). The finding that caveolin-1 interacts with claudin-2 and occludin, but notwith claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1393.0" y="3027.7266"/> <port id="pr_dd7cd20d-6464-4d4e-9966-15581b474921_p1" x="1383.0" y="3032.7266"/> <port id="pr_dd7cd20d-6464-4d4e-9966-15581b474921_p2" x="1413.0" y="3032.7266"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dadd767c-4c99-4c23-a0c1-613bd20769b0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11309411 Claudin-11 forms a complex with TSPAN3 and ITGB1. This interaction potentially regulates proliferation and migration of oligodendrocytes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1121.0" y="3160.7314"/> <port id="pr_dadd767c-4c99-4c23-a0c1-613bd20769b0_p1" x="1111.0" y="3165.7314"/> <port id="pr_dadd767c-4c99-4c23-a0c1-613bd20769b0_p2" x="1141.0" y="3165.7314"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_60ea6c7b-f317-43cc-a8b4-c740822fca63"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15471980 PMID:17498653 The phosphorylation of caveolin-1 served to recruit C-terminal Src-like kinase (Csk) to the integrin/caveolin-1 complex. This recruitment results in additional regulation of SFK activity and induction of myosin light chain (MLC) phosphorylation. Key components of this pathway were recruited to caveolar microdomains and dependent on the presence of the caveolin-1 protein. PMID:21051664 p190RhoGAP links integrins and caveolin-1 (and thus caveolae) to RhoA in a mechanotransduction cascade References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1381.75" y="3079.5"/> <port id="pr_60ea6c7b-f317-43cc-a8b4-c740822fca63_p1" x="1371.75" y="3084.5"/> <port id="pr_60ea6c7b-f317-43cc-a8b4-c740822fca63_p2" x="1401.75" y="3084.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_17520c9e-607d-4db2-9efa-497469a5066e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12668723 Snail binds directly to the E-boxes of the promoters of claudin et occludin genes, resulting in complete repression of their promoter activity PMID:16232121 Snail and Slug bind to the E-box motifs present in the human Claudin-1 promoter. High levels of Snail and Slug correlatedwith lowlevels of Claudin-1 expression. It is proposed that Claudin-1 is a direct downstream target gene of Snail family factors in epithelial cells PMID:15151915 The transcription factors B-catenin/Tcf complex has been shown to bind directly to the claudin-1 and claudin-2 promoters. PMID:17550342 SNAI2 represses Claudin-1 expression SNAI1 represses Claudin-1 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2328.5" y="2717.2393"/> <port id="pr_17520c9e-607d-4db2-9efa-497469a5066e_p1" x="2348.5" y="2722.2393"/> <port id="pr_17520c9e-607d-4db2-9efa-497469a5066e_p2" x="2318.5" y="2722.2393"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_202054af-6c9d-4ab6-8f71-1366daee3ea0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1410.0" y="2704.4187"/> <port id="pr_202054af-6c9d-4ab6-8f71-1366daee3ea0_p1" x="1430.0" y="2709.4187"/> <port id="pr_202054af-6c9d-4ab6-8f71-1366daee3ea0_p2" x="1400.0" y="2709.4187"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0db4e195-d7f4-4bc5-8ca7-1ab5dc00e9de"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15151915 The transcription factors B-catenin/Tcf complex has been shown to bind directly to the claudin-1 and claudin-2 promoters. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2329.0" y="2782.0205"/> <port id="pr_0db4e195-d7f4-4bc5-8ca7-1ab5dc00e9de_p1" x="2349.0" y="2787.0205"/> <port id="pr_0db4e195-d7f4-4bc5-8ca7-1ab5dc00e9de_p2" x="2319.0" y="2787.0205"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_a5ed8db8-ac56-4f38-a393-514dbaaef86d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1416.5" y="2777.7334"/> <port id="pr_a5ed8db8-ac56-4f38-a393-514dbaaef86d_p1" x="1436.5" y="2782.7334"/> <port id="pr_a5ed8db8-ac56-4f38-a393-514dbaaef86d_p2" x="1406.5" y="2782.7334"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f94c8ab5-4839-4a1a-9a77-ae44eb1e9e06"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19751508 PMID:22270359 PMID:16940750 -In the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin. Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded. -In the presence of Wnt lignads, upon ligand binding, DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3. Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex. Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs PMID:19020303 When Wnt binds its receptor, Frizzled, beta-catenin is released to translocate from the cytoplasm to the nucleus, where it forms a complex with TCF and/or LEF transcription factors and stimulates cyclin D1 gene transcription (Beta-catenin/TCF)- mediated cyclin D1 gene transcription is further regulated by active Rac signaling, phosphorylation by protein kinase A (PKA) PMID:15377999 Rac1-GTP augments nuclear accumulation of b-catenin and physical association of Rac1 with b-catenin and/or TCF-4 may facilitate this process. This culminates in the amplification of b-catenin signaling activity, resulting in enhanced transcriptional activation of perhaps a specific subset of Wnt target genes important in cancer progression. PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin–TCF complex with DNA. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2279.2798" y="3524.25"/> <port id="pr_f94c8ab5-4839-4a1a-9a77-ae44eb1e9e06_p1" x="2284.2798" y="3544.25"/> <port id="pr_f94c8ab5-4839-4a1a-9a77-ae44eb1e9e06_p2" x="2284.2798" y="3514.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8c8a6d2d-e9a6-4ce8-8a41-1da9a79301bb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="560.50464" y="5062.75"/> <port id="pr_8c8a6d2d-e9a6-4ce8-8a41-1da9a79301bb_p1" x="565.50464" y="5052.75"/> <port id="pr_8c8a6d2d-e9a6-4ce8-8a41-1da9a79301bb_p2" x="565.50464" y="5082.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_30f5d386-a6b1-4715-87b4-569a18656850"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="560.50464" y="5202.75"/> <port id="pr_30f5d386-a6b1-4715-87b4-569a18656850_p1" x="565.50464" y="5192.75"/> <port id="pr_30f5d386-a6b1-4715-87b4-569a18656850_p2" x="565.50464" y="5222.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_eebfc775-3318-435d-a4e7-d58e1c3e0141"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="560.20795" y="5302.75"/> <port id="pr_eebfc775-3318-435d-a4e7-d58e1c3e0141_p1" x="565.20795" y="5292.75"/> <port id="pr_eebfc775-3318-435d-a4e7-d58e1c3e0141_p2" x="565.20795" y="5322.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_251588c2-de0d-4b23-8020-b27f6b2c77c2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="560.50464" y="5402.75"/> <port id="pr_251588c2-de0d-4b23-8020-b27f6b2c77c2_p1" x="565.50464" y="5392.75"/> <port id="pr_251588c2-de0d-4b23-8020-b27f6b2c77c2_p2" x="565.50464" y="5422.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b72dce22-4c24-4a98-9c3d-59571935e4f6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="560.62146" y="5503.375"/> <port id="pr_b72dce22-4c24-4a98-9c3d-59571935e4f6_p1" x="565.62146" y="5493.375"/> <port id="pr_b72dce22-4c24-4a98-9c3d-59571935e4f6_p2" x="565.62146" y="5523.375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ebd04760-619f-4ed6-8b32-eeb678a3ef61"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="580.50464" y="5642.75"/> <port id="pr_ebd04760-619f-4ed6-8b32-eeb678a3ef61_p1" x="585.50464" y="5632.75"/> <port id="pr_ebd04760-619f-4ed6-8b32-eeb678a3ef61_p2" x="585.50464" y="5662.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_8ab70381-69e1-485c-8ea0-2fdbcd076478"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15980428 PMID:19284610 The associations between Cx43 and ZO-1 and ZO-2 proteins were shown to be under cell-cycle stage-specific control. Connexin 43 interacts preferentially with ZO-1 during G0 stage, whereas the interaction with ZO-2 is approximately the same during the various stages References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="854.0" y="4919.3823"/> <port id="pr_8ab70381-69e1-485c-8ea0-2fdbcd076478_p1" x="844.0" y="4924.3823"/> <port id="pr_8ab70381-69e1-485c-8ea0-2fdbcd076478_p2" x="874.0" y="4924.3823"/> </glyph> <glyph class="process" orientation="vertical" id="pr_713708d3-68d4-4811-bd5e-09001d64eb73"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:9592087 Cx32 (GJB1) interacts with Cx26(GJB2), Cx46(GJA3), and Cx50(GJA8) but failing to do so with Cx40(GJA5). PMID:15782139 Cx32 has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line. 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The LEF/TCF family exhibits extensive patterns of alternative splicing, alternative promoter usage and activities of both repression and activation. All LEF/TCFs bind b-catenin. 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PMID:17568974 Connexins induce and maintain tight junctions in epithelial cells.References_end References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="916.579" y="5567.0"/> <port id="pr_34dc4651-4de5-4b04-9b65-82dfba15e399_p1" x="921.579" y="5557.0"/> <port id="pr_34dc4651-4de5-4b04-9b65-82dfba15e399_p2" x="921.579" y="5587.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4654d364-bc16-4bdc-8b15-e9ce970cd5b5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: GJB1 is so-called Connexin 32 or Cx32 PMID:11978007 Cx32 Formation and / or Cx32-Mediated Intercellular Communication Induces Expression and Function of Tight Junctions in Hepatocytic Cell Line PMID:19284610 Cx32, colocalizes with tight junction proteins ZO-1 and ZO-2 in rat hepatocytes, and small gap junction plaques were found within tight junction strands. It was suggested that Cx32 can participate in the formation of functional tight junctions and in actin organization. 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References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1152.2058" y="5563.5"/> <port id="pr_c713987d-1c17-4403-9ffe-4fd1e5ffe397_p1" x="1157.2058" y="5553.5"/> <port id="pr_c713987d-1c17-4403-9ffe-4fd1e5ffe397_p2" x="1157.2058" y="5583.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3908bc20-cb9c-4090-a2d8-c72e7b8060be"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19418635 GJD2 is widely expressed in neurons and was previously shown to interact with the PDZ domain-containing protein ZO-1. Direct association of connexin36 (GJD2) with ZO-2 and ZO-3 was also demonstrated. PMID:15558297 Association of connexin36 with ZO-1 in HeLa cells, betaTC-3 cells, pancreas, and adrenal gland. The functional significance of Cx36/ZO-1 interaction remains to be established Interestingly, ZO-1 was not associated with Cx36 intracellularly, suggesting that functions of its interaction with at least Cx36 may be restricted to intact gap junctions at plasma membranes. PMID:16650609 Association of connexin36 and ZO-1 with ZO-2 and the transcription factor ZO-1-associated nucleic acid-binding protein at neuronal gap junctions in rodent retina. PMID:17681699 In the outer plexiform layer of mouse retina, ZO-1 interacts with connexin36 but not with Cx57, and there is an absence of connexin57/connexin36 heterotypic gap junctional coupling in mouse retina References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1306.7157" y="5555.0"/> <port id="pr_3908bc20-cb9c-4090-a2d8-c72e7b8060be_p1" x="1311.7157" y="5545.0"/> <port id="pr_3908bc20-cb9c-4090-a2d8-c72e7b8060be_p2" x="1311.7157" y="5575.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_35ae85d6-4262-4b4e-88c2-a189ab24e1e6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="562.59705" y="5962.75"/> <port id="pr_35ae85d6-4262-4b4e-88c2-a189ab24e1e6_p1" x="567.59705" y="5952.75"/> <port id="pr_35ae85d6-4262-4b4e-88c2-a189ab24e1e6_p2" x="567.59705" y="5982.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7fd673bd-9ffe-440e-976b-5e5af41b8e10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="560.50464" y="5862.75"/> <port id="pr_7fd673bd-9ffe-440e-976b-5e5af41b8e10_p1" x="565.50464" y="5852.75"/> <port id="pr_7fd673bd-9ffe-440e-976b-5e5af41b8e10_p2" x="565.50464" y="5882.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_763630a2-a9a6-4d99-9940-ec23ee30d85a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2669.5" y="2395.0"/> <port id="pr_763630a2-a9a6-4d99-9940-ec23ee30d85a_p1" x="2674.5" y="2415.0"/> <port id="pr_763630a2-a9a6-4d99-9940-ec23ee30d85a_p2" x="2674.5" y="2385.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0605a110-ac5e-4027-b325-ccfdace1380d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: GJB5 is so-called Connexin 31.1 PMID:21777377 Cx31.1 (GJB5) is predominantly expressed in the testes and the skin epidermis. Cx31.1 rarely form functional gap junction channels, either with itself or with other Cx isoforms. Gap junctions play important roles in various physiologic functions such as regulation of cell proliferation, cell differentiation, tissue development and cell apoptosis. In most cases, Cxs act as tumour suppressors: Gap junctions play an important role as tumour suppressors in maintaining cell differentiation and preventing transformation Cx31.1 reduced tumour cell proliferation, anchorage-independent growth, migration and invasion. Moreover, development of tumours in a xenograft model was suppressed by Cx31.1, suggesting that Cx31.1 may act as a tumour suppressor in NSCLC cell lines. Further studies are required to investigate the mechanism by which Cx31.1 repress cyclin D3 expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2670.5" y="1952.5"/> <port id="pr_0605a110-ac5e-4027-b325-ccfdace1380d_p1" x="2675.5" y="1972.5"/> <port id="pr_0605a110-ac5e-4027-b325-ccfdace1380d_p2" x="2675.5" y="1942.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_478e2d35-7cf6-488e-a1e4-d3d8b9aef65c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:EMT_REGULATORS Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3859.875" y="2151.1704"/> <port id="pr_478e2d35-7cf6-488e-a1e4-d3d8b9aef65c_p1" x="3879.875" y="2156.1704"/> <port id="pr_478e2d35-7cf6-488e-a1e4-d3d8b9aef65c_p2" x="3849.875" y="2156.1704"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_3b50350f-856f-4313-bfe5-10f91ea4b426"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5139.798" y="1828.25"/> <port id="pr_3b50350f-856f-4313-bfe5-10f91ea4b426_p1" x="5144.798" y="1848.25"/> <port id="pr_3b50350f-856f-4313-bfe5-10f91ea4b426_p2" x="5144.798" y="1818.25"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_3ad1bcc5-e849-4529-b4d7-d7a5c5af1347"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5401.75" y="1827.1614"/> <port id="pr_3ad1bcc5-e849-4529-b4d7-d7a5c5af1347_p1" x="5391.75" y="1832.1614"/> <port id="pr_3ad1bcc5-e849-4529-b4d7-d7a5c5af1347_p2" x="5421.75" y="1832.1614"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_0e46e901-6fd5-4102-af86-5cec92daab9c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5474.5" y="1827.4128"/> <port id="pr_0e46e901-6fd5-4102-af86-5cec92daab9c_p1" x="5464.5" y="1832.4128"/> <port id="pr_0e46e901-6fd5-4102-af86-5cec92daab9c_p2" x="5494.5" y="1832.4128"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_137a4edd-3f26-4925-986c-eb375848a2b4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5323.801" y="2740.75"/> <port id="pr_137a4edd-3f26-4925-986c-eb375848a2b4_p1" x="5328.801" y="2730.75"/> <port id="pr_137a4edd-3f26-4925-986c-eb375848a2b4_p2" x="5328.801" y="2760.75"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_fa6f9a48-ad1a-453d-aa19-b2c364c639e2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. ARHGDIG is about 50 percent identical to ARHGDIA and ARHGDIB. ARHGFIG binds to CDC42 and RhoA with less affinity compared with ARHGDIA and does not bind with Rac1, Rac2, or Ras. ARHGDIG functions as a GDI for CDC42 but with about 20 times less efficiency than ARHGDIA. PMID:9490022 ARHGDIA,B,G are CDC42_GDIs References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5042.671" y="1894.75"/> <port id="pr_fa6f9a48-ad1a-453d-aa19-b2c364c639e2_p1" x="5062.671" y="1899.75"/> <port id="pr_fa6f9a48-ad1a-453d-aa19-b2c364c639e2_p2" x="5032.671" y="1899.75"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_e36508f4-70cf-4d0d-afdb-f52bb6e107da"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. ARHGDIG is about 50 percent identical to ARHGDIA and ARHGDIB. ARHGFIG binds to CDC42 and RhoA with less affinity compared with ARHGDIA and does not bind with Rac1, Rac2, or Ras. ARHGDIG functions as a GDI for CDC42 but with about 20 times less efficiency than ARHGDIA. PMID:9490022 ARHGDIA,B,G are CDC42_GDIs References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5043.2744" y="1912.25"/> <port id="pr_e36508f4-70cf-4d0d-afdb-f52bb6e107da_p1" x="5063.2744" y="1917.25"/> <port id="pr_e36508f4-70cf-4d0d-afdb-f52bb6e107da_p2" x="5033.2744" y="1917.25"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_80a6f7b7-31ca-4d52-b795-b6197a9ab061"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. ARHGDIG is about 50 percent identical to ARHGDIA and ARHGDIB. ARHGFIG binds to CDC42 and RhoA with less affinity compared with ARHGDIA and does not bind with Rac1, Rac2, or Ras. ARHGDIG functions as a GDI for CDC42 but with about 20 times less efficiency than ARHGDIA. PMID:9490022 ARHGDIA,B,G are CDC42_GDIs References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5024.25" y="1927.5555"/> <port id="pr_80a6f7b7-31ca-4d52-b795-b6197a9ab061_p1" x="5044.25" y="1932.5555"/> <port id="pr_80a6f7b7-31ca-4d52-b795-b6197a9ab061_p2" x="5014.25" y="1932.5555"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_3e3a45a3-6453-4803-85bb-aa36f7eea558"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5217.243" y="2049.25"/> <port id="pr_3e3a45a3-6453-4803-85bb-aa36f7eea558_p1" x="5222.243" y="2069.25"/> <port id="pr_3e3a45a3-6453-4803-85bb-aa36f7eea558_p2" x="5222.243" y="2039.25"/> </glyph> 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<glyph class="uncertain process" orientation="horizontal" id="pr_93d73cf8-0381-461d-b82f-a8dbd4d1421e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5218.7134" y="2152.893"/> <port id="pr_93d73cf8-0381-461d-b82f-a8dbd4d1421e_p1" x="5208.7134" y="2157.893"/> <port id="pr_93d73cf8-0381-461d-b82f-a8dbd4d1421e_p2" x="5238.7134" y="2157.893"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c6ec2e3e-ea77-4055-b4b9-73c5f54ee22e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4850.625" y="2058.0"/> <port id="pr_c6ec2e3e-ea77-4055-b4b9-73c5f54ee22e_p1" x="4855.625" y="2078.0"/> <port id="pr_c6ec2e3e-ea77-4055-b4b9-73c5f54ee22e_p2" x="4855.625" y="2048.