</head> <body>Natural Killer Cell Map Natural killers (NK) are big granular lymphocytes which can be cytotoxic for tumor cells. The markers of this cell type are specific NK-receptors as NKp30, NKp46, NKG2D, etc. The main role of NK cells in innate immunity is elimination of cells lacking MHC1 molecules that therefore cannot be recognized by T-cells. NK are stimulated by the target cells expressing NK receptors activating ligands such as MICA, MICB, etc. The activity of NK cells is modulated by inflammatory cytokines as IL15, IL12, produced by macrophages and dendritic cells. NK cells secrete granules contains lytic enzymes (granzymes, perforin, granulysin, etc) and express apoptosis inducers TRAIL and FASL. Presence of active NK cells in cancer is correlated with good prognosis. To escape NK control, tumor cells express immunosuppressive ligands as MIF, IL10, TGFB and downregulation of NK ligands expression that collectively inhibit cytotoxic activity of NK cells. Pro-tumor polarization of NK cells is not described in the literature, however suppressed NK cells are incapable to reject tumor cells and therefore indirectly promote cancer progression.</body> </html> </notes> <extension> <renderInformation backgroundColor="#ffffff" id="renderInformation" programName="cd2sbgnml" programVersion="0.1" xmlns="http://www.sbml.org/sbml/level3/version1/render/version1"> <listOfColorDefinitions> <colorDefinition id="color_11" value="#66ff66ff"/> <colorDefinition id="color_2" value="#cccc00ff"/> <colorDefinition id="color_5" value="#ccffccff"/> <colorDefinition id="color_7" value="#ccff66ff"/> <colorDefinition id="color_14" value="#808080ff"/> <colorDefinition id="color_8" value="#f7f7f7ff"/> <colorDefinition id="color_12" value="#ffccccff"/> <colorDefinition id="color_6" value="#ffffccff"/> <colorDefinition id="color_10" value="#ffff66ff"/> <colorDefinition id="color_16" value="#00ff00ff"/> <colorDefinition id="color_3" value="#cc99ffff"/> <colorDefinition 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<glyph class="compartment" id="c4_ca4"> <label text="Cytolytic granules"> <bbox w="95.0" h="10.0" x="2413.9214" y="2983.3545"/> </label> <bbox w="763.75" h="358.75" x="2100.0" y="2830.0"/> </glyph> <glyph class="compartment" id="c5_ca5"> <label text="Lysosome"> <bbox w="45.0" h="10.0" x="4973.0" y="2024.4026"/> </label> <bbox w="300.0" h="190.0" x="4880.0" y="1875.0"/> </glyph> <glyph class="compartment" id="c7_ca7"> <label text="Cytosol"> <bbox w="40.0" h="10.0" x="4038.75" y="3393.4832"/> </label> <bbox w="5827.5" h="2550.0" x="1150.0" y="880.0"/> </glyph> <glyph class="compartment" id="c6_ca6"> <label text="Membrane"> <bbox w="45.0" h="10.0" x="3904.5" y="3774.4937"/> </label> <bbox w="7025.0" h="3560.0" x="515.0" y="450.0"/> </glyph> <glyph class="phenotype" id="s1_sa1" compartmentRef="c6_ca6"> <label text="inhibitory receptors"/> <bbox w="190.0" h="35.0" x="695.0" y="2882.5"/> </glyph> <glyph class="macromolecule" id="s4_sa4" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:21350056, PMID:23906377 Human perforin is expressed in natural killer cells.NK cytotoxicity is mediated by the directed exocytosis of cytolytic granules to release perforins and granzymes, which perforate the target cell plasma cell membrane and trigger apoptosis, respectively. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="80.0" h="40.0" x="2250.0" y="3050.0"/> </glyph> <glyph class="macromolecule" id="s5_sa5" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:GZMA Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:16106370, PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11413196, PMID:11413196 VAV1 induces granule exocytosis of granzyme A probably via RAC1-ERK pathway. The absence of Vav1 results in defective granule exocytosis and reduced ability to lyse tumor targets. References_end</body> </html> </notes> <label text="GZMA"/> <bbox w="80.0" h="40.0" x="2490.0" y="3120.0"/> </glyph> <glyph class="macromolecule" id="s6_sa6" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:16106370,PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:20189481 NKG2D, 2B4 signalings induces Granzyme B release probaly via VAV1/ERK pathway PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. PMID:24248158 Hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="80.0" h="40.0" x="2340.0" y="3090.0"/> </glyph> <glyph class="macromolecule" id="s7_sa7" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:GZMK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:16106370, PMID:15607806,PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end</body> </html> </notes> <label text="GZMK"/> <bbox w="80.0" h="40.0" x="2140.0" y="3010.0"/> </glyph> <glyph class="macromolecule" id="s8_sa733" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor PMID:12917349, PMID:18835194 Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DL1"/> <bbox w="80.0" h="50.0" x="860.0" y="2685.0"/> <glyph class="state variable" id="_3d215bca-8406-4091-a37c-b6976f03d1c7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="855.0" y="2705.0"/> </glyph> <glyph class="unit of information" id="_7c4acf2a-f01c-4c65-bded-7feba038e510"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="877.5" y="2680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s9_sa732" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR2DL2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:21339333 KIR2DL2 signaling blocks the initiation of activating responses downstream of HLA-C via SHP-1,SHP-2. KIR2DL2 signaling inhibits IFNG secretion and Ca2+ mobilization, probably via inhibition of NKG2D-DAP10 signaling. PMID:9605119 Interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3) with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor cell lysis. References_end</body> </html> </notes> <label text="KIR2DL2"/> <bbox w="80.0" h="50.0" x="790.0" y="2555.0"/> <glyph class="unit of information" id="_33f100bc-4b4b-4ad7-a293-d30847034bdd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="807.5" y="2550.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s10_sa734" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8574854 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. KIR2DL3 inhibits NK cells downstream of HLA-C via SHP-1 binding and activation. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DL3"/> <bbox w="80.0" h="50.0" x="970.0" y="2795.0"/> <glyph class="state variable" id="_9635ee72-c0dd-4b16-ab3d-eb520f3f3ea7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="965.0" y="2815.0"/> </glyph> <glyph class="unit of information" id="_9130373d-af7e-4824-91e4-f79402ab1f50"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="987.5" y="2790.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s11_sa11" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR3LD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. Recognition of Inhibitory HLA-B Allotypes (Bw4+) by the KIR NKB1 Alters Stimulatory Signal Transduction Pathways in NK Cells via inhibition of PI3K pathway and Ca2+ mobilization. Probably it acts via LAT inhibition.KIR recognition of inhibitory class I molecules disrupted the ability of pp36 (LAT) to associate with Grb2 in vitro. PTP-1C (SHP-1) activated by KIR3DL1 binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2. PMID:11994457 Tyrosine-phosphorylated KIR3DL1 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2, SHP-1.3DL1-mediated inhibition of cytotoxicity was abolished upon overexpression of SHP-1. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end</body> </html> </notes> <label text="KIR3DL1"/> <bbox w="80.0" h="50.0" x="1280.0" y="3215.0"/> <glyph class="state variable" id="_b9acf63a-983b-4564-92c2-c4e1171a4d67"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1275.0" y="3235.0"/> </glyph> <glyph class="unit of information" id="_01c935cd-b81e-4c33-9a29-73c62ff7db98"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1297.5" y="3210.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s13_sa13" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:LILRB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:15771571, PMID:10591185, PMID:9933109 LILRB1 binds with low afﬁnity to a conserved region in the α3 domain of essentially all HLA class I glycoproteins, including HLA-A, -B, -C, -E, -F, and -G. LILRB1 receptors on NK cells can suppress their activation (cytotoxicity) upon encountering HLA classI–bearing targets (demonstrated for HLA-G, only). References_end</body> </html> </notes> <label text="LILRB1"/> <bbox w="80.0" h="50.0" x="1630.0" y="3275.0"/> <glyph class="unit of information" id="_3f2333fa-d229-4403-929b-393cc98593aa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1647.5" y="3270.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s14_sa14" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KLRG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end</body> </html> </notes> <label text="KLRG1"/> <bbox w="80.0" h="50.0" x="540.0" y="2265.0"/> <glyph class="state variable" id="_e963ad58-7a53-43c2-a234-242c9df73d56"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="535.0" y="2285.0"/> </glyph> <glyph class="unit of information" id="_3f4b4b59-4dff-455c-809b-346979e13972"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="557.5" y="2260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s15_sa15" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:18159636 Transcription of the KLRB1 gene is suppressed in human cancer tissues PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:22378844, PMID:24227772 miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. IL15 and KLRB1 (NK1.1) ligation also induce MIR155 expression. References_end</body> </html> </notes> <label text="KLRB1"/> <bbox w="80.0" h="50.0" x="730.0" y="2135.0"/> <glyph class="unit of information" id="_c185b068-b535-4016-9652-4afc54e59ce9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="747.5" y="2130.