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_fc17b65a-8c5c-44b2-b3c4-1905a187b674"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11149925 2 classes of negative regulators of Rho proteins have been described. GAPs and GDIs. Rho proteins have relatively slow intrinsic rates of GTP hydrolysis that can be accelerated by GAPs (GTPase activating proteins). Another class of proteins shown to inhibit the release of GDP from Rho proteins, GDIs (GDP Dissociation Inhibitors (GDIs) have been described. Perhaps more important than their effects on the GDP/GTP cycle is the ability of GDIs to solubilize membrane-associated Rho proteins. RhoA is sequestered in the cytosol by a RhoGDI-dependent and -independent mechanisms. RhoGDI binding is not affected by the length of the prenyl chain (farnesylation versus geranylgeranylation) Palmitoylation blocks RhoGDI binding. PMID:9113980 GDIs play a primary role in modulating the activation of GTPases and may also be critical for the cellular compartmentalization of GTPases. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4883.875" y="2058.0"/> <port id="pr_fc17b65a-8c5c-44b2-b3c4-1905a187b674_p1" x="4888.875" y="2048.0"/> <port id="pr_fc17b65a-8c5c-44b2-b3c4-1905a187b674_p2" x="4888.875" y="2078.0"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_7ff0f067-6b64-4d61-92fa-bca01fc18572"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4854.918" y="2425.5"/> <port id="pr_7ff0f067-6b64-4d61-92fa-bca01fc18572_p1" x="4859.918" y="2415.5"/> <port id="pr_7ff0f067-6b64-4d61-92fa-bca01fc18572_p2" x="4859.918" y="2445.5"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_7deace84-7c06-4bed-b7a1-036c4deefe18"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4839.4697" y="2436.75"/> <port id="pr_7deace84-7c06-4bed-b7a1-036c4deefe18_p1" x="4844.4697" y="2426.75"/> <port id="pr_7deace84-7c06-4bed-b7a1-036c4deefe18_p2" x="4844.4697" y="2456.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ee6c2a3b-f8bf-4736-a9e2-acde1c7849fe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12778124 In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop. Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4865.408" y="2273.0"/> <port id="pr_ee6c2a3b-f8bf-4736-a9e2-acde1c7849fe_p1" x="4870.408" y="2263.0"/> <port id="pr_ee6c2a3b-f8bf-4736-a9e2-acde1c7849fe_p2" x="4870.408" y="2293.0"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_745b35d2-1a03-42c4-8726-b4fb2e1c2bc7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5032.0" y="2418.8481"/> <port id="pr_745b35d2-1a03-42c4-8726-b4fb2e1c2bc7_p1" x="5022.0" y="2423.8481"/> <port id="pr_745b35d2-1a03-42c4-8726-b4fb2e1c2bc7_p2" x="5052.0" y="2423.8481"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_67750420-5551-44a9-81e9-ecee8d7b36c9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5016.54" y="2457.25"/> <port id="pr_67750420-5551-44a9-81e9-ecee8d7b36c9_p1" x="5021.54" y="2447.25"/> <port id="pr_67750420-5551-44a9-81e9-ecee8d7b36c9_p2" x="5021.54" y="2477.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a49198fc-0975-4b4e-8016-daf8f2ba41e1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15866170 DRFs (DIAPH1,2,3) are autoinhibited through intramolecular binding of a Diaphanous autoinhibitory domain to a conserved N-terminal regulatory element. Autoinhibition is relieved through binding of the GTPase RhoA to the N-terminal element. PMID:16292343 DRFs are regulated by a RhoGTPase-binding domain situated in the N-terminal region and a C-terminal Diaphanous-autoregulatory domain, whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia PMID:17575049 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5000.665" y="2292.0"/> <port id="pr_a49198fc-0975-4b4e-8016-daf8f2ba41e1_p1" x="5005.665" y="2282.0"/> <port id="pr_a49198fc-0975-4b4e-8016-daf8f2ba41e1_p2" x="5005.665" y="2312.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_cf6ffd3b-ba46-4166-866e-9e00300e9916"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12788081 p250GAP (so-called ARHGAP32 or p200RhoGAP) is a RhoGAP protein that is expressed predominantly in brain. ARHGAP32 is associated with and phosphorylated by Fyn, a member of Src-family protein tyrosine kinase. p250GAP is phosphorylated by Fyn in oligodendrocytes and Fyn activity is up-regulated during oligodendrocyte maturation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5799.75" y="1759.75"/> <port id="pr_cf6ffd3b-ba46-4166-866e-9e00300e9916_p1" x="5804.75" y="1749.75"/> <port id="pr_cf6ffd3b-ba46-4166-866e-9e00300e9916_p2" x="5804.75" y="1779.75"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_923a0ffe-08fe-4795-b321-9203c6e406d0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5239.3594" y="1938.85"/> <port id="pr_923a0ffe-08fe-4795-b321-9203c6e406d0_p1" x="5244.3594" y="1958.85"/> <port id="pr_923a0ffe-08fe-4795-b321-9203c6e406d0_p2" x="5244.3594" y="1928.85"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_86c17e6c-a9f1-4f35-9ad9-5ddf9189664c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5272.6997" y="1945.85"/> <port id="pr_86c17e6c-a9f1-4f35-9ad9-5ddf9189664c_p1" x="5277.6997" y="1965.85"/> <port id="pr_86c17e6c-a9f1-4f35-9ad9-5ddf9189664c_p2" x="5277.6997" y="1935.85"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_68e4babb-fe77-4e9d-bd04-a79f9ecc8032"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5255.77" y="1942.85"/> <port id="pr_68e4babb-fe77-4e9d-bd04-a79f9ecc8032_p1" x="5260.77" y="1962.85"/> <port id="pr_68e4babb-fe77-4e9d-bd04-a79f9ecc8032_p2" x="5260.77" y="1932.85"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_7c8d1f02-9bef-4339-8f69-e94648df73a7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9287351 ERM family (ezrin/radixin/moesin) Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein. PMID:10047517 Regulation of cortical structure by the ERM protein family. PMID:12045227 Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo. ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli. ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation. Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type. The Rho-independent activation mechanism of ERM proteins therefore exists. Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo. PMID:7579708 Cell extracts contain ezrin dimers and ezrin-moesin heterodimers in addition to monomers. Dimerization in vivo requires an activation step that exposes this masked domain. The conformationally inaccessible C-terminal region included the F-actin binding site, suggesting that this activity is likewise regulated by masking. PMID:8527459 Ezrin, a membrane-microfilament linking protein, exists largely as a monomeric protein in solution. Purified ezrin monomers normally have a masked C-terminal domain (termed a C-ERMAD) that, upon exposure, can associate with an N-terminal domain (termed N-ERMAD) of another ezrin molecule. Purified ezrin dimers also have masked C-ERMADs. Since radixin and moesin, the two other members of the closely related ERM protein family, both contain N- and C-ERMADs, the results we have documented and models proposed for ezrin are likely to apply to radixin and moesin as well PMID:12802084 ERM proteins exist in the cytoplasm as dormant monomers in which the F-actin cytoskeleton and the plasma membrane binding sites are masked. This closed conformation is due to an intramolecular N- to C-ERM association domain (ERMAD) interaction. Abrogation of the N and C-ERMAD interaction is required to open up the molecules and to expose their cryptic binding sites 2 factors have been implicated in the activation of ERM proteins: -The binding to phosphatidylinositol 4,5-biphosphate is required for their interaction with actin in vitro and with membrane proteins in vivo -Phosphorylation of a conserved threonine residue in the C-ERMAD, T567, inhibits the N and C-ERMAD interaction in vitro and in vivo, converts inactive oligomers to active monomers PMID:8522586 PMID:10970850 Phosphorylation of ezrin by the Rho kinase ROCK is required for Rho-induced focal adhesion assembly. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5186.3" y="2004.7"/> <port id="pr_7c8d1f02-9bef-4339-8f69-e94648df73a7_p1" x="5206.3" y="2009.7"/> <port id="pr_7c8d1f02-9bef-4339-8f69-e94648df73a7_p2" x="5176.3" y="2009.7"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_e3529f79-6c61-477b-9e9a-ca0ccb195b92"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3052.5015" y="966.0"/> <port id="pr_e3529f79-6c61-477b-9e9a-ca0ccb195b92_p1" x="3057.5015" y="986.0"/> <port id="pr_e3529f79-6c61-477b-9e9a-ca0ccb195b92_p2" x="3057.5015" y="956.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_69433b77-824c-453e-895b-74d3378207f0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20008297 ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. PMID:22074495 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4044.75" y="881.056"/> <port id="pr_69433b77-824c-453e-895b-74d3378207f0_p1" x="4049.75" y="901.056"/> <port id="pr_69433b77-824c-453e-895b-74d3378207f0_p2" x="4049.75" y="871.056"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_57bf9c9e-7193-4ea3-9c19-555bc9919a3f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5218.3994" y="2450.25"/> <port id="pr_57bf9c9e-7193-4ea3-9c19-555bc9919a3f_p1" x="5223.3994" y="2440.25"/> <port id="pr_57bf9c9e-7193-4ea3-9c19-555bc9919a3f_p2" x="5223.3994" y="2470.25"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_f710a5e1-dd7d-4b3f-b788-53bea2db5dc0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5245.913" y="2440.75"/> <port id="pr_f710a5e1-dd7d-4b3f-b788-53bea2db5dc0_p1" x="5235.913" y="2445.75"/> <port id="pr_f710a5e1-dd7d-4b3f-b788-53bea2db5dc0_p2" x="5265.913" y="2445.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1a0a2aa5-1d70-492a-b45f-c3763a7f89cb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:18172008 p53 induces PTEN transcription Snai1 inhibits gene expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4055.4973" y="2015.25"/> <port id="pr_1a0a2aa5-1d70-492a-b45f-c3763a7f89cb_p1" x="4060.4973" y="2035.25"/> <port id="pr_1a0a2aa5-1d70-492a-b45f-c3763a7f89cb_p2" x="4060.4973" y="2005.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_33dd4384-811c-4b25-bce7-b3f44591e991"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4050.372" y="1453.67"/> <port id="pr_33dd4384-811c-4b25-bce7-b3f44591e991_p1" x="4055.372" y="1473.67"/> <port id="pr_33dd4384-811c-4b25-bce7-b3f44591e991_p2" x="4055.372" y="1443.67"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4a955a53-211e-44fc-b6ff-99b1523f8766"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2752.5007" y="1953.0"/> <port id="pr_4a955a53-211e-44fc-b6ff-99b1523f8766_p1" x="2757.5007" y="1973.0"/> <port id="pr_4a955a53-211e-44fc-b6ff-99b1523f8766_p2" x="2757.5007" y="1943.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_99e2898a-cce1-498b-a9f3-76c63b05e5ff"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15155580 Snail regulates cell-cycle progression and survival: Snail regulates components of the early to late G1 transition and the G1/S checkpoint. Snail represses Cyclin D2 transcription and increases p21/Cip1 transcription. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2752.75" y="2394.5"/> <port id="pr_99e2898a-cce1-498b-a9f3-76c63b05e5ff_p1" x="2757.75" y="2414.5"/> <port id="pr_99e2898a-cce1-498b-a9f3-76c63b05e5ff_p2" x="2757.75" y="2384.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a5c8f729-2ebb-4675-86e4-309d5726fa00"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5505.5" y="1963.5"/> <port id="pr_a5c8f729-2ebb-4675-86e4-309d5726fa00_p1" x="5510.5" y="1983.5"/> <port id="pr_a5c8f729-2ebb-4675-86e4-309d5726fa00_p2" x="5510.5" y="1953.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_87417f08-c936-4979-8da7-65a75bdfa7a5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9857026 GEF-H1 is so-called ARHGEF2 GEFH1, which associates with tubulin in a manner dependent on a Zn-finger motif, is a regulator of the Rho family GEFH1 is known to activate Rho A, B, C, and Rac1 but is inactive toward Cdc42, TC10, or Ras. GEFH1 may have a direct role in activation of Rac and/or Rho and in bringing the activated GTPase to specific target sites such as microtubules. PMID:16917499 The activation of GEFH1- RhoB through the TRIF-dependent pathway of LPS in DC might be a critical target for controlling the activation of CD4+ T cells. PMID:12221096 XPLN (so-called ARHGEF3) is a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. PMID:16112081 In vitro, GrinchGEF (ARHGEF10L) induced the GDP/ GTP exchange at RhoA, but not at Rac1 or Cdc42. In intact cells, GrinchGEF induced specifically Rho activation and enhanced RhoA,B,C-specific downstream effect. GrinchGEF, similar to its relative p164-RhoGEF (ARHGEF17), is a Rho-specific GEF. Although RhoA, B, and C have different cellular functions, and some regulators and effectors show preferential interaction with these Rho isoforms, GrinchGEF apparently does not distinguish between RhoA,B,C and similarly activates these Rho proteins PMID:9822605 Phosphorylated Vav-2 was found to be active on RhoA, RhoB and the more distantly related RhoG protein References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5470.5" y="1963.5"/> <port id="pr_87417f08-c936-4979-8da7-65a75bdfa7a5_p1" x="5475.5" y="1953.5"/> <port id="pr_87417f08-c936-4979-8da7-65a75bdfa7a5_p2" x="5475.5" y="1983.5"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_68dd02cd-71c5-497d-ae70-0bdd60db4373"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: The most known RhoB_GDIs are ARHGDIA and ARHGDIG. They bind to RhoB and suppress its activation. PMID:11368848 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5159.25" y="1880.593"/> <port id="pr_68dd02cd-71c5-497d-ae70-0bdd60db4373_p1" x="5179.25" y="1885.593"/> <port id="pr_68dd02cd-71c5-497d-ae70-0bdd60db4373_p2" x="5149.25" y="1885.593"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_2d10b4b5-32f7-41d0-8b0d-7d75b794a3e0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: The most known RhoB_GDIs are ARHGDIA and ARHGDIG. They bind to RhoB and suppress its activation. PMID:11368848 PMID:8939998 RhoGDI-3 (ARHGDIG) interacts specifically with GDP- and GTP-bound forms of post-translationally processed RhoB and RhoG proteins. No interaction is found with RhoA, RhoC, or Rac1 proteins. RhoGDI-3 is able to inhibit GDP/GTP exchange of RhoB and to release GDP-bound but not GTP-bound RhoB from cell membranes. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5163.25" y="1916.3035"/> <port id="pr_2d10b4b5-32f7-41d0-8b0d-7d75b794a3e0_p1" x="5183.25" y="1921.3035"/> <port id="pr_2d10b4b5-32f7-41d0-8b0d-7d75b794a3e0_p2" x="5153.25" y="1921.3035"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_70ffa921-9494-4683-a133-42aaeb24f4a0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9857026 GEF-H1 is so-called ARHGEF2 GEFH1, which associates with tubulin in a manner dependent on a Zn-finger motif, is a regulator of the Rho family GEFH1 is known to activate Rho A, B, C, and Rac1 but is inactive toward Cdc42, TC10, or Ras. GEFH1 may have a direct role in activation of Rac and/or Rho and in bringing the activated GTPase to specific target sites such as microtubules. PMID:16917499 The activation of GEFH1- RhoB through the TRIF-dependent pathway of LPS in DC might be a critical target for controlling the activation of CD4+ T cells. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5331.5" y="2000.7112"/> <port id="pr_70ffa921-9494-4683-a133-42aaeb24f4a0_p1" x="5351.5" y="2005.7112"/> <port id="pr_70ffa921-9494-4683-a133-42aaeb24f4a0_p2" x="5321.5" y="2005.7112"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_897a94c8-4259-447a-a735-1f47deff08d0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12221096 XPLN (so-called ARHGEF3) is a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5335.416" y="2013.7855"/> <port id="pr_897a94c8-4259-447a-a735-1f47deff08d0_p1" x="5355.416" y="2018.7855"/> <port id="pr_897a94c8-4259-447a-a735-1f47deff08d0_p2" x="5325.416" y="2018.7855"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_f99584c5-4bab-4956-8f36-6bfc95725a7d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16112081 In vitro, GrinchGEF (ARHGEF10L) induced the GDP/ GTP exchange at RhoA, but not at Rac1 or Cdc42. In intact cells, GrinchGEF induced specifically Rho activation and enhanced RhoA,B,C-specific downstream effect. GrinchGEF, similar to its relative p164-RhoGEF (ARHGEF17), is a Rho-specific GEF. Although RhoA, B, and C have different cellular functions, and some regulators and effectors show preferential interaction with these Rho isoforms, GrinchGEF apparently does not distinguish between RhoA,B,C and similarly activates these Rho proteins References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5335.7827" y="2039.5715"/> <port id="pr_f99584c5-4bab-4956-8f36-6bfc95725a7d_p1" x="5355.7827" y="2044.5715"/> <port id="pr_f99584c5-4bab-4956-8f36-6bfc95725a7d_p2" x="5325.7827" y="2044.5715"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_e212ecc2-344b-4b3e-9afe-38cf999418a2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9822605 Phosphorylated Vav-2 was found to be active on RhoA, RhoB and the more distantly related RhoG protein References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5347.0" y="2116.9285"/> <port id="pr_e212ecc2-344b-4b3e-9afe-38cf999418a2_p1" x="5352.0" y="2106.9285"/> <port id="pr_e212ecc2-344b-4b3e-9afe-38cf999418a2_p2" x="5352.0" y="2136.9285"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_60ce6990-cbd2-4c16-bb06-c883d869402e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16112081 In vitro, GrinchGEF (ARHGEF10L) induced the GDP/ GTP exchange at RhoA, but not at Rac1 or Cdc42. In intact cells, GrinchGEF induced specifically Rho activation and enhanced RhoA,B,C-specific downstream effect. GrinchGEF, similar to its relative p164-RhoGEF (ARHGEF17), is a Rho-specific GEF. Although RhoA, B, and C have different cellular functions, and some regulators and effectors show preferential interaction with these Rho isoforms, GrinchGEF apparently does not distinguish between RhoA,B,C and similarly activates these Rho proteins References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5219.509" y="2099.8215"/> <port id="pr_60ce6990-cbd2-4c16-bb06-c883d869402e_p1" x="5209.509" y="2104.8215"/> <port id="pr_60ce6990-cbd2-4c16-bb06-c883d869402e_p2" x="5239.509" y="2104.8215"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_bf7e1610-12e1-4c51-b0b7-81f0465c34bd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9822605 Phosphorylated Vav-2 was found to be active on RhoA, RhoB and the 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References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5145.494" y="2286.4678"/> <port id="pr_78968855-11fc-46a0-9132-e22480cff6ff_p1" x="5165.494" y="2291.4678"/> <port id="pr_78968855-11fc-46a0-9132-e22480cff6ff_p2" x="5135.494" y="2291.4678"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_8ebb73b6-08fc-455f-9afa-2fc876dc60cf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5449.994" y="2223.0"/> <port id="pr_8ebb73b6-08fc-455f-9afa-2fc876dc60cf_p1" x="5454.994" y="2243.0"/> <port id="pr_8ebb73b6-08fc-455f-9afa-2fc876dc60cf_p2" x="5454.994" y="2213.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3c847c4d-ce01-4138-938a-364d9bba1edf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8571126 PKN1 and RHPN1 as targets of small GTPase Rho. PMID:8662891 RTKN is a new putative target for Rho bearing homology to PKN1, and RHPN proteins in the rho-binding domain. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5432.0" y="2437.7788"/> <port id="pr_3c847c4d-ce01-4138-938a-364d9bba1edf_p1" x="5452.0" y="2442.7788"/> <port id="pr_3c847c4d-ce01-4138-938a-364d9bba1edf_p2" x="5422.0" y="2442.7788"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8bf2973a-04c8-4a7b-a497-86d1134f00d9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16371504 The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5770.5" y="1989.0"/> <port id="pr_8bf2973a-04c8-4a7b-a497-86d1134f00d9_p1" x="5775.5" y="1979.0"/> <port id="pr_8bf2973a-04c8-4a7b-a497-86d1134f00d9_p2" x="5775.5" y="2009.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b4942f69-d21f-430e-aa0b-ff7adaf0d30e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:25234227 Upon recruitment, NDPK promotes endocytic vesicle fission and downstream inactivation of Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5805.5" y="1989.0"/> <port id="pr_b4942f69-d21f-430e-aa0b-ff7adaf0d30e_p1" x="5810.5" y="2009.0"/> <port id="pr_b4942f69-d21f-430e-aa0b-ff7adaf0d30e_p2" x="5810.5" y="1979.0"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_d19a8bfa-3231-48a4-b278-5e968a184538"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5761.799" y="2313.1497"/> <port id="pr_d19a8bfa-3231-48a4-b278-5e968a184538_p1" x="5781.799" y="2318.1497"/> <port id="pr_d19a8bfa-3231-48a4-b278-5e968a184538_p2" x="5751.799" y="2318.1497"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_3cff4b8f-e3eb-416d-9f0d-48aa68643c3f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5763.25" y="2327.6545"/> <port id="pr_3cff4b8f-e3eb-416d-9f0d-48aa68643c3f_p1" x="5783.25" y="2332.6545"/> <port id="pr_3cff4b8f-e3eb-416d-9f0d-48aa68643c3f_p2" x="5753.25" y="2332.6545"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_259a7519-2a7c-4577-b05d-6d25a7017b2b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5761.786" y="2297.5"/> <port id="pr_259a7519-2a7c-4577-b05d-6d25a7017b2b_p1" x="5781.786" y="2302.5"/> <port id="pr_259a7519-2a7c-4577-b05d-6d25a7017b2b_p2" x="5751.786" y="2302.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_88aa1fd4-32b8-401c-8de0-f4aeecafd619"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8805275 PMID:8910277 PMID:9744077 PMID:10023776 PMID:11728826 GTP-bound Rac1 activates PAK1,2,3. The binding of the active GTP form of Rac1 and the PBD domain of PAK1,2,3 promotes autophosphorylation of PAK1,2,3 and activation of JNK pathway. 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When expressed in fibroblasts, MLK2 co-localizes with active, dually phosphorylated JNK to punctate structures along microtubules. MLK2 and MLK3 interact with members of the KIF3 family of kinesin superfamily motor proteins and with KAP3A, the putative targeting component of KIF3 motor complex PMID:11713255 Rac1 coordinately activates p70S6K and JNK via MLK3 activation References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5716.0" y="2451.9893"/> <port id="pr_3cd9e2d6-f0b5-44e6-b359-72a850fb6597_p1" x="5706.0" y="2456.9893"/> <port id="pr_3cd9e2d6-f0b5-44e6-b359-72a850fb6597_p2" x="5736.0" y="2456.9893"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_10a48e34-c16d-4030-90bf-e45a4292a0b4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3855.25" y="2439.1758"/> <port id="pr_10a48e34-c16d-4030-90bf-e45a4292a0b4_p1" x="3875.25" y="2444.1758"/> <port id="pr_10a48e34-c16d-4030-90bf-e45a4292a0b4_p2" x="3845.25" y="2444.1758"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_e477fb43-89fd-4165-927b-b145eb86fabb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5573.5" y="2515.5"/> <port id="pr_e477fb43-89fd-4165-927b-b145eb86fabb_p1" x="5593.5" y="2520.5"/> <port id="pr_e477fb43-89fd-4165-927b-b145eb86fabb_p2" x="5563.5" y="2520.5"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_490fa758-b411-4c77-baa8-bf39d575987a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5573.5" y="2530.5"/> <port id="pr_490fa758-b411-4c77-baa8-bf39d575987a_p1" x="5593.5" y="2535.5"/> <port id="pr_490fa758-b411-4c77-baa8-bf39d575987a_p2" x="5563.5" y="2535.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_99468026-f35a-4483-8ffb-4bb932efe787"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: RAC1 binds directly to PARD6 that activates PRKCZ. This leads to establishment of the cell polarity and promotes cellular transformation. PMID:10873802 PARD6 links Rac1 and Cdc42 to PKCzeta signaling and cell transformation. PMID:10934475 PARD6 binds to Cdc42; Rac1; PARD3; PRKC isoforms. In vitro, PARD3 acts as a substrate and an inhibitor of PRKC. PARD3 and PARD6 have a scaffolding function, coordinating the activities of several signalling proteins that are implicated in mammalian cell polarity. PMID:10954424 PARD6 is a binding partner for the Rho GTPases Cdc42 and Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5688.5" y="2526.5"/> <port id="pr_99468026-f35a-4483-8ffb-4bb932efe787_p1" x="5678.5" y="2531.5"/> <port id="pr_99468026-f35a-4483-8ffb-4bb932efe787_p2" x="5708.5" y="2531.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_90d97d39-38f7-45af-8d22-17c412055b2d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: RAC1 binds directly to PARD6 that activates PRKCZ. This leads to establishment of the cell polarity and promotes cellular transformation. PMID:10873802 PARD6 links Rac1 and Cdc42 to PKCzeta signaling and cell transformation. PMID:10934475 PARD6 binds to Cdc42; Rac1; PARD3; PRKC isoforms. In vitro, PARD3 acts as a substrate and an inhibitor of PRKC. PARD3 and PARD6 have a scaffolding function, coordinating the activities of several signalling proteins that are implicated in mammalian cell polarity. PMID:10954424 PARD6 is a binding partner for the Rho GTPases Cdc42 and Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5826.5" y="2524.0"/> <port id="pr_90d97d39-38f7-45af-8d22-17c412055b2d_p1" x="5831.5" y="2544.0"/> <port id="pr_90d97d39-38f7-45af-8d22-17c412055b2d_p2" x="5831.5" y="2514.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9b2b79ad-3112-411b-9dd0-56092b9ef884"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5458.0303" y="2574.5"/> <port id="pr_9b2b79ad-3112-411b-9dd0-56092b9ef884_p1" x="5463.0303" y="2564.5"/> <port id="pr_9b2b79ad-3112-411b-9dd0-56092b9ef884_p2" x="5463.0303" y="2594.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2b14bc2b-460b-4711-bad8-2b69a20b2d31"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: RAC1 modulates cytoskeleton remodeling by activating ARFP2 and PIP5K1 PMID:9312003 ARFP2 functions as an important regulatory element in orchestrating cytoskeletal rearrangements at the cell periphery induced by ARF6 and Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5695.75" y="2577.5"/> <port id="pr_2b14bc2b-460b-4711-bad8-2b69a20b2d31_p1" x="5685.75" y="2582.5"/> <port id="pr_2b14bc2b-460b-4711-bad8-2b69a20b2d31_p2" x="5715.75" y="2582.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_018d86e4-8753-42a1-8ccd-c063014c7b37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: RAC1 modulates cytoskeleton remodeling by activating ARFP2 and PIP5K1 PMID:10679324 Rac-associated PIP 5-kinase as the PIP 5-kinase isoforms alpha and beta. When added to permeabilized platelets, PIP 5-kinase alpha induced actin filament uncapping and assembly. PIP 5-kinase alpha is a critical mediator of thrombin- and Rac-dependent actin assembly. PMID:14681219 PIP5K catalyzes the formation of the phospholipid, phosphatidylinositol 4,5-bisphosphate PIP2 RhoA and Rac1 bind and activate PIP5K. 3 isoforms of type I PIP5K (alpha,beta, and gamma) have been identified RhoA and Rac1, as well as Cdc42, but not RalA and Rap1A, markedly stimulate PIP2 synthesis by all three PIP5K isoforms expressed in human embryonic kidney 293 cells, both in vitro and in vivo. RhoA-stimulated PIP2 synthesis by the PIP5K isoforms was mediated by the RhoA effector, Rho kinase. Stimulation of PIP5K isoforms by Rac1 and Cdc42 was apparently independent of and additive with RhoA- and Rho-kinase RhoA, and to a lesser extent Rac1, but not Cdc42, interacted in a nucleotide-independent form with all three PIP5K isoforms. Binding of PIP5K isoforms to GTP-bound, but not GDP-bound, RhoA could be displaced by Rho-kinase, suggesting a direct and constitutive PIP5K-Rho GTPase binding, which, however, does not trigger PIP5K activation. Synthesis of PIP2 by the three PIP5K isoforms is controlled by RhoA, acting via Rho-kinase, as well as Rac1 and Cdc42, implicating that regulation of PIP2 synthesis has a central position in signaling by these three Rho GTPases. 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This stimulates ARP2/3 and leads to actin cytoskeleal polymerization. PMID:16702231 WAVE2 (so-called WASF2) activates the ARP2/3 complex for Rac-induced actin polymerization during lamellipodium formation PMID:9843499 WASF (WAVE) as regulator of actin reorganization downstream of Rac. Expressed WAVE induces the formation of actin filament clusters. WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for mem- brane rufflin PMID:12054568 WAVE2 serves a functional partner of IRSp53 by regulating its interaction with Rac. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5717.0" y="2697.5"/> <port id="pr_ab11203a-e096-4255-b2ed-94e5832dccd2_p1" x="5707.0" y="2702.5"/> <port id="pr_ab11203a-e096-4255-b2ed-94e5832dccd2_p2" x="5737.0" y="2702.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_510f531c-78d5-4d65-9d38-d2cde84694ac"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Rac1 binds to BAIAP2 which in turn associates with WASF2. This stimulates ARP2/3 and leads to actin cytoskeleal polymerization. PMID:16702231 WAVE2 (so-called WASF2) activates the ARP2/3 complex for Rac-induced actin polymerization during lamellipodium formation PMID:9843499 WASF (WAVE) as regulator of actin reorganization downstream of Rac. Expressed WAVE induces the formation of actin filament clusters. WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for mem- brane ruffling PMID:12054568 WAVE2 serves a functional partner of IRSp53 by regulating its interaction with Rac. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5769.0" y="2757.5"/> <port id="pr_510f531c-78d5-4d65-9d38-d2cde84694ac_p1" x="5759.0" y="2762.5"/> <port id="pr_510f531c-78d5-4d65-9d38-d2cde84694ac_p2" x="5789.0" y="2762.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0801ac02-7c31-4418-8099-6d2b9e24560e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Rac1 binds to BAIAP2 which in turn associates with WASF2. This stimulates ARP2/3 and leads to actin cytoskeleal polymerization. PMID:16702231 WAVE2 (so-called WASF2) activates the ARP2/3 complex for Rac-induced actin polymerization during lamellipodium formation PMID:9843499 WASF (WAVE) as regulator of actin reorganization downstream of Rac. Expressed WAVE induces the formation of actin filament clusters. WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for mem- brane ruffling PMID:12054568 WAVE2 serves a functional partner of IRSp53 by regulating its interaction with Rac. PMID:8625410 PMID:16293614 PMID:10467124 PMID:10511705 CDC42 induces actin cytoskeleton changes by activating WASP and N-WASP. WASP and N-WASP binds to ARP2/3 and this lieads to actin cytoskeletal polymerization and filopodia formation. PMID:14749719 PAK1 phosphorylates and activates ARP2_3 complex. 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This stimulates ARP2/3 and leads to actin cytoskeleal polymerization. PMID:16702231 WAVE2 (so-called WASF2) activates the ARP2/3 complex for Rac-induced actin polymerization during lamellipodium formation PMID:9843499 WASF (WAVE) as regulator of actin reorganization downstream of Rac. Expressed WAVE induces the formation of actin filament clusters. WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for mem- brane ruffling PMID:12054568 WAVE2 serves a functional partner of IRSp53 by regulating its interaction with Rac. PMID:15094799 ARP2_3 complex nucleates new actin filaments from the sides of preexisting filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5665.5" y="2805.0298"/> <port id="pr_d279432a-9d03-4755-a8ac-cb710c987ba1_p1" x="5685.5" y="2810.0298"/> <port id="pr_d279432a-9d03-4755-a8ac-cb710c987ba1_p2" x="5655.5" y="2810.0298"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1b15e2fb-a6b0-4003-8d07-4e6f2531365c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Rac1 binds to BAIAP2 which in turn associates with WASF2. This stimulates ARP2/3 and leads to actin cytoskeleal polymerization. PMID:16702231 WAVE2 (so-called WASF2) activates the ARP2/3 complex for Rac-induced actin polymerization during lamellipodium formation PMID:9843499 WASF (WAVE) as regulator of actin reorganization downstream of Rac. Expressed WAVE induces the formation of actin filament clusters. WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for mem- brane ruffling PMID:12054568 WAVE2 serves a functional partner of IRSp53 by regulating its interaction with Rac. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5883.2686" y="2925.5"/> <port id="pr_1b15e2fb-a6b0-4003-8d07-4e6f2531365c_p1" x="5888.2686" y="2915.5"/> <port id="pr_1b15e2fb-a6b0-4003-8d07-4e6f2531365c_p2" x="5888.2686" y="2945.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c245c09a-3399-4e6d-a947-27cde4cae81c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Rac1 stimulates actin polymerization by activation of WAS protein family (WASF1 and WASF2) PMID:16212495 PMID:9843499 PMID:16702231 PMID:12181570 Rac1 binds to NCKAP1 and CYFIP2 and also promotes NCK1 binding to NCKAP1. This binding inhibits NCKAP1 and CYFIP2 binding to WASF1 and promotes release of the complex of WASF1 and BRK1, thus activating WASF1. 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PMID:12134164 PMID:7673236 HRAS activates TIAM1 which is a GEF for Rac1. 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RalBP1 (which is an effector for RalA and RalB) inactivates Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5798.6753" y="1829.5698"/> <port id="pr_94474b57-f2c0-43a8-aa4a-20fe1de0c158_p1" x="5788.6753" y="1834.5698"/> <port id="pr_94474b57-f2c0-43a8-aa4a-20fe1de0c158_p2" x="5818.6753" y="1834.5698"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_61d37fac-f205-4af9-aebd-35fb0a6959db"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5228.5" y="2208.571"/> <port id="pr_61d37fac-f205-4af9-aebd-35fb0a6959db_p1" x="5218.5" y="2213.571"/> <port id="pr_61d37fac-f205-4af9-aebd-35fb0a6959db_p2" x="5248.5" y="2213.571"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_5c167dcb-f3d0-469e-aa8e-f96a7e4e05b0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11394904 PMID:10652228 GEF activity of MCF2 (DBL) towards CDC42 or Rac1 is enhanced upon TNK2 (ACK1) phosphorylation. PMID:18470881 Nm23-H1 binds Dbl-1 and thus interferes with the ability of Dbl-1 to load GTP onto CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5257.0" y="2285.928"/> <port id="pr_5c167dcb-f3d0-469e-aa8e-f96a7e4e05b0_p1" x="5247.0" y="2290.928"/> <port id="pr_5c167dcb-f3d0-469e-aa8e-f96a7e4e05b0_p2" x="5277.0" y="2290.928"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_73dff636-7baa-41aa-ab2a-1a0d908afddf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: VAV1,2 are GEFs for Rac1. PMID:11080163 VAV2 is recruited by the CD19 co-receptor of the B cells and participates in the B cell receptor signaling. PMID:12165654 in the T cell, VAV1 forms complex with LCP2. This complex is involved in the T cell receptor and CD28 signaling cascades. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5227.0" y="2236.9285"/> <port id="pr_73dff636-7baa-41aa-ab2a-1a0d908afddf_p1" x="5217.0" y="2241.9285"/> <port id="pr_73dff636-7baa-41aa-ab2a-1a0d908afddf_p2" x="5247.0" y="2241.9285"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_737f2128-5b91-488b-875c-9ed6ab460e05"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. PMID:15713627 Spatially distinct binding of Cdc42 to PAK1 and N-WASP References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5629.5" y="2271.5"/> <port id="pr_737f2128-5b91-488b-875c-9ed6ab460e05_p1" x="5619.5" y="2276.5"/> <port id="pr_737f2128-5b91-488b-875c-9ed6ab460e05_p2" x="5649.5" y="2276.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0adc9347-1584-4395-accd-566adfe9e159"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5629.5" y="2298.0"/> <port id="pr_0adc9347-1584-4395-accd-566adfe9e159_p1" x="5619.5" y="2303.0"/> <port id="pr_0adc9347-1584-4395-accd-566adfe9e159_p2" x="5649.5" y="2303.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c0503c49-f64e-48e1-a406-c270cf414a44"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5629.5" y="2241.5"/> <port id="pr_c0503c49-f64e-48e1-a406-c270cf414a44_p1" x="5619.5" y="2246.5"/> <port id="pr_c0503c49-f64e-48e1-a406-c270cf414a44_p2" x="5649.5" y="2246.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_bebf944d-ff0a-4d7d-aba6-b39de2b74c96"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5629.5" y="2324.0"/> <port id="pr_bebf944d-ff0a-4d7d-aba6-b39de2b74c96_p1" x="5619.5" y="2329.0"/> <port id="pr_bebf944d-ff0a-4d7d-aba6-b39de2b74c96_p2" x="5649.5" y="2329.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9ae51728-0fa5-4a29-8b89-7373768b86ef"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10816584 PMID:17045588 CDC42SE1 (SPEC1) binds to CDC42 and supresses CDC42-induced JNK activation and cytoskeleton remodeling. PMID:9113980 RhoGDI (so-called ARHGDIA) and GDIG4 (so-called ARHGDIB) are two known GDIs for the Rho-subfamily of GTPases. ARHGDIG is about 50 percent identical to ARHGDIA and ARHGDIB. ARHGFIG binds to CDC42 and RhoA with less affinity compared with ARHGDIA and does not bind with Rac1, Rac2, or Ras. ARHGDIG functions as a GDI for CDC42 but with about 20 times less efficiency than ARHGDIA. PMID:9490022 ARHGDIA,B,G are CDC42_GDIs References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6065.125" y="2099.5"/> <port id="pr_9ae51728-0fa5-4a29-8b89-7373768b86ef_p1" x="6070.125" y="2089.5"/> <port id="pr_9ae51728-0fa5-4a29-8b89-7373768b86ef_p2" x="6070.125" y="2119.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_69ebfe9b-8a9d-4208-84e4-4598d0c57c0e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16371504 The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6027.375" y="2099.5"/> <port id="pr_69ebfe9b-8a9d-4208-84e4-4598d0c57c0e_p1" x="6032.375" y="2119.5"/> <port id="pr_69ebfe9b-8a9d-4208-84e4-4598d0c57c0e_p2" x="6032.375" y="2089.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_343f1c6f-ac47-4025-8a04-145129a27e9e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5128.75" y="2716.5"/> <port id="pr_343f1c6f-ac47-4025-8a04-145129a27e9e_p1" x="5148.75" y="2721.5"/> <port id="pr_343f1c6f-ac47-4025-8a04-145129a27e9e_p2" x="5118.75" y="2721.5"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_cc46b9a7-f305-47f6-b7cc-6f32409e1039"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4841.375" y="2714.625"/> <port id="pr_cc46b9a7-f305-47f6-b7cc-6f32409e1039_p1" x="4846.375" y="2734.625"/> <port id="pr_cc46b9a7-f305-47f6-b7cc-6f32409e1039_p2" x="4846.375" y="2704.625"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_8e1829a9-e370-4455-9b26-27fe96429538"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4900.659" y="2655.75"/> <port id="pr_8e1829a9-e370-4455-9b26-27fe96429538_p1" x="4920.659" y="2660.75"/> <port id="pr_8e1829a9-e370-4455-9b26-27fe96429538_p2" x="4890.659" y="2660.75"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_5f5c04de-11b0-4f83-b952-2db65d19e575"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4894.0" y="2684.3667"/> <port id="pr_5f5c04de-11b0-4f83-b952-2db65d19e575_p1" x="4914.0" y="2689.3667"/> <port id="pr_5f5c04de-11b0-4f83-b952-2db65d19e575_p2" x="4884.0" y="2689.3667"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_ea6c64a9-71f2-4adb-88fa-b2c397e6410f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4915.0" y="2911.0"/> <port id="pr_ea6c64a9-71f2-4adb-88fa-b2c397e6410f_p1" x="4935.0" y="2916.0"/> <port id="pr_ea6c64a9-71f2-4adb-88fa-b2c397e6410f_p2" x="4905.0" y="2916.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_31beb234-c742-4cda-a247-f60f3234a347"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: CDC42 promotes changes in actin cytoskeleton by several pathways. PMID:10461188 PMID:11950587 PMID:11340065 PMID:10559936 PMID:10613909 PMID:11413130 CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2. LIMK1,2 subsquently phosphorylate and inhibit Cofilin Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5117.681" y="3029.0"/> <port id="pr_31beb234-c742-4cda-a247-f60f3234a347_p1" x="5122.681" y="3049.0"/> <port id="pr_31beb234-c742-4cda-a247-f60f3234a347_p2" x="5122.681" y="3019.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9f7228dd-110a-43d3-ad6e-9e765bfb4c6b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9069260 Activated HRAS (GTP bound forn) is associated with the plasma membrane. Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site. RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD). RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD. YWHAB has been displaced from S259 may now bind its higher affinity S621 site. This stabilises an OPEN RAF1 conformation that is catalytically active. Active and open RAF1 binds to RAS via both CRD and RBD domains. An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341. This Tyrosine phosphorylation serves to further stabilise the active OPEN RAF1 conformation. While the kinase has not been definitively identified, SRC is a plausible candidate. RAF1 interacts with SRC and co-immunoprecipates with SRC-FYN. PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: S338, Y374 and T491 PMID:10712905 PMID:9823899 PAK3 phosphorylates RAF1 at S338 and upregulates RAF1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5592.75" y="830.5"/> <port id="pr_9f7228dd-110a-43d3-ad6e-9e765bfb4c6b_p1" x="5612.75" y="835.5"/> <port id="pr_9f7228dd-110a-43d3-ad6e-9e765bfb4c6b_p2" x="5582.75" y="835.5"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_7a02a9ff-2c21-424d-8314-f4ea99089c0b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6111.751" y="1260.0"/> <port id="pr_7a02a9ff-2c21-424d-8314-f4ea99089c0b_p1" x="6116.751" y="1280.0"/> <port id="pr_7a02a9ff-2c21-424d-8314-f4ea99089c0b_p2" x="6116.751" y="1250.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0d415953-00af-492c-8c89-9dd99f14a4e0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10873802 PARD6 contains a PDZ domain and a Cdc42/Rac interactive binding (CRIB) motif PARD6 interacts with Rac1 and Cdc42 in a GTP-dependent manner PMID:10934475 PARD6 binds to Cdc42/Rac1 GTPases PMID:10954424 PARD6 is a binding partner for the Rho GTPases Cdc42 and Rac1 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6063.4565" y="2418.5"/> <port id="pr_0d415953-00af-492c-8c89-9dd99f14a4e0_p1" x="6068.4565" y="2408.5"/> <port id="pr_0d415953-00af-492c-8c89-9dd99f14a4e0_p2" x="6068.4565" y="2438.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6ad8fbbc-964c-40c4-a82b-41c48105d03a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8625410 PMID:16293614 PMID:10467124 PMID:10511705 CDC42 induces actin cytoskeleton changes by activating WASP and N-WASP. WASP and N-WASP binds to ARP2/3 and this lieads to actin cytoskeletal polymerization and filopodia formation. PMID:10940259 CDC42 initiates WASP/Arp2_3 nucleation of actin. PMID:15713627 Spatially distinct binding of Cdc42 to PAK1 and N-WASP References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6049.25" y="2567.0"/> <port id="pr_6ad8fbbc-964c-40c4-a82b-41c48105d03a_p1" x="6039.25" y="2572.0"/> <port id="pr_6ad8fbbc-964c-40c4-a82b-41c48105d03a_p2" x="6069.25" y="2572.0"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_f59ce803-be73-4e95-951d-16aa12d79e66"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5972.5586" y="2591.75"/> <port id="pr_f59ce803-be73-4e95-951d-16aa12d79e66_p1" x="5977.5586" y="2581.75"/> <port id="pr_f59ce803-be73-4e95-951d-16aa12d79e66_p2" x="5977.5586" 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References_begin: PMID:14633674 DLC1as a GAP of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6033.549" y="1842.3066"/> <port id="pr_3c5cb355-c87b-46df-b56a-581dd5c3a8e3_p1" x="6023.549" y="1847.3066"/> <port id="pr_3c5cb355-c87b-46df-b56a-581dd5c3a8e3_p2" x="6053.549" y="1847.3066"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_6378b7cc-74e2-40ed-a9a0-0e500dd82d56"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10551883 FGFR1 regulates activity of CDC42 by binding and phosphorylating thus inactivating BCL2. 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They promote the exchange of GDP to GTP to generate the activated form of CDC42 capable of recognizing downstram targets. PMID:17145773 SPATA13 (Asef2) as a GEF of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="6006.088" y="1944.75"/> <port id="pr_3cea9ac0-b7a9-4e0e-89c9-f893a7ef3ffc_p1" x="6011.088" y="1934.75"/> <port id="pr_3cea9ac0-b7a9-4e0e-89c9-f893a7ef3ffc_p2" x="6011.088" y="1964.75"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_07eed2a0-4811-4269-af06-f4cd3fc74975"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8836113 GEFs are essential for CDC42 activation. They promote the exchange of GDP to GTP to generate the activated form of CDC42 capable of recognizing downstram targets. PMID:10579713 ARHGEF31 as a GEF of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5571.186" y="2059.389"/> <port id="pr_07eed2a0-4811-4269-af06-f4cd3fc74975_p1" x="5591.186" y="2064.389"/> <port id="pr_07eed2a0-4811-4269-af06-f4cd3fc74975_p2" x="5561.186" y="2064.389"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_cda538cd-f464-4bbd-b98f-7b377ba50100"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8836113 GEFs are essential for CDC42 activation. They promote the exchange of GDP to GTP to generate the activated form of CDC42 capable of recognizing downstram targets. PMID:10843989 MCF2 (DBL) as a GEF of CDC42 PMID:11394904 PMID:10652228 GEF activity of MCF2 (DBL) towards CDC42 or Rac1 is enhanced upon TNK2 (ACK1) phosphorylation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5648.2217" y="2098.7139"/> <port id="pr_cda538cd-f464-4bbd-b98f-7b377ba50100_p1" x="5668.2217" y="2103.7139"/> <port id="pr_cda538cd-f464-4bbd-b98f-7b377ba50100_p2" x="5638.2217" y="2103.7139"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_0fa8778d-db16-4868-b091-cf915ee0a50b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8836113 GEFs are essential for CDC42 activation. They promote the exchange of GDP to GTP to generate the activated form of CDC42 capable of recognizing downstram targets. PMID:15023524 DEF6 as a GEF of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5648.3677" y="2111.6074"/> <port id="pr_0fa8778d-db16-4868-b091-cf915ee0a50b_p1" x="5668.3677" y="2116.6074"/> <port id="pr_0fa8778d-db16-4868-b091-cf915ee0a50b_p2" x="5638.3677" y="2116.6074"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_b09edb84-7323-44da-9acf-c8706804e5c7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8836113 GEFs are essential for CDC42 activation. They promote the exchange of GDP to GTP to generate the activated form of CDC42 capable of recognizing downstram targets. PMID:11889037 ARHGAP14 (MCF2L or DBS) as a GEF of CDC42 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5706.25" y="1848.4211"/> <port id="pr_b09edb84-7323-44da-9acf-c8706804e5c7_p1" x="5726.25" y="1853.4211"/> <port id="pr_b09edb84-7323-44da-9acf-c8706804e5c7_p2" x="5696.25" y="1853.4211"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_b828280d-c01a-4ed6-9e37-719b736350e5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10551883 FGFR1 regulates activity of CDC42 by binding and phosphorylating thus inactivating BCL2. Phosphorylated BCL2 binds to another CDC42_GAP, ARHGAP1 and neutralize the GAP activity of ARHGAP1 as well. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5985.0" y="2433.25"/> <port id="pr_b828280d-c01a-4ed6-9e37-719b736350e5_p1" x="5975.0" y="2438.25"/> <port id="pr_b828280d-c01a-4ed6-9e37-719b736350e5_p2" x="6005.0" y="2438.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_7630af47-b68d-444a-888b-5760edf4c8cd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10551883 FGFR1 regulates activity of CDC42 by binding and phosphorylating thus inactivating BCL2. Phosphorylated BCL2 binds to another CDC42_GAP, ARHGAP1 and neutralize the GAP activity of ARHGAP1 as well. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5913.5" y="2498.8535"/> <port id="pr_7630af47-b68d-444a-888b-5760edf4c8cd_p1" x="5903.5" y="2503.8535"/> <port id="pr_7630af47-b68d-444a-888b-5760edf4c8cd_p2" x="5933.5" y="2503.8535"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_3fa43d65-b34f-453f-b3fc-b62cbb5bff97"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11989976 PMID:17959595 Caspase1,3 promote proteosomal degradation of ARHGDIB References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4333.823" y="1592.3208"/> <port id="pr_3fa43d65-b34f-453f-b3fc-b62cbb5bff97_p1" x="4353.823" y="1597.3208"/> <port id="pr_3fa43d65-b34f-453f-b3fc-b62cbb5bff97_p2" x="4323.823" y="1597.3208"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_a0aae685-fa23-4c90-bcd5-7b076382892a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8537347 PMID:10769036 GAP activity of ARHGAP5 is abrogated by binding to RASA1 (p120GAP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5204.25" y="1750.5"/> <port id="pr_a0aae685-fa23-4c90-bcd5-7b076382892a_p1" x="5194.25" y="1755.5"/> <port id="pr_a0aae685-fa23-4c90-bcd5-7b076382892a_p2" x="5224.25" y="1755.