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s22_sa22" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR2DS4 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:11390475, PMID:15265913 KIR2DS4 interacts with HLA-Cw4, but not with HLA-Cw6. Additionally it is involeved in MHC class I-independent recognition of target cells. KIR2DS4 signaling is involved in the killing of melanoma cells PMID:9521070 KIR2DS4 (NKAT8) signaling induces significant intracellular calcium mobilization, and phosphorylation of the MAP kinases ERK1 and ERK2.Recognition of HLA-Cw3 on target cells by NKAT8 resulted in enhanced cytotoxicity. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DS4"/> <bbox w="80.0" h="50.0" x="2580.0" y="3675.0"/> <glyph class="unit of information" id="_cc86ecf7-8898-48c2-8539-4841dfeec63f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2597.5" y="3670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s26_sa26" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CD226 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. DNAM-1 does not associate with any ITAM-bearing molecule but, after receptor crosslinking, its intracellular domain gets phosphorylated and delivers an intracellular signal. PKC induces phosphorylation of the Ser329 and probably FYN mediates phosphorylation of DNAM-1 at tyrosine residue 322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. References_end</body> </html> </notes> <label text="DNAM1*"/> <bbox w="80.0" h="50.0" x="6780.0" y="2065.0"/> <glyph class="state variable" id="_aaf92403-806d-45d5-971e-49013426ec9b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6775.0" y="2067.2046"/> </glyph> <glyph class="state variable" id="_b49fa84d-8f07-4777-94ec-b664a5681cef"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6775.0" y="2093.554"/> </glyph> <glyph class="unit of information" id="_01062354-93e1-41d7-a956-4b3e13af2b58"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6797.5" y="2060.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s35_sa35"> <notes> <html xmlns="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: HUGO:PCNA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611, PMID:22021614 Proliferating cell nuclear antigen (PCNA), which is overexpressed by cancer cells, has been reported as an inhibitory ligand of NKp44. References_end</body> </html> </notes> <label text="PCNA"/> <bbox w="80.0" h="40.0" x="2655.0" y="4265.0"/> </glyph> <glyph class="simple chemical" id="s39_sa40"> <notes> <html xmlns="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:NK Maps_Modules_end References_begin: PMID:23414611, PMID:19196184, PMID:15294952 Heparin is ligand of NKp30, NKp44 and Nkp46. The NCRs initiate tumor targeting by recognition of heparan sulfate on cancer cells. Tumor cells expressing cell surface heparanase or lacking membranal heparan manifest reduced recognition by NKp30 and NKp46 and are lysed to a lesser extent by NK cells. References_end</body> </html> </notes> <label text="Heparin"/> <bbox w="70.0" h="25.0" x="4745.0" y="4207.5"/> </glyph> <glyph class="macromolecule" id="s53_sa54" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SYK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9396765 Syk-dependent signaling plays a critical role in NK cytotoxicity. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:21149606, PMID:23609447 Syk kinase is part of the NKp80-signaling pathway, and phosphorylation of Syk requires integrity of the Y7-containing motif of NKp80. NKp80 activates PI33/ERK pathway probably via SYK. References_end</body> </html> </notes> <label text="SYK"/> <bbox w="80.0" h="40.0" x="5330.0" y="3130.0"/> <glyph class="state variable" id="_b82b7706-d915-4b9f-a1fd-67eb6e906fe5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5325.0" y="3145.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s56_sa56"> <notes> <html xmlns="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: HUGO:NCR3LG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611, PMID:19528259, PMID:19528259, PMID:23801635 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. References_end</body> </html> </notes> <label text="B7H6*"/> <bbox w="80.0" h="40.0" x="5110.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s57_sa57"> <notes> <html xmlns="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: HUGO:BAG6 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:23414611, PMID:18055229 BAG6 (BAT3) is a NKp30 ligand expressed on tumor cells. NKp30 recognises BAG6, which leads to NK cell killing of the tumour cell. References_end</body> </html> </notes> <label text="BAG6"/> <bbox w="80.0" h="40.0" x="5230.