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d5f40787-3591-4d99-a95e-173bb4dd0361"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15866889 The ARP2_3 complex and Cofilin are involved in protrusion at the leading edge: the actin-severing activity of cofilin and the actin-branching activity of Arp2_3 act in synergy to drive the extension of lamellipodia. Cofilin is also required for the maintenance of a polarized cytoskeleton and thus for directional cell migration. Integrins control motile strategy through a Rho-cofilin pathway. Adhesion to fibronectin by a5b1 integrin leads to phosphorylation and thus inactivation of cofilin. Cells thus fail to polarize their cytoskeleton but extend thin protrusion with cell-matrix adhesions in multiple directions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5116.662" y="2791.0"/> <port id="pr_d5f40787-3591-4d99-a95e-173bb4dd0361_p1" x="5121.662" y="2781.0"/> <port id="pr_d5f40787-3591-4d99-a95e-173bb4dd0361_p2" x="5121.662" y="2811.0"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_feef732f-c368-485e-9671-cf3a8175b246"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4777.123" y="6105.75"/> <port id="pr_feef732f-c368-485e-9671-cf3a8175b246_p1" x="4797.123" y="6110.75"/> <port id="pr_feef732f-c368-485e-9671-cf3a8175b246_p2" x="4767.123" y="6110.75"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_7b55eff0-2093-4ee2-9ece-112875197575"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4798.883" y="5951.0"/> <port id="pr_7b55eff0-2093-4ee2-9ece-112875197575_p1" x="4803.883" y="5971.0"/> <port id="pr_7b55eff0-2093-4ee2-9ece-112875197575_p2" x="4803.883" y="5941.0"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_3b9126b2-5481-4651-b967-9fc449335070"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3571.1162" y="6173.5625"/> <port id="pr_3b9126b2-5481-4651-b967-9fc449335070_p1" x="3576.1162" y="6193.5625"/> <port id="pr_3b9126b2-5481-4651-b967-9fc449335070_p2" x="3576.1162" y="6163.5625"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_846dfb49-3b43-43b6-a864-3cf800142e37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3597.3477" y="6173.5625"/> <port id="pr_846dfb49-3b43-43b6-a864-3cf800142e37_p1" x="3602.3477" y="6193.5625"/> <port id="pr_846dfb49-3b43-43b6-a864-3cf800142e37_p2" x="3602.3477" y="6163.5625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a0819da4-a9c5-4eec-8665-eb3f5b1f4784"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3948.413" y="6431.625"/> <port id="pr_a0819da4-a9c5-4eec-8665-eb3f5b1f4784_p1" x="3953.413" y="6421.625"/> <port id="pr_a0819da4-a9c5-4eec-8665-eb3f5b1f4784_p2" x="3953.413" y="6451.625"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_bd54e690-4b07-46a9-aee9-cf8ef7985f23"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3646.7144" y="6174.0625"/> <port id="pr_bd54e690-4b07-46a9-aee9-cf8ef7985f23_p1" x="3651.7144" y="6194.0625"/> <port id="pr_bd54e690-4b07-46a9-aee9-cf8ef7985f23_p2" x="3651.7144" y="6164.0625"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_e8e1c0e3-671e-4272-b6b6-91d5a7ff8096"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3700.6196" y="6174.0625"/> <port id="pr_e8e1c0e3-671e-4272-b6b6-91d5a7ff8096_p1" x="3705.6196" y="6194.0625"/> <port id="pr_e8e1c0e3-671e-4272-b6b6-91d5a7ff8096_p2" x="3705.6196" y="6164.0625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ba03f29d-83f5-4e1e-a12d-be435c0874c2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. 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Monomeric integrins never reach the cell surface. Integrins a1b1, a2b1, a10b1 and a11b1 bind to collagens PMID:12297042 Cell adhesion to components of the ECM is important in the angiogenesis PMID:2153105 PMID:2786007 PMID:7639691 PMID:10809728 integrins are receptors for different ECM proteins: Collagen 1, 4; Laminin 1, 8; Fibronectin and Vitronectin PMID:7522194 PMID:16195317 Interactions between integrins and the ECM proteins result in focal cell adhesion and cytoskeleton remodeling. PMID:15866889 Fibronectin binds to alphaV/beta3 integrins supports persistent migration( directional cell migration) Fibronectin binds to alpha5/beta1 integrins supports random migration. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4416.7114" y="6429.828"/> <port id="pr_2ce1b687-961f-46ff-a41b-a61e9d0279a6_p1" x="4421.7114" y="6419.828"/> <port id="pr_2ce1b687-961f-46ff-a41b-a61e9d0279a6_p2" x="4421.7114" y="6449.828"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a1a33ce0-3d09-4ce2-afa7-bd8012f076e0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19161977 In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers. Monomeric integrins never reach the cell surface. 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Monomeric integrins never reach the cell surface. PMID:10809728 Laminin-8 contains LAMA4, LAMB1, LAMC1 Laminin-8 interacts with integrins. 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The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by CSK or by PTK6. 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PMID:18829532 RasGAP actvity of RASA1 is reduced when associated with ARHGAP35 which is a specific GAP for RhoA ARHGAP35 is tyrosine-phosphorylated. The association of ARHGAP35 (p190) with RASA1 (p120) is promoted and stabilized by phosphorylation of p190 at Y1105 by PTK6.. 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Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4847.0" y="3584.3164"/> <port id="pr_3a35566e-899b-4a2c-9df7-371b39074e9e_p1" x="4837.0" y="3589.3164"/> <port id="pr_3a35566e-899b-4a2c-9df7-371b39074e9e_p2" x="4867.0" y="3589.3164"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_47132a76-307a-4863-b0a3-05ae168bea2c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11121431 PMID:15157156 PMID:15229651 Nischarin binds preferentially to the cytoplasmic tail of ITGA5 subunit ti inhibit cell migration. Nischarin is not found in focal adhesion sites. Once integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1 in order to inactive PAK1.. This binding is enhaced by active Rac1. The ability of Nischarin to inhibit PAK1 is related to its ability to inhibit cell motility. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4959.917" y="3524.3853"/> <port id="pr_47132a76-307a-4863-b0a3-05ae168bea2c_p1" x="4949.917" y="3529.3853"/> <port id="pr_47132a76-307a-4863-b0a3-05ae168bea2c_p2" x="4979.917" y="3529.3853"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_34f8b64e-e724-4862-b5ca-d93e9c69741e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9822663 FYN is required for VAV1 phosphorylation and thus activation. PMID:15699036 tyrosine phosphorylation of beta3 integrin and aVb3-mediated adhesion are required for VAV1 assocaition and Rho activation. Vav1 associates with aVb3 upon cell adhesion to vitronectin References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5412.25" y="2260.8215"/> <port id="pr_34f8b64e-e724-4862-b5ca-d93e9c69741e_p1" x="5432.25" y="2265.8215"/> <port id="pr_34f8b64e-e724-4862-b5ca-d93e9c69741e_p2" x="5402.25" y="2265.8215"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_758d7473-ee24-4869-9c07-163106ed8794"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3095.5" y="5274.117"/> <port id="pr_758d7473-ee24-4869-9c07-163106ed8794_p1" x="3115.5" y="5279.117"/> <port id="pr_758d7473-ee24-4869-9c07-163106ed8794_p2" x="3085.5" y="5279.117"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_5c6a3a21-8adb-456d-9e32-90357638bae2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3580.0308" y="4272.5"/> <port id="pr_5c6a3a21-8adb-456d-9e32-90357638bae2_p1" x="3600.0308" y="4277.5"/> <port id="pr_5c6a3a21-8adb-456d-9e32-90357638bae2_p2" x="3570.0308" y="4277.5"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_b0797539-e8ca-4bfe-a932-96515b72b3ae"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5284.25" y="3842.25"/> <port id="pr_b0797539-e8ca-4bfe-a932-96515b72b3ae_p1" x="5289.25" y="3862.25"/> <port id="pr_b0797539-e8ca-4bfe-a932-96515b72b3ae_p2" x="5289.25" y="3832.25"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_76e488a4-7e2d-4d9b-b4a5-88a677ee65da"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5154.755" y="5427.0"/> <port id="pr_76e488a4-7e2d-4d9b-b4a5-88a677ee65da_p1" x="5159.755" y="5417.0"/> <port id="pr_76e488a4-7e2d-4d9b-b4a5-88a677ee65da_p2" x="5159.755" y="5447.0"/> </glyph> <glyph class="uncertain process" orientation="vertical" id="pr_7e645135-b18c-4331-a047-8242a4e3f9c1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5190.821" y="5428.0"/> <port id="pr_7e645135-b18c-4331-a047-8242a4e3f9c1_p1" x="5195.821" y="5418.0"/> <port id="pr_7e645135-b18c-4331-a047-8242a4e3f9c1_p2" x="5195.821" y="5448.0"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_8e11e4ee-521b-4489-9aa9-379cf45f714d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5219.6826" y="5429.0"/> <port id="pr_8e11e4ee-521b-4489-9aa9-379cf45f714d_p1" x="5209.6826" y="5434.0"/> <port id="pr_8e11e4ee-521b-4489-9aa9-379cf45f714d_p2" x="5239.6826" y="5434.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_3908ead2-3ba8-4b40-a637-fbd0221d8e65"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Autophosphorylation of PTK2: PMID:7529872 PMID:19339212 PMID:7657702 PMID:16919435 Autophosphorylation of PTK2 at Y397 creates binding site for CSK, a member of Scr family kinases. In response to integrin engagement with the ECM, FAK is autophosphorylated predominantly on Y397 This Y397 is the consensus binding site for the SH2 domain of c-Src (CSK) PMID:11114741 Interaction of CSK with FAK leads to phosphorylation of FAK on other tyrosine residues including Y407, 576, 577, 861, 925/ These phosphorylation events promote PTK2 to its maximal catalytic activity. Upon autophosphorylation of FAK, a signaling complex of FAK, CSK binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5138.625" y="5693.0"/> <port id="pr_3908ead2-3ba8-4b40-a637-fbd0221d8e65_p1" x="5143.625" y="5683.0"/> <port id="pr_3908ead2-3ba8-4b40-a637-fbd0221d8e65_p2" x="5143.625" y="5713.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_03138509-75b9-4a63-a1ee-2f47c8451cbe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Autophosphorylation of PTK2: PMID:7529872 PMID:19339212 PMID:7657702 PMID:16919435 FAK (PTK2) is first recruited to sites of integrin clustering via interactions wiith integrin-associated proteins such as talin, paxillin. FAK binds to the cytoplasmic domain of b1 integrin via Paxillin (PXN) and Talin (TLN) Binding to aVb3 or a5b1 integrins induces PTK2 (FAK1) autophosphorylation at Y397. PMID:10545505 FAK associates with paxillin, vinculin, and p130cas (BCAR1) in the focal adhesion complex PMID: Integrins control motile strategy through a Rho-cofilin pathway. beta1 integrins promote random migration, whereas beta3 integrins promote persistent migration in the same epithelial cell background. Adhesion to fibronectin by aVb3 supports actin cytoskeletal reorganization via cofilin, resulting in a single broad lamellipod with static cell-matrix adhesions at the leading edge. Adhesion by a5b1 instead leads to the phosphorylation and thus inactivation of cofilin, and these cells fail to polarize their cytoskeleton but extend thin protrusions containing highly dynamic cell-matrix adhesions in multiple directions. The activity of the small GTPase RhoA is particularly high in cells adhering by a5b1, and inhibition of Rho signaling causes a switch from a beta1 to a beta3-associated mode of migration, whereas increased Rho activity has the opposite effect. Alterations in integrin expression profiles thus allow cells to modulate several critical aspects of the motile machinery through Rho GTPases. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5154.5" y="5551.5"/> <port id="pr_03138509-75b9-4a63-a1ee-2f47c8451cbe_p1" x="5159.5" y="5541.5"/> <port id="pr_03138509-75b9-4a63-a1ee-2f47c8451cbe_p2" x="5159.5" y="5571.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3fe1aeae-6313-4847-8141-edcd7de78959"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: Autophosphorylation of PTK2: PMID:7529872 PMID:19339212 PMID:7657702 PMID:16919435 Autophosphorylation of PTK2 at Y397 creates binding site for CSK, a member of Scr family kinases. In response to integrin engagement with the ECM, FAK is autophosphorylated predominantly on Y397 This Y397 is the consensus binding site for the SH2 domain of c-Src (CSK) PMID:11114741 Interaction of CSK with FAK leads to phosphorylation of FAK on other tyrosine residues including Y407, 576, 577, 861, 925/ These phosphorylation events promote PTK2 to its maximal catalytic activity. Upon autophosphorylation of FAK, a signaling complex of FAK, CSK binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5253.25" y="5610.0"/> <port id="pr_3fe1aeae-6313-4847-8141-edcd7de78959_p1" x="5243.25" y="5615.0"/> <port id="pr_3fe1aeae-6313-4847-8141-edcd7de78959_p2" x="5273.25" y="5615.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_54d079d0-6b02-4969-a146-72ceb8e64121"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16919435 PMID:16000375 Upon autophosphorylation of FAK, a signaling complex of FAK, CSK binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5400.6807" y="5541.997"/> <port id="pr_54d079d0-6b02-4969-a146-72ceb8e64121_p1" x="5390.6807" y="5546.997"/> <port id="pr_54d079d0-6b02-4969-a146-72ceb8e64121_p2" x="5420.6807" y="5546.997"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0bc81b71-221e-4512-8030-3e1e575e9d72"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16000375 Src and FAK kinases cooperate to phosphorylate paxillin, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Phosphorylated paxillin binding to Crk is implicated in Rac activation and stimulation of cell motility PMID:15308668 CRK bound to DOCK1 (so-called DOCK180) forms complex with phosphorylated paxillin. The complex is necessary for collagen-dependent cell migration, mainly through Rac1 activation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5524.5" y="5542.0503"/> <port id="pr_0bc81b71-221e-4512-8030-3e1e575e9d72_p1" x="5514.5" y="5547.0503"/> <port id="pr_0bc81b71-221e-4512-8030-3e1e575e9d72_p2" x="5544.5" y="5547.0503"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_6cbd9069-c0c5-4070-b769-87ff226c6363"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15308668 DOCK1 (so-called DOCK180) is a GEF of Rac1. DOCK1 together with paxillin-Crk constitutes the main pathway transducing collagen-mediated signals for the activation of Rac1. This signaling pathway is down-regulated when cell migration is counteracted by C3G/Rap1 activation. A balance between Rac1 and Rap1 GTPases in controlling the migratory versus the stationary state of the cell is suggested. PMID:12432077 DOCK1 is a GEF for Rac1 and possibly for CDC42 PMID:9808620 DOCK1 is involved in integrin signaling through Crk-p130Cas complexes. DOCK1 activates JNK in a Rac1, Cdc42 - dependent manner Overexpression of DOCK1 increases the amount of GTP-bound Rac1 Coexpression of Crk2 and p130Cas (BCAR1) enhances this DOCK1-dependent activation of Rac1. Direct binding of DOCK1 to Rac1, but not to RhoA or Cdc42. To sum up, DOCK1 is a novel activator of Rac1 and involved in integrin signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5891.9307" y="2000.75"/> <port id="pr_6cbd9069-c0c5-4070-b769-87ff226c6363_p1" x="5881.9307" y="2005.75"/> <port id="pr_6cbd9069-c0c5-4070-b769-87ff226c6363_p2" x="5911.9307" y="2005.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f2405795-b811-4efd-b534-4ad7f0040747"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5290.0" y="5748.75"/> <port id="pr_f2405795-b811-4efd-b534-4ad7f0040747_p1" x="5295.0" y="5738.75"/> <port id="pr_f2405795-b811-4efd-b534-4ad7f0040747_p2" x="5295.0" y="5768.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_d98c27b1-7f7a-4698-9ab3-59ab618951a1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15688067 Alpha-actinin servers a link between cytoskeletal actin (in stress fibres) and vinculin at the focal contacts. Phosphorylation of alpha-actinin by FAK1 (PTK2) redues this ability of linking actin to vinculin, thus prevents the maturation of focal contacts. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5422.5" y="5795.245"/> <port id="pr_d98c27b1-7f7a-4698-9ab3-59ab618951a1_p1" x="5412.5" y="5800.245"/> <port id="pr_d98c27b1-7f7a-4698-9ab3-59ab618951a1_p2" x="5442.5" y="5800.245"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b29ff2d9-3fc2-43b8-9b6e-faeb87177baf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15688067 Zyxin is an alpha-actinin- and stress-fibre- binding protein that is present in mature contacts References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5735.1875" y="5867.0"/> <port id="pr_b29ff2d9-3fc2-43b8-9b6e-faeb87177baf_p1" x="5740.1875" y="5857.0"/> <port id="pr_b29ff2d9-3fc2-43b8-9b6e-faeb87177baf_p2" x="5740.1875" y="5887.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_89eb9e94-328e-4be5-aed4-bcc767cdb7b0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5575.0" y="5690.0"/> <port id="pr_89eb9e94-328e-4be5-aed4-bcc767cdb7b0_p1" x="5565.0" y="5695.0"/> <port id="pr_89eb9e94-328e-4be5-aed4-bcc767cdb7b0_p2" x="5595.0" y="5695.0"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_0bf77ad3-67ec-430f-9b50-5bfe9302032c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15688067 Alpha-actinin is a cytoskeletal protein that binds to viculin (VCL). Via this binding, Alpha-actinin crosslinks actin (in actomyosin stress fibres) and tether them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 (PTK2) reduces the crossliking of stress fibres and prevents the maturation of focal contacts. 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id="pr_c19f06fd-873b-4a1b-981c-8354689d3bdb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10685062 Adherens junctions are ubiquitously expressed in endothelia of all vascular beds? Adherens junction in endothelila cells are formed by homofilic binding of VE-cahderin (cadherin-5) Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with catenins is nessesary for cadherin-mediated cell adhesion. PMID:12426320 VE-cadhein interacts with catenin delta 1 (p120-catenin, CTNND1) VE-cadhein interacts with Plakophilin 4 (PKP4) PMID:7962210 VE-cadhein interacts with catenin beta 1 (CTNNB1) PKP4 and CTNND1 bind to the same region on the cytoplasmic tail of VE-cadherin. Overexpression of PKP4 can displace CTNND1 from intercellular junctions. PMID:9739078 VE-cadhein interacts with Plakoglobin (JUP) References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="746.7898" y="4310.0"/> <port id="pr_c19f06fd-873b-4a1b-981c-8354689d3bdb_p1" x="751.7898" y="4300.0"/> <port id="pr_c19f06fd-873b-4a1b-981c-8354689d3bdb_p2" x="751.7898" y="4330.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_7cd19426-2ead-4f7f-ac38-4ee40b5f5675"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10671552 PMID:11348595 PMID:17928543 in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins. GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="880.75" y="3356.0"/> <port id="pr_7cd19426-2ead-4f7f-ac38-4ee40b5f5675_p1" x="870.75" y="3361.0"/> <port id="pr_7cd19426-2ead-4f7f-ac38-4ee40b5f5675_p2" x="900.75" y="3361.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_bf74edf9-ac77-435b-af42-4ee2d95d80ea"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17353278 Phosphorylation of E-cadherin at S846 by casein kinase I decreases its ability to bind to CTNNB1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="879.25" y="3430.5"/> <port id="pr_bf74edf9-ac77-435b-af42-4ee2d95d80ea_p1" x="869.25" y="3435.5"/> <port id="pr_bf74edf9-ac77-435b-af42-4ee2d95d80ea_p2" x="899.25" y="3435.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_8acde799-9046-43e9-b7a9-78f9780717c2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16371504 Phosphorylation of N-cadherin at Y860 by SRC decreases its ability to bind to CTNNB1 CTNNB1 dissociated from the complex with N-cadherin enters to the nucleus. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1030.75" y="3864.0"/> <port id="pr_8acde799-9046-43e9-b7a9-78f9780717c2_p1" x="1020.75" y="3869.0"/> <port id="pr_8acde799-9046-43e9-b7a9-78f9780717c2_p2" x="1050.75" y="3869.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_8a6940b1-0148-4c82-b73f-207efdcb43e2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10593980 PMID:12123611 Phosphorylation of CTNNB1 at Y654 by SRC prevents the interaction between Cadherin and CTNNB1. This phosphorylation therefore reduces adhesive function. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="943.25" y="3904.2488"/> <port id="pr_8a6940b1-0148-4c82-b73f-207efdcb43e2_p1" x="963.25" y="3909.2488"/> <port id="pr_8a6940b1-0148-4c82-b73f-207efdcb43e2_p2" x="933.25" y="3909.2488"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b32fd830-004e-4977-bd43-0fd205d7c862"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10581160 PMID:17318175 PMID:10421629 Recruitment of CTNNB1 via the degradation complex of APC/AXIN1 is regulated by a series of ordered phosphorylation events. Phosphorylation of AXIN1 by CSNK1 (casein kinase 1) and GSK3B can increase axin binding to CTNNB1. PMID:8638126 PMID:11487578 PMID:15327768 AXIN1 also promotes phosphorylation of APC by CSNK1 and GSK3B. Phosphorylated APC has higher affinity to CTNNB1. PMID:12554650 Finally, these phosphorylation events allo CTNNB1 to be a more efficient substrate of both CSNK1 (at S45) and the GSK3B (at T41, S33, S37). The affinity of phosphorylated APC to CTNNB1 is higher than that of phosphorylated AXIN1. Therefore upon phosphorylation, APC can displace AXIN1 from CTNNB1, allowing AXIN1 to bind another molecule of CTNNB1. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="972.5" y="3634.5"/> <port id="pr_b32fd830-004e-4977-bd43-0fd205d7c862_p1" x="962.5" y="3639.5"/> <port id="pr_b32fd830-004e-4977-bd43-0fd205d7c862_p2" x="992.5" y="3639.5"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_2dfe1a70-6cd6-491b-9ee0-78a5ae9a6a5f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10581160 PMID:17318175 PMID:10421629 Recruitment of CTNNB1 via the degradation complex of APC/AXIN1 is regulated by a series of ordered phosphorylation events. Phosphorylation of AXIN1 by CSNK1 (casein kinase 1) and GSK3B can increase axin binding to CTNNB1. PMID:8638126 PMID:11487578 PMID:15327768 AXIN1 also promotes phosphorylation of APC by CSNK1 and GSK3B. Phosphorylated APC has higher affinity to CTNNB1. PMID:12554650 Finally, these phosphorylation events allo CTNNB1 to be a more efficient substrate of both CSNK1 (at S45) and the GSK3B (at T41, S33, S37). The affinity of phosphorylated APC to CTNNB1 is higher than that of phosphorylated AXIN1. Therefore upon phosphorylation, APC can displace AXIN1 from CTNNB1, allowing AXIN1 to bind another molecule of CTNNB1. 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PPP1 reverses CSNK1 (casein kinase 1) - mediated phosphorylation of AXIN1. This dephosphorylation allows CTNNB1 to escape the degradation complex of AXIN1 and APC. 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Cadherin recruits CTNNA1 (alpha-catenin) to the complex. CTNNA1 (alpha-catenin) binds to Actin filaments directly CTNNA1 (alpha-catenin) and can also associate with other actin-binding proteins (MLLT4 or Formin) CTNND1 (delta-catenin or p120) binds directly to Cadherin independently of the other catenins. Catenins/Cadherin complex can further interact with a range of singaling molecules which participate in either cellular signaling or control of cytoskeletal dynamics. Stability of Cadherin/Catenins complex and thereby the integrity of adherens junctions is controlled by phosphorylation/dephosphorylation. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="944.38513" y="3459.789"/> <port id="pr_9eb1709c-aa6b-435a-b241-16934e8323de_p1" x="934.38513" y="3464.789"/> <port id="pr_9eb1709c-aa6b-435a-b241-16934e8323de_p2" x="964.38513" y="3464.789"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3f3c475f-9c4d-4f00-b194-45806921ec2c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1438.5" y="3465.0"/> <port id="pr_3f3c475f-9c4d-4f00-b194-45806921ec2c_p1" x="1428.5" y="3470.0"/> <port id="pr_3f3c475f-9c4d-4f00-b194-45806921ec2c_p2" x="1458.5" y="3470.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6cf05411-79b2-401c-8571-136f1797e8f4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16325583 Monomeric CTNNA1 binds more strongly to E-cadherin/CTNNB1, whereas the dimer preferentially binds actin filaments References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1771.2258" y="3374.75"/> <port id="pr_6cf05411-79b2-401c-8571-136f1797e8f4_p1" x="1776.2258" y="3394.75"/> <port id="pr_6cf05411-79b2-401c-8571-136f1797e8f4_p2" x="1776.2258" y="3364.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_807c5852-d394-4a14-bbd0-d4f96ec8e9cb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15609097 CTNNB1 (beta-catenin) binds with high affinity to the distal Cadherin cytoplasmic tail. 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<notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22945800 PMID:22286765 Six1 induces ZEB1 and EMT through transcriptional repression of miR200. PMID:22311119 miR-200b regulates ZEB2 expression and thus controls metastasis in gastric cancer References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2215.7002" y="5314.0"/> <port id="pr_4c9580bb-5cf3-410f-93f9-6cdf01f707d7_p1" x="2220.7002" y="5304.0"/> <port id="pr_4c9580bb-5cf3-410f-93f9-6cdf01f707d7_p2" x="2220.7002" y="5334.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_54043fc3-5270-42e9-bfc2-b42f6c3426bc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1677.75" y="3903.753"/> <port id="pr_54043fc3-5270-42e9-bfc2-b42f6c3426bc_p1" x="1697.75" y="3908.753"/> <port id="pr_54043fc3-5270-42e9-bfc2-b42f6c3426bc_p2" x="1667.75" y="3908.753"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bb2f0871-8294-448b-a828-21a11dc6269d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19931509 miR-200a downregulates ZEB2 and CTNNB1 This downregulation inhibits carcinoma cell growth, migration and invasion. PMID:19703993 Upregulation of miR-200a decreased the expression of ZEB1 and ZEB2, with consequent increased expression of E-cadherin, Downregulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of beta-catenin and cyclin D1 involved in cell proliferation PMID:20592490 PMID:22211245 CTNNB1 is direct target of MIR200A References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2402.5" y="5315.75"/> <port id="pr_bb2f0871-8294-448b-a828-21a11dc6269d_p1" x="2407.5" y="5305.75"/> <port id="pr_bb2f0871-8294-448b-a828-21a11dc6269d_p2" x="2407.5" y="5335.75"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_ac46d1f8-65d5-42cb-af2c-7f9c6a7fa6e4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3394.25" y="4415.0"/> <port id="pr_ac46d1f8-65d5-42cb-af2c-7f9c6a7fa6e4_p1" x="3384.25" y="4420.0"/> <port id="pr_ac46d1f8-65d5-42cb-af2c-7f9c6a7fa6e4_p2" x="3414.25" y="4420.0"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_79527f85-039a-4ef6-a872-57aea9240da0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3396.231" y="4445.7876"/> <port id="pr_79527f85-039a-4ef6-a872-57aea9240da0_p1" x="3386.231" y="4450.7876"/> <port id="pr_79527f85-039a-4ef6-a872-57aea9240da0_p2" x="3416.231" y="4450.7876"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_6c6f0737-8ffb-4161-92b2-3490ff69e666"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3396.4707" y="4476.667"/> <port id="pr_6c6f0737-8ffb-4161-92b2-3490ff69e666_p1" x="3386.4707" y="4481.667"/> <port id="pr_6c6f0737-8ffb-4161-92b2-3490ff69e666_p2" x="3416.4707" y="4481.667"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_d0198fe6-dbb5-40d3-b3f3-a1343a4b56c7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3395.3125" y="4507.25"/> <port id="pr_d0198fe6-dbb5-40d3-b3f3-a1343a4b56c7_p1" x="3385.3125" y="4512.25"/> <port id="pr_d0198fe6-dbb5-40d3-b3f3-a1343a4b56c7_p2" x="3415.3125" y="4512.25"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_dd8ce721-be02-47b5-922e-55cc022c714f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20592490 The MIR200 family comprises 5 members (MIR200A, B, C, MIR141 and MIR429). These 5 members are clustered and expressed as 2 separate polycistronic pri-miRNA transcripts, miR200B-200A-429 and miR200C-141. These 2 transcripts are located on human chromosomes 1 and 12, respectively. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3394.8438" y="4537.833"/> <port id="pr_dd8ce721-be02-47b5-922e-55cc022c714f_p1" x="3384.8438" y="4542.833"/> <port id="pr_dd8ce721-be02-47b5-922e-55cc022c714f_p2" x="3414.8438" y="4542.833"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7755f0e4-9f1a-4eb3-a73f-8ab020adbe2b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15810077 Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis. PMID:22943793 Role of TGFB in regulation of cell cycle: Physiologically, TGFB is a potent inhibitor of cell cycle. 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<body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22286770 The inhibitory Smad7 mRNA is repressed by MIR106B, MIR93, MIR25. Smad7 antagonizes TGF-b signaling through multiple mechanisms, including binding to TGFBR1 and interfering with recruitment and downstream phosphorylation and activation of Smad2 and Smad3. Smad7 also functions to recruit E3 ubiquitin ligases to TGRFBR1, resulting in its degradation. Repression of Smad7 therefore activates TGF-beta signaling. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5075.5" y="4334.621"/> <port id="pr_306ec851-c836-46ff-8a9b-c250f2b4670f_p1" x="5065.5" y="4339.621"/> <port id="pr_306ec851-c836-46ff-8a9b-c250f2b4670f_p2" x="5095.5" y="4339.621"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c3c73e76-df69-4505-98e1-6de719898ec8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22286770 The inhibitory Smad7 mRNA is repressed by MIR106B, MIR93, MIR25. Smad7 antagonizes TGF-b signaling through multiple mechanisms, including binding to TGFBR1 and interfering with recruitment and downstream phosphorylation and activation of Smad2 and Smad3. Smad7 also functions to recruit E3 ubiquitin ligases to TGRFBR1, resulting in its degradation. Repression of Smad7 therefore activates TGF-beta signaling. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. 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PMID:14673164 Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2782.0" y="3517.0"/> <port id="pr_0d899c18-a84c-45b0-83cf-525fccd7921a_p1" x="2787.0" y="3537.0"/> <port id="pr_0d899c18-a84c-45b0-83cf-525fccd7921a_p2" x="2787.0" y="3507.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_361c9a06-c1b0-4a79-9202-b7cd679daf76"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22796940 Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2. PMID:21685935 EZH2 supports carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1 and HDAC2 and Snail to inhibit E-cadherin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2780.1812" y="3634.25"/> <port id="pr_361c9a06-c1b0-4a79-9202-b7cd679daf76_p1" x="2785.1812" y="3624.25"/> <port id="pr_361c9a06-c1b0-4a79-9202-b7cd679daf76_p2" x="2785.1812" y="3654.25"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_8b12a8c6-f011-461b-a3cf-d75787f791f7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21502402 Phosphorylation of serine 68 of Twist1 stabilizes Twist1 protein and promotes breast cancer cell invasiveness. 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PMID:20818389 Twist1 directly activates BMI1 transcription by binding to the E-box in intron 1 of the BMI1 gene. PMID:17550342 SNAI2 induces BMI1 expression PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair PMID:20713526 MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. PMID : PMID:17055429 MYC stimulate P53 and ARF References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2367.75" y="4105.085"/> <port id="pr_2d080743-3c42-48c2-ae2c-aee444bdc39e_p1" x="2387.75" y="4110.085"/> <port id="pr_2d080743-3c42-48c2-ae2c-aee444bdc39e_p2" x="2357.75" y="4110.085"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_799f6328-1933-46be-8471-10e833651457"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19935649 Protein expression of Bmi1, Sox2, p63 was reduced after ZEB1 knockdown. ZEB1 knockdown not only resulted in reduced invasion and metastasis, but also in reduced tumorigenicity. ZEB1 is also necessary for the self-renewing capacity. ZEB1 is crucial for drug resistance in pancreatic cancer cells. This supports data showing that EMT activators (Twist and Snail) confer anti-apoptotic properties References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2206.5" y="4093.08"/> <port id="pr_799f6328-1933-46be-8471-10e833651457_p1" x="2226.5" y="4098.08"/> <port id="pr_799f6328-1933-46be-8471-10e833651457_p2" x="2196.5" y="4098.08"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_00e4c912-a717-4733-be83-c69065ec199b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19935649 Expression of Bmi1, Sox2, p63 was reduced after ZEB1 knockdown. ZEB1 knockdown not only resulted in reduced invasion and metastasis, but also in reduced tumorigenicity. ZEB1 is also necessary for the self-renewing capacity. ZEB1 is crucial for drug resistance in pancreatic cancer cells. This supports data showing that EMT activators (Twist and Snail) confer anti-apoptotic properties References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4177.75" y="4630.283"/> <port id="pr_00e4c912-a717-4733-be83-c69065ec199b_p1" x="4167.75" y="4635.283"/> <port id="pr_00e4c912-a717-4733-be83-c69065ec199b_p2" x="4197.75" y="4635.283"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_49684f51-6fb4-4da8-84fb-9f17aeac3a0f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19935649 Expression of Bmi1, Sox2, p63 was reduced after ZEB1 knockdown. ZEB1 knockdown not only resulted in reduced invasion and metastasis, but also in reduced tumorigenicity. ZEB1 is also necessary for the self-renewing capacity. ZEB1 is crucial for drug resistance in pancreatic cancer cells. This supports data showing that EMT activators (Twist and Snail) confer anti-apoptotic properties References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4318.75" y="4630.3086"/> <port id="pr_49684f51-6fb4-4da8-84fb-9f17aeac3a0f_p1" x="4308.75" y="4635.3086"/> <port id="pr_49684f51-6fb4-4da8-84fb-9f17aeac3a0f_p2" x="4338.75" y="4635.3086"/> </glyph> <glyph class="process" orientation="vertical" id="pr_42a28c84-3e26-4caa-8bb1-8bebc38240f0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19935649 Targets of miR-200c include stem cell factors, such as Bmi1, Sox2 and KLF4 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2817.1501" y="5307.403"/> <port 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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3918.0" y="2015.0"/> <port id="pr_c95b7823-fbff-499d-bad6-3e39f1c46e1d_p1" x="3938.0" y="2020.0"/> <port id="pr_c95b7823-fbff-499d-bad6-3e39f1c46e1d_p2" x="3908.0" y="2020.