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s58_sa58"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:16106370,PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:20189481 NKG2D, 2B4 signalings induces Granzyme B release probaly via VAV1/ERK pathway PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. PMID:24248158 Hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="80.0" h="40.0" x="1950.0" y="4100.0"/> </glyph> <glyph class="macromolecule" id="s59_sa59"> <notes> <html xmlns="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: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:21350056, PMID:23906377 Human perforin is expressed in natural killer cells.NK cytotoxicity is mediated by the directed exocytosis of cytolytic granules to release perforins and granzymes, which perforate the target cell plasma cell membrane and trigger apoptosis, respectively. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="80.0" h="40.0" x="1760.0" y="4090.0"/> </glyph> <glyph class="complex" id="s61_csa1" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD247:NKp30* Identifiers_end</body> </html> </notes> <label text="s61"/> <bbox w="103.75" h="130.0" x="4556.25" y="3620.0"/> <glyph class="macromolecule" id="s65_sa17"> <notes> <html xmlns="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: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals. PMID:10562324 NKp30 is involeded in the Induction of natural cytotoxicity against tumor cells. References_end</body> </html> </notes> <label text="NKp30*"/> <bbox w="80.0" h="50.0" x="4573.75" y="3677.5"/> <glyph class="unit of information" id="_f9126612-9902-4ca3-807f-8d93dac6cd4d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4591.25" y="3672.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s66_sa45"> <notes> <html xmlns="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: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="4573.75" y="3637.5"/> <glyph class="state variable" id="_464a8d3e-fb32-4be1-8890-99ec97bb50e0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4568.75" y="3657.5"/> </glyph> <glyph class="unit of information" id="_fc9cd975-725e-4cdf-b511-8ba3b4e8f7f2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4591.25" y="3632.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s70_csa2" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD247:NKp30* Identifiers_end</body> </html> </notes> <label text="s61"/> <bbox w="120.0" h="140.0" x="4730.0" y="3430.0"/> <glyph class="macromolecule" id="s74_sa63"> <notes> <html xmlns="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: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals. PMID:10562324 NKp30 is involeded in the Induction of natural cytotoxicity against tumor cells. References_end</body> </html> </notes> <label text="NKp30*"/> <bbox w="80.0" h="50.0" x="4750.0" y="3495.0"/> <glyph class="unit of information" id="_75a41986-be4b-4b87-a436-a9cfa09db7e9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4767.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s75_sa64"> <notes> <html xmlns="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: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="4750.0" y="3455.0"/> <glyph class="state variable" id="_5e5a7a04-f45c-48e3-8622-52965ed3e21f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4742.5" y="3475.0"/> </glyph> <glyph class="unit of information" id="_b99789f3-82e6-4860-bdd4-359f18ff7396"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4767.5" y="3450.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s52_sa61" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:FYN Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:10591186, PMID:24440149 Cross-Linking of LFA-1 induces tyrosine Phosphorylation of DNAM-,FYN probably phosphorylates DNAM1 Y322 in NK cells PMID: PMID:22683124 Fyn-deficient NK cells exhibited defective killing. References_end</body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="4510.0" y="3090.0"/> <glyph class="state variable" id="_0ddcf2b1-795c-4863-98f4-a532bd6107d4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4502.5" y="3105.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s51_sa62" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LCK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:12740575 Src kinaze LCK participate in activation of NKG2D signaling and induction of PLCG phosphorylation, probably via DAP10 phosphorylation. PMID:9751747, PMID:8986721 LCK phosphorylates KIR receptors in NK cells downstream of HLA binding. PMID:22513334 Probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 in NK cells (demonstrated in T cells). PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK. References_end</body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="4300.0" y="3220.0"/> <glyph class="state variable" id="_e877baa0-a77a-41b9-9fb4-a30fe2b00f58"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4292.5" y="3235.