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_13e714d1-fff6-40a5-9cf4-f6d27a5856f6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15140942 Phosphorylations on p53 prevent its binding to MDM2. PMID:15574337 S186 phosphorylation of MDM2 by AKT favors the binding of MDM2 to p53 and its following degradation. 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PMID:15574337 S186 phosphorylation of MDM2 by AKT favors the binding of MDM2 to p53 and its following degradation. PMID:19448627 Complex of p53, MDM2 and Slug faciliates the proteasomal degradation of Slug by MDM2. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3909.834" y="1873.5"/> <port id="pr_068a03d9-bd12-457b-a67b-84c7e876a684_p1" x="3914.834" y="1893.5"/> <port id="pr_068a03d9-bd12-457b-a67b-84c7e876a684_p2" x="3914.834" y="1863.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_596a2d10-a7e4-48c3-a9fb-8b02308f8337"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2990.97" y="506.0"/> <port id="pr_596a2d10-a7e4-48c3-a9fb-8b02308f8337_p1" x="2995.97" y="496.0"/> <port id="pr_596a2d10-a7e4-48c3-a9fb-8b02308f8337_p2" x="2995.97" y="526.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0655bf6f-c39b-4a03-bd3e-52cf4518e644"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17537911 Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3547.5" y="4347.5"/> <port id="pr_0655bf6f-c39b-4a03-bd3e-52cf4518e644_p1" x="3537.5" y="4352.5"/> <port id="pr_0655bf6f-c39b-4a03-bd3e-52cf4518e644_p2" x="3567.5" y="4352.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1ecc74a5-ef45-455a-95d7-6d5503619316"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17537911 Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3745.0" y="4347.5"/> <port id="pr_1ecc74a5-ef45-455a-95d7-6d5503619316_p1" x="3735.0" y="4352.5"/> <port id="pr_1ecc74a5-ef45-455a-95d7-6d5503619316_p2" x="3765.0" y="4352.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_ad7b4f02-5919-450c-b490-dbd083c964e0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17490644 Snai1 and TCF3 (E47) upregulate both mRNA and protein level of ID1 This upregulation depends on SP1 or AP1 co-transcription factors Erk contributes to the recruitment or assembly of proteins to Id-1 promoter PMID:16831886 PMID:18832382 HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter. 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Rac1B does not lead to lamellipodia formation, or the activation of PAK1, AKT1, or c-Jun-NH2- kinase activities. However, Rac1B retains the ability to stimulate the NF-kappa-B pathway. PMID:16001073 MMP3 can induce the expression of RACB1. RACB1 increases the cellular levels of ROS, causing an upregulation of Snail and induction of EMT. 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PMID:18832382 PMID:15181457 ID proteins can form complexes with TCF3 (E47), and inhibit the process of EMT. 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<notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17673906 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 association with Grb2 and Sos PMID:12767520 Upon IGF stimulation, the activated IGF1R recruits and directly phosphorylates SHC1, leading to cellular proliferation References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5968.373" y="3623.5"/> <port id="pr_ea75ff0f-74b4-427b-aa44-f6ee3113cc7f_p1" x="5973.373" y="3643.5"/> <port id="pr_ea75ff0f-74b4-427b-aa44-f6ee3113cc7f_p2" x="5973.373" y="3613.5"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_e55c0fac-41bc-4ce6-8828-42668a973a10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5862.0" y="3349.247"/> <port id="pr_e55c0fac-41bc-4ce6-8828-42668a973a10_p1" x="5882.0" y="3354.247"/> <port id="pr_e55c0fac-41bc-4ce6-8828-42668a973a10_p2" x="5852.0" y="3354.247"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_8198400b-0adf-4c74-bca5-e9fe0cadedf9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5862.0" y="3366.5984"/> <port id="pr_8198400b-0adf-4c74-bca5-e9fe0cadedf9_p1" x="5882.0" y="3371.5984"/> <port id="pr_8198400b-0adf-4c74-bca5-e9fe0cadedf9_p2" x="5852.0" y="3371.5984"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_637552bc-a08a-401b-a42a-bfd94926db82"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: In general, growth factor stimulation leads to the activation of receptor tyrosine kinases and to the phosphorylation of the receptor tail. The resultant phosphotyrosines form docking sites for adaptator proteins (e.g. GRB2 via its SH2 domain). The SH3 domain of adaptator (e.g. GRB2) then binds to the proline-rich motifs in the GTP exchange factor (i.e. GEF) for RAS (e.g. SOS) Via this process that GEF (e.g. SOS) is recruited to the membrane where it colocalizes with and activates Ras. PMID:17673906 SHC1 gene has 3 corresponding protein isoforms: p66, p52 and p46 Upon TGFB stimulation, the activated TGFBR1 recruits and directly phosphorylates SHC1 (p66 or p52) on tyrosine and serine. TGFB-induced SHC1 phosphorylation induces SHC1 (p66 or p52) association with Grb2 and Sos References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5933.7734" y="3427.85"/> <port id="pr_637552bc-a08a-401b-a42a-bfd94926db82_p1" x="5923.7734" y="3432.85"/> <port id="pr_637552bc-a08a-401b-a42a-bfd94926db82_p2" x="5953.7734" y="3432.85"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_ef915ad4-4327-4ae6-97fa-ba8ad4e064b5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10197981 PMID:12193595 PMID:16156666 Erk kinases phosphorylate Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFB receptor phosphorylation sites that activate Smad nuclear translocation. Feedback loop: TGFB activates Ras/Raf/Mek/Erk signaling (PMID:17673906) and Erk reduces TGFB/Smads transcriptional activity. PMID:15241418 Feedback loop CDK phosphorylation of Smad3 on Thr8/Thr179/Ser213 inhibits its transcriptional activity and antiproliferative function. Because cancer cells often contain high levels of CDK activity, diminishing Smad3 activity by CDK phosphorylation may contribute to tumorigenesis and TGFB- resistance in cancers. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5815.5" y="4480.5"/> <port id="pr_ef915ad4-4327-4ae6-97fa-ba8ad4e064b5_p1" x="5820.5" y="4470.5"/> <port id="pr_ef915ad4-4327-4ae6-97fa-ba8ad4e064b5_p2" x="5820.5" y="4500.5"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_5224ebfb-e552-4d27-aedd-03b16ab671f4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10197981 PMID:12193595 PMID:16156666 Erk kinases phosphorylate Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFB receptor phosphorylation sites that activate Smad nuclear translocation. Feedback loop: TGFB activates Ras/Raf/Mek/Erk signaling (PMID:17673906) and Erk reduces TGFB/Smads transcriptional activity. 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The binding involves a PY motif in SMAD7. PMID:11163210 SMAD7 binds to SMURF2 to form a complex that targets the TGFBR1 for degradation. PMID:12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. PMID:21897371 SMAD6 binds to SMURF1 and SMURF2 References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4711.87" y="4408.214"/> <port id="pr_bcd1eafc-c30f-4eab-a777-9b4f5405834f_p1" x="4731.87" y="4413.214"/> <port id="pr_bcd1eafc-c30f-4eab-a777-9b4f5405834f_p2" x="4701.87" y="4413.214"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0bd7c6b4-e98d-4865-98fc-f0cc08234540"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11278251 Inhibitory Smad7 associates with Smurf1 in the nucleus and is exported to the cytoplasm. Smad7 thus recruits Smurf1 to TGFBR1, resulting in the degradation and rapid turnover of the TGFBR1 protein. 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induction of genes such as Hes1 but stabilizes Notch1/ICD. 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TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457) ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1. Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3) References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4018.5" y="4433.232"/> <port id="pr_3a69ea04-4447-4cad-a3d1-0f31dcf9c555_p1" x="4008.5" y="4438.232"/> <port id="pr_3a69ea04-4447-4cad-a3d1-0f31dcf9c555_p2" x="4038.5" y="4438.232"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_85a89932-0d46-41f9-bdce-77ee63293566"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4212.5" y="4433.7715"/> <port id="pr_85a89932-0d46-41f9-bdce-77ee63293566_p1" x="4202.5" y="4438.7715"/> <port id="pr_85a89932-0d46-41f9-bdce-77ee63293566_p2" x="4232.5" y="4438.7715"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_76182924-faa6-4949-a18f-1f9af5e8f9e7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3144.9395" y="3879.0981"/> <port id="pr_76182924-faa6-4949-a18f-1f9af5e8f9e7_p1" x="3164.9395" y="3884.0981"/> <port id="pr_76182924-faa6-4949-a18f-1f9af5e8f9e7_p2" x="3134.9395" y="3884.0981"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_3f6cce2c-8a31-4115-8ecb-77b39f0a38a2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3955.7568" y="4227.8906"/> <port id="pr_3f6cce2c-8a31-4115-8ecb-77b39f0a38a2_p1" x="3975.7568" y="4232.8906"/> <port id="pr_3f6cce2c-8a31-4115-8ecb-77b39f0a38a2_p2" x="3945.7568" y="4232.8906"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_89f68868-1474-4044-9c74-639871bfc488"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:18758450 The ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TGFBR1. The TGFBR1–TRAF6 interaction is required for TGFB-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway TGFB specifically activates TAK1 (MAP3K7) through interaction of TGFBRI with TRAF6. The kinase activity of TGFBRI is not required for activation of TAK1 and p38. Model in which TGFB - induced activation of TAK1 is initiated by ligand-induced oligomerization of TGFBreceptors. This in turn cause dimerization of TRAF6, followed by auto-ubiquitylation and activation. This possibility is consistent with the observation that artifical dimerization of TRAF6 causes its auto-ubiquitylation. Activated TRAF6 then causes Lys 63-linked ubiquitylation and activation of TAK1 (MAP3K7). TAK1 may be further activated by juxtaposition-induced autophosphorylation. The recruitment of TAK1 may be facilitated by Smad7, which has been shown to have an adaptor function in the pathway PMID:18922473 TRAF6 is specifically required for the Smad-independent activation of JNK and p38. The carboxyl TRAF homology domain physically interacts with TGFB receptors. TGFB induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1 (MAP3K7). TGFB activates JNK and p38 through a mechanism similar to that operating in the interleukin1B/Toll- like receptor pathway. 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The TGFBR1–TRAF6 interaction is required for TGFB-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway TGFB specifically activates TAK1 (MAP3K7) through interaction of TGFBRI with TRAF6. The kinase activity of TGFBRI is not required for activation of TAK1 and p38. Model in which TGFB - induced activation of TAK1 is initiated by ligand-induced oligomerization of TGFBreceptors. This in turn cause dimerization of TRAF6, followed by auto-ubiquitylation and activation. This possibility is consistent with the observation that artifical dimerization of TRAF6 causes its auto-ubiquitylation. Activated TRAF6 then causes Lys 63-linked ubiquitylation and activation of TAK1 (MAP3K7). TAK1 may be further activated by juxtaposition-induced autophosphorylation. The recruitment of TAK1 may be facilitated by Smad7, which has been shown to have an adaptor function in the pathway PMID:18922473 TRAF6 is specifically required for the Smad-independent activation of JNK and p38. The carboxyl TRAF homology domain physically interacts with TGFB receptors. TGFB induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1 (MAP3K7). TGFB activates JNK and p38 through a mechanism similar to that operating in the interleukin1B/Toll- like receptor pathway. 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Immediate-early activation of HEY1 by TGFB is mediated directly by Smad3/4 binding at two distinct sequences in the distal HEY1 promoter region and does not require Notch signalling. The Smad-dependent, Notch-independent immediate-early activation is followed by a second wave of HEY1 activation. 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p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. 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components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. 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Three IGF1R-induced anti-apoptotic pathways: 1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation. Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death. Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death. 2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD. 3. 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TNF-dependent production of ROS triggers the dissociation of Trx from ASK1 and the consequently liberalised ASK1 binds to TRAF2. Finally TRAF2 appears to activate ASK1 (by phosphorylation) by enhancing and stabilising the oligomerisation of ASK1. PMID:12556535 IGF1R signaling suppresses the ASK1-mediated stimulation of JNK/p38 thus supresses the induction of apoptosis. 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PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. http://d-scholarship.pitt.edu/18634/1/Zimmerman_ETD-2013.pdf c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3. Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2365.5" y="4372.2637"/> <port id="pr_4ae6cb1c-46d1-4b38-a9bd-30678be02311_p1" x="2385.5" y="4377.2637"/> <port id="pr_4ae6cb1c-46d1-4b38-a9bd-30678be02311_p2" x="2355.5" y="4377.2637"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_de029ff8-f1ab-402f-8819-31edcaa37081"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2045.6223" y="4440.25"/> <port id="pr_de029ff8-f1ab-402f-8819-31edcaa37081_p1" x="2065.6223" y="4445.25"/> <port id="pr_de029ff8-f1ab-402f-8819-31edcaa37081_p2" x="2035.6223" y="4445.25"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_5463eaea-9426-4e1b-8b3e-0c32608228a2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:24376839 PTP4A3 is implicated in cell adhesion and the regulation of focal adhesion components including integrin beta-1, Src, paxillin and p130Cas Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2. PTP4A3 is also involved in EMT: PTP4A3 overexpression in colorectal carcinoma cells downregulates epithelial markers (E-cadherin, plakoglobin, and integrin beta-3) and upregulates expression of mesenchymal markers (fibronectin and snail1). PMID:23691193 Src-mediated phosphorylation of PTP4A3 Is required for Rho activation, motility and invasion promoted by PTP4A3. http://d-scholarship.pitt.edu/18634/1/Zimmerman_ETD-2013.pdf c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3. Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. 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Phosphorylation of Tyr-860 (Tyr-835 in E-cadherin) can disrupt cadherin binding to beta-catenin PMID :10402472 We conclude that a pool of surface E-cadherin is constantly trafficked through an endocytic, recycling pathway and that this may provide a mechanism for regulating the availability of E-cadherin for junction formation in development, tissue remodeling, and tumorigenesis. 