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s84_sa68" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ZAP70 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:20814939, PMID:12731048 Phosphorylation of the ITAM sequence in the associated partner chains induces binding and phosphorylation of tyrosine kinases Syk and ZAP70 to the ITAM downstream of NKp30 or NKp46 or NKp44 References_end</body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="4940.0" y="3050.0"/> <glyph class="state variable" id="_ab72f493-e925-4811-b237-8fb6032b7e6e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4935.0" y="3065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s85_sa67" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SYK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9396765 Syk-dependent signaling plays a critical role in NK cytotoxicity. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:21149606, PMID:23609447 Syk kinase is part of the NKp80-signaling pathway, and phosphorylation of Syk requires integrity of the Y7-containing motif of NKp80. NKp80 activates PI33/ERK pathway probably via SYK. References_end</body> </html> </notes> <label text="SYK"/> <bbox w="80.0" h="40.0" x="5330.0" y="3000.0"/> <glyph class="state variable" id="_e1b22dde-b441-4cd4-b662-3e593e455393"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5322.5" y="3015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s86_sa55" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ZAP70 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:20814939, PMID:12731048 Phosphorylation of the ITAM sequence in the associated partner chains induces binding and phosphorylation of tyrosine kinases Syk and ZAP70 to the ITAM downstream of NKp30 or NKp46 or NKp44 References_end</body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="4940.0" y="2970.0"/> <glyph class="state variable" id="_1079aa3c-85f2-4640-bfa2-e16ef43e1c63"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4932.5" y="2985.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s744_sa71" compartmentRef="c7_ca7"> <notes> <html xmlns="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:NK Maps_Modules_end References_begin: PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. References_end</body> </html> </notes> <label text="PIP2*"/> <bbox w="70.0" h="25.0" x="5655.0" y="2597.5"/> </glyph> <glyph class="simple chemical" id="s745_sa72" compartmentRef="c7_ca7"> <notes> <html xmlns="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:NK Maps_Modules_end References_begin: PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:9438848 PI3K product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav proteins PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. References_end</body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="5655.0" y="2507.5"/> </glyph> <glyph class="macromolecule" id="s91_sa77" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK3 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 GENECARDS:MAPK3 HUGO:MAPK1 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 GENECARDS:MAPK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 PMID:17395718, PMID:11062502, PMID: 15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:21149606 NKp80 activates PI33/ERK pathway probably via SYK. PMID:22786724 DNAM1 induces ERK pathway probably via VAV1. PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. PMID:10903731 IL18 signaling induces activation of ERK1/2 kinases. The cytolytic activity of NK cells downstream of IL18 is inhibited by ERK inhibitors. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. PMID:11489965, PMID:10843677 The IFN-γ secretion by NK cells induced by IL-2 depends on an ERK mitogen-activated protein kinase pathway. IL-2 activation of an MKK/ERK pathway is required for NK cells to acquire enhanced cytolytic function (LAK activity). IL-2-driven IFN-γ secretion and induction of CD25 and CD69 (CLEC2C) activation markers require intact MKK/ERK pathway. PMID: PMID:9862693 CD16-induced ERK activation provides IFN-γ mRNA accumulation and ADCC and spontaneous cytotoxicity of NK cells PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 PMID:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells. PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. References_end</body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="3960.0" y="2150.0"/> <glyph class="state variable" id="_84b77e97-736d-48fb-b026-281d452d9d41"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3955.0" y="2165.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s92_sa78" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK3 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 GENECARDS:MAPK3 HUGO:MAPK1 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 GENECARDS:MAPK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 PMID:17395718, PMID:11062502, PMID: 15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:21149606 NKp80 activates PI33/ERK pathway probably via SYK. PMID:22786724 DNAM1 induces ERK pathway probably via VAV1. PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. PMID:10903731 IL18 signaling induces activation of ERK1/2 kinases. The cytolytic activity of NK cells downstream of IL18 is inhibited by ERK inhibitors. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. PMID:11489965, PMID:10843677 The IFN-γ secretion by NK cells induced by IL-2 depends on an ERK mitogen-activated protein kinase pathway. IL-2 activation of an MKK/ERK pathway is required for NK cells to acquire enhanced cytolytic function (LAK activity). IL-2-driven IFN-γ secretion and induction of CD25 and CD69 (CLEC2C) activation markers require intact MKK/ERK pathway. PMID: PMID:9862693 CD16-induced ERK activation provides IFN-γ mRNA accumulation and ADCC and spontaneous cytotoxicity of NK cells PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 PMID:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells. PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. References_end</body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="3960.0" y="2060.0"/> <glyph class="state variable" id="_e7665cd0-80fd-4a06-9675-68d7f5b9e1a0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3952.5" y="2075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s93_sa79" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAP2K1 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 GENECARDS:MAP2K1 HUGO:MAP2K2 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 GENECARDS:MAP2K2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:59503 KEGG:5604 ATLASONC:GC_MAP2K1 WIKI:MAP2K1 REACTOME:59505 KEGG:5605 ATLASONC:GC_MAP2K2 WIKI:MAP2K2 PMID:17395718, PMID:11062502, PMID: 15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:10843677 IL2 activates MEK (MKK)/ERK pathway in NK cells. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. PMID:11034387 MAPK activation in NK cells resulted in lysis is Ras-independent. References_end</body> </html> </notes> <label text="MEK*"/> <bbox w="80.0" h="40.0" x="4110.0" y="2100.0"/> <glyph class="state variable" id="_2e6e8fcd-e1cc-4d35-a970-1d1358156721"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4102.5" y="2114.9683"/> </glyph> </glyph> <glyph class="complex" id="s94_csa4" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GDP:RAC1 Identifiers_end</body> </html> </notes> <label text="s94"/> <bbox w="100.0" h="115.0" x="4550.0" y="2242.5"/> <glyph class="macromolecule" id="s95_sa81"> <notes> <html xmlns="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: HUGO:RAC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. References_end</body> </html> </notes> <label text="RAC1"/> <bbox w="80.0" h="40.0" x="4560.0" y="2250.0"/> </glyph> <glyph class="simple chemical" id="s96_sa82"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="4568.75" y="2299.375"/> </glyph> </glyph> <glyph class="complex" id="s97_csa5" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GTP:RAC1 Identifiers_end</body> </html> </notes> <label text="s94"/> <bbox w="90.0" h="105.0" x="4365.0" y="2247.5"/> <glyph class="macromolecule" id="s98_sa83"> <notes> <html xmlns="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: HUGO:RAC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. References_end</body> </html> </notes> <label text="RAC1"/> <bbox w="80.0" h="40.0" x="4375.0" y="2255.0"/> </glyph> <glyph class="simple chemical" id="s99_sa85"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="4380.0" y="2300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s90_sa76" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAP2K1 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 GENECARDS:MAP2K1 HUGO:MAP2K2 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 GENECARDS:MAP2K2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:59503 KEGG:5604 ATLASONC:GC_MAP2K1 WIKI:MAP2K1 REACTOME:59505 KEGG:5605 ATLASONC:GC_MAP2K2 WIKI:MAP2K2 PMID:17395718, PMID:11062502, PMID: 15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:10843677 IL2 activates MEK (MKK)/ERK pathway in NK cells. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. PMID:11034387 MAPK activation in NK cells resulted in lysis is Ras-independent. References_end</body> </html> </notes> <label text="MEK*"/> <bbox w="80.0" h="40.0" x="4110.0" y="2170.0"/> <glyph class="state variable" id="_b7f54231-6d02-4c3a-b697-ad7a9d222932"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4105.0" y="2184.9683"/> </glyph> </glyph> <glyph class="complex" id="s747_csa6" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD247:FCER1G:NKp46* Identifiers_end</body> </html> </notes> <label text="s747"/> <bbox w="200.0" h="160.0" x="4920.0" y="3540.0"/> <glyph class="macromolecule" id="s749_sa16"> <notes> <html xmlns="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: HUGO:NCR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . Ncr1 knockout mice exhibit an increase in tumour metastasis. PMID:22267813 NK cells with defective cell-surface expression of NKp46 are hyperreactive in responses to the prototypic NK cell tumor target cell line. But Ncr1 knockout mice have been reported to be highly susceptible to the infections. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="NKp46*"/> <bbox w="80.0" h="50.0" x="4977.5" y="3615.0"/> <glyph class="unit of information" id="_2910b138-cd54-424a-b7f7-97b047236b66"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4995.0" y="3610.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s750_sa41"> <notes> <html xmlns="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: HUGO:FCER1G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . References_end</body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="4940.0" y="3565.0"/> <glyph class="state variable" id="_a61d749c-b947-4c14-97ef-49b36c43159f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4935.0" y="3585.0"/> </glyph> <glyph class="unit of information" id="_e12f0f7c-c79b-4128-be73-0cf2b191b6b2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4957.5" y="3560.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s751_sa42"> <notes> <html xmlns="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: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="5020.0" y="3565.0"/> <glyph class="state variable" id="_fb0880d5-59cd-490e-8b1a-0ecfada13cec"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5015.0" y="3585.0"/> </glyph> <glyph class="unit of information" id="_7bc18007-fcbb-40a6-8716-95dbbfbe6743"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5037.5" y="3560.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s752_csa7" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD247:FCER1G:NKp46* Identifiers_end</body> </html> </notes> <label text="s747"/> <bbox w="200.0" h="160.0" x="5120.0" y="3360.0"/> <glyph class="macromolecule" id="s753_sa108"> <notes> <html xmlns="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: HUGO:NCR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . Ncr1 knockout mice exhibit an increase in tumour metastasis. PMID:22267813 NK cells with defective cell-surface expression of NKp46 are hyperreactive in responses to the prototypic NK cell tumor target cell line. But Ncr1 knockout mice have been reported to be highly susceptible to the infections. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="NKp46*"/> <bbox w="80.0" h="50.0" x="5177.5" y="3435.0"/> <glyph class="unit of information" id="_4ba142bc-8e79-45f6-8270-756d3ab6b5c7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5195.0" y="3430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s755_sa109"> <notes> <html xmlns="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: HUGO:FCER1G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . References_end</body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="5140.0" y="3385.0"/> <glyph class="state variable" id="_af0a1a31-41c3-46b0-b794-928e5282e36e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5135.0" y="3405.0"/> </glyph> <glyph class="unit of information" id="_e34c2015-a2df-4b46-810c-38430fe0927e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5157.5" y="3380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s756_sa110"> <notes> <html xmlns="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: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="5220.0" y="3385.0"/> <glyph class="state variable" id="_6092d040-3293-4438-9f4f-0fc08ae0eb3a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5212.5" y="3405.0"/> </glyph> <glyph class="unit of information" id="_272523bb-90be-4ca1-9bae-42f34c985187"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5237.5" y="3380.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s757_sa111" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GRB2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16887996, PMID:16582911 Vav1 interacts with DAP10 YxNM motifs through the adaptor protein Grb2 and is required for activation of PI3K-dependent Akt signaling. binding of DAP10‭ ‬to either p85‭ ‬or Grb2‭ ‬alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 References_end