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id="pr_97974015-5def-441f-81b6-1206e3b90161"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1075.25" y="137.16446"/> <port id="pr_97974015-5def-441f-81b6-1206e3b90161_p1" x="1065.25" y="142.16446"/> <port id="pr_97974015-5def-441f-81b6-1206e3b90161_p2" x="1095.25" y="142.16446"/> </glyph> <glyph class="omitted process" orientation="vertical" id="pr_9e7d7c00-0db8-411c-b51f-bfa520c5cb60"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21776389 Src participates in the activation of various downstream signaling pathways through molecular interactions with growth factor receptors such as the epidermal growth factor receptor (EGFR) family, hepatocyte growth factor receptor (Met), integrin cell adhesion receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="2001.75" y="3080.0"/> <port id="pr_9e7d7c00-0db8-411c-b51f-bfa520c5cb60_p1" x="2006.75" y="3070.0"/> <port id="pr_9e7d7c00-0db8-411c-b51f-bfa520c5cb60_p2" x="2006.75" y="3100.0"/> </glyph> <glyph class="uncertain process" orientation="horizontal" id="pr_6c5b1f66-41c6-4bce-9be2-517880e30cb6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox 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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:25234227 Dynamin 2 act on the actin cytoskeleton by: - Promoting membrane remodeling and endocytosis of cell receptor thanks to NDPKA (NME1) and NDPKB (NME2) DNM2 induces E-cadherin internalisation References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="772.61475" y="1231.625"/> <port id="pr_cb2c1d27-b733-4387-9ff5-a0134c319f95_p1" x="777.61475" y="1251.625"/> <port id="pr_cb2c1d27-b733-4387-9ff5-a0134c319f95_p2" x="777.61475" y="1221.625"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_cb1b2bd3-4d0e-487c-bb98-2275687e9772"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end 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id="pr_a2eb070a-7a37-4c0c-9a8f-57b6750d569f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1787.6162" y="656.3672"/> <port id="pr_a2eb070a-7a37-4c0c-9a8f-57b6750d569f_p1" x="1807.6162" y="661.3672"/> <port id="pr_a2eb070a-7a37-4c0c-9a8f-57b6750d569f_p2" x="1777.6162" y="661.3672"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5fc1e829-aa13-4863-be38-48e71da0646e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID :10402472 We conclude that a pool of surface E-cadherin is constantly trafficked through an endocytic, recycling pathway and that this may provide a mechanism for regulating the availability of E-cadherin for junction formation in development, tissue remodeling, and tumorigenesis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1137.4135" y="2231.625"/> <port id="pr_5fc1e829-aa13-4863-be38-48e71da0646e_p1" x="1142.4135" y="2251.625"/> <port id="pr_5fc1e829-aa13-4863-be38-48e71da0646e_p2" x="1142.4135" y="2221.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6ee71f4a-7cc3-435b-869a-69ab69e22b3b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID :10402472 We conclude that a pool of surface E-cadherin is constantly trafficked through an endocytic, recycling pathway and that this may provide a mechanism for regulating the availability of E-cadherin for junction formation in development, tissue remodeling, and tumorigenesis. PMID:22674073 Clathrin-mediated endocytosis appears to be responsible for two types of growth factor-induced cadherin internalization, FGF-mediated internalization of E-cadherin () and VEGF-mediated internalization of VE-cadherin. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1394.7694" y="2232.0278"/> <port id="pr_6ee71f4a-7cc3-435b-869a-69ab69e22b3b_p1" x="1399.7694" y="2252.0278"/> <port id="pr_6ee71f4a-7cc3-435b-869a-69ab69e22b3b_p2" x="1399.7694" y="2222.0278"/> </glyph> <glyph class="and" orientation="vertical" id="logicglyph_eb28b3ba-b1a7-4af8-8e26-1f19ca027c3f"> <bbox w="20.0" h="20.0" x="1366.75" y="1137.0"/> <port id="logicglyph_eb28b3ba-b1a7-4af8-8e26-1f19ca027c3f_p1" x="1376.75" y="1127.0"/> <port id="logicglyph_eb28b3ba-b1a7-4af8-8e26-1f19ca027c3f_p2" x="1376.75" y="1167.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_75135b8c-56ab-4158-8890-6a7e553692b1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID :10402472 We conclude that a pool of surface E-cadherin is constantly trafficked through an endocytic, recycling pathway and that this may provide a mechanism for regulating the availability of E-cadherin for junction formation in development, tissue remodeling, and tumorigenesis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1327.5181" y="2251.125"/> <port id="pr_75135b8c-56ab-4158-8890-6a7e553692b1_p1" x="1332.5181" y="2271.125"/> <port id="pr_75135b8c-56ab-4158-8890-6a7e553692b1_p2" x="1332.5181" y="2241.125"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9a9f8f03-4697-4b1e-a11c-09cb3fe64dac"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID :10402472 We conclude that a pool of surface E-cadherin is constantly trafficked through an endocytic, recycling pathway and that this may provide a mechanism for regulating the availability of E-cadherin for junction formation in development, tissue remodeling, and tumorigenesis. 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Internalized cadherin is then sorted either for lysosomal degradation or recycling back to the plasma membrane. 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</glyph> <glyph class="process" orientation="vertical" id="pr_6c23c450-2e6f-432b-80e3-a7deaf81083d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin Akhtar and colleagues found that a dominant-active form of the small GTPase Rac1 could disrupt cell-cell adhesion in keratinocytes. 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This was associated with the endocytosis of E-cadherin through a pathway that appeared to be distinct from the uptake of transferrin, which is clathrin-mediated, and through structures that co-localized with caveolin In contrast, Bryant and colleagues characterized the EGF-induced internalization of E-cadherin in a breast carcinoma cell line, in which E-cadherin was internalized along with the cadherin-binding proteins p120 and β-catenin, as Rac1-modulated macropinocytosis References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1329.5" y="1682.5"/> <port id="pr_4c6e5fcd-50e5-4daf-ada6-896466149447_p1" x="1334.5" y="1702.5"/> <port id="pr_4c6e5fcd-50e5-4daf-ada6-896466149447_p2" x="1334.5" y="1672.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_875ab169-3025-4ce7-aa11-3f411a8efdd7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 Studies have suggested that cadherin endocytosis may occur through both caveolin-mediated and macropinocytosis-like pathways. 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Internalized cadherin is then sorted either for lysosomal degradation or recycling back to the plasma membrane. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1160.375" y="1057.012"/> <port id="pr_493e7db8-8a6c-470b-8b14-3d7c37f4053b_p1" x="1165.375" y="1047.012"/> <port id="pr_493e7db8-8a6c-470b-8b14-3d7c37f4053b_p2" x="1165.375" y="1077.012"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bde12a80-144b-4f92-a937-b7e612b263eb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 Cadherin internalization can occur through either clathrin-mediated, caveolin-mediated, or macropinocytosis-like pathways. Internalized cadherin is then sorted either for lysosomal degradation or recycling back to the plasma membrane. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1161.875" y="898.012"/> <port id="pr_bde12a80-144b-4f92-a937-b7e612b263eb_p1" x="1166.875" y="888.012"/> <port id="pr_bde12a80-144b-4f92-a937-b7e612b263eb_p2" x="1166.875" y="918.012"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6c0dd3c2-7f08-4be3-94d9-a7a344d28f80"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 Cadherin internalization can occur through either clathrin-mediated, caveolin-mediated, or macropinocytosis-like pathways. Internalized cadherin is then sorted either for lysosomal degradation or recycling back to the plasma membrane. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1160.375" y="1023.0"/> <port id="pr_6c0dd3c2-7f08-4be3-94d9-a7a344d28f80_p1" x="1165.375" y="1013.0"/> <port id="pr_6c0dd3c2-7f08-4be3-94d9-a7a344d28f80_p2" x="1165.375" y="1043.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_95f776b8-8347-42f8-aecb-c48b7c6045f7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 Cadherin internalization can occur through either clathrin-mediated, caveolin-mediated, or macropinocytosis-like pathways. Internalized cadherin is then sorted either for lysosomal degradation or recycling back to the plasma membrane. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1161.875" y="879.0"/> <port id="pr_95f776b8-8347-42f8-aecb-c48b7c6045f7_p1" x="1166.875" y="869.0"/> <port id="pr_95f776b8-8347-42f8-aecb-c48b7c6045f7_p2" x="1166.875" y="899.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5f96b486-79e0-403e-9036-57288456e630"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:24970086 Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocytosis of the transferrin (Tf) and epidermal growth factor (EGF) receptors References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="661.5662" y="808.25"/> <port id="pr_5f96b486-79e0-403e-9036-57288456e630_p1" x="666.5662" y="798.25"/> <port id="pr_5f96b486-79e0-403e-9036-57288456e630_p2" x="666.5662" y="828.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6ee59d6d-d9f6-4618-b629-882438d284b9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15263019 Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1824.0" y="1712.3813"/> <port id="pr_6ee59d6d-d9f6-4618-b629-882438d284b9_p1" x="1844.0" y="1717.3813"/> <port id="pr_6ee59d6d-d9f6-4618-b629-882438d284b9_p2" x="1814.0" y="1717.3813"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_33606cb0-2142-4b31-bae6-7b9ff05c5e87"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15263019 Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1827.5" y="1599.429"/> <port id="pr_33606cb0-2142-4b31-bae6-7b9ff05c5e87_p1" x="1847.5" y="1604.429"/> <port id="pr_33606cb0-2142-4b31-bae6-7b9ff05c5e87_p2" x="1817.5" y="1604.429"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0419382a-873f-45b1-a44e-7c0ed964f5d7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 E-cadherin does not travel directly from the Golgi complex to the cell surface, but transits first through Rab11-positive recycling endosomes. Rab11 is involved in E-cadherin localization to the surface of the cell . In addition to acting as way stations for newly synthesized cadherin on its way to the plasma membrane, Rab11-positive recycling endosomes can also sort internalized cadherin for recycling back to the cell surface. Desclozeaux and colleagues also found that cadherin recycling is necessary for maintaining adherens junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1093.625" y="2379.2622"/> <port id="pr_0419382a-873f-45b1-a44e-7c0ed964f5d7_p1" x="1098.625" y="2369.2622"/> <port id="pr_0419382a-873f-45b1-a44e-7c0ed964f5d7_p2" x="1098.625" y="2399.2622"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1499bb08-3a86-441d-a580-4a0d0f6aac29"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22674073 Desclozeaux and colleagues also found that cadherin recycling is necessary for maintaining adherens junctions. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="1278.0801" y="2518.75"/> <port id="pr_1499bb08-3a86-441d-a580-4a0d0f6aac29_p1" x="1283.0801" y="2538.75"/> <port id="pr_1499bb08-3a86-441d-a580-4a0d0f6aac29_p2" x="1283.0801" y="2508.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c34f3478-3edc-47a8-b60a-366408bb4a7f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. 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The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4177.0" y="2654.0"/> <port id="pr_24879c49-dd6e-47ae-902e-9bf661663cab_p1" x="4167.0" y="2659.0"/> <port id="pr_24879c49-dd6e-47ae-902e-9bf661663cab_p2" x="4197.0" y="2659.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_18a899ae-f0a1-4ee7-b2b0-3019019acda9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4617.0" y="2643.8413"/> <port id="pr_18a899ae-f0a1-4ee7-b2b0-3019019acda9_p1" x="4607.0" y="2648.8413"/> <port id="pr_18a899ae-f0a1-4ee7-b2b0-3019019acda9_p2" x="4637.0" y="2648.8413"/> </glyph> <glyph class="process" orientation="vertical" id="pr_327cbde1-99ff-4843-8d95-486723ebe36d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15082531 The activation of MP3K7(TAK1) by TAB1 activates NLK. the TAK1–NLK MAPK pathway regulates Wnt signaling by phosphorylating TCF in mammalian cells. The TAB1 protein is a specific partner of TAK1 and promotes TAK1 autophosphorylation. Coexpression of TAK1 and TAB1 in mammalian cells activate HIPK2, that activate NLK. THe coexpression of NLK and HIPK2 induces the degradation of the c-Myb protein. Degradation of c-Myb protein by Wnt-1 signal via the pathway involving TAK1, HIPK2, and NLK leads to G1 arrest. PMID:10391247 TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. PMID:21795403 GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4337.0" y="1994.0"/> <port id="pr_327cbde1-99ff-4843-8d95-486723ebe36d_p1" x="4342.0" y="2014.0"/> <port id="pr_327cbde1-99ff-4843-8d95-486723ebe36d_p2" x="4342.0" y="1984.0"/> </glyph> <glyph class="and" orientation="vertical" id="logicglyph_1268b778-3561-4bf9-b225-83ad20026fd9"> <bbox w="20.0" h="20.0" x="4130.0" y="2398.0"/> <port id="logicglyph_1268b778-3561-4bf9-b225-83ad20026fd9_p1" x="4140.0" y="2428.0"/> <port id="logicglyph_1268b778-3561-4bf9-b225-83ad20026fd9_p2" x="4140.0" y="2388.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_14eae701-68aa-4958-8799-9c3aa1a10e7b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22439866 c-Myb regulates matrix metalloproteinases 1/9, and cathepsin D, there is implications for matrix-dependent breast cancer cell invasion and metastasis. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4484.5" y="3443.8347"/> <port id="pr_14eae701-68aa-4958-8799-9c3aa1a10e7b_p1" x="4474.5" y="3448.8347"/> <port id="pr_14eae701-68aa-4958-8799-9c3aa1a10e7b_p2" x="4504.5" y="3448.8347"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b18dd3bb-1263-41f8-916b-2ba5a39c7041"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4792.0" y="3444.0"/> <port id="pr_b18dd3bb-1263-41f8-916b-2ba5a39c7041_p1" x="4782.0" y="3449.0"/> <port id="pr_b18dd3bb-1263-41f8-916b-2ba5a39c7041_p2" x="4812.0" y="3449.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_eb9f11da-6982-4bb8-85e7-0197be9456db"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:24335145 β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3108.25" y="5204.0"/> <port id="pr_eb9f11da-6982-4bb8-85e7-0197be9456db_p1" x="3098.25" y="5209.0"/> <port id="pr_eb9f11da-6982-4bb8-85e7-0197be9456db_p2" x="3128.25" y="5209.0"/> </glyph> <glyph class="omitted process" orientation="horizontal" id="pr_5ee03b04-ef10-435b-94f4-e60c67442515"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:24335145 β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3113.25" y="5254.0"/> <port id="pr_5ee03b04-ef10-435b-94f4-e60c67442515_p1" x="3103.25" y="5259.0"/> <port id="pr_5ee03b04-ef10-435b-94f4-e60c67442515_p2" x="3133.25" y="5259.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_18469171-cc16-41bd-ba36-0c3a22eba7cc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:18281283 production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4277.0" y="1999.0"/> <port id="pr_18469171-cc16-41bd-ba36-0c3a22eba7cc_p1" x="4282.0" y="2019.0"/> <port id="pr_18469171-cc16-41bd-ba36-0c3a22eba7cc_p2" x="4282.0" y="1989.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_719ccb4c-bbaa-45d6-b53a-1b31e1ae897b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:18281283 production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression References_end Confidence_begin: Confidence_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4266.0454" y="1651.25"/> <port id="pr_719ccb4c-bbaa-45d6-b53a-1b31e1ae897b_p1" x="4271.0454" y="1671.25"/> <port id="pr_719ccb4c-bbaa-45d6-b53a-1b31e1ae897b_p2" x="4271.0454" y="1641.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_744f37f5-9d68-4d45-b816-e20baf73bec8"> <notes> <html 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MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. 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The inhibition of CDK2 by p27KIP1*, allows MYC to exert its pro-senescence effect PMID:11283614 Myc: an ubiquitous mediator of cell growth and proliferation Myc can both activate and repress transcription, depending on the nature of associated factors TGFB downregulates Myc to cause cell cycle arrest. TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB PMID:2191300 Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. PMID :28536364 c-myc is transcriptionally upregulated by NF-κB PMID:20027199 MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes PMID :20713526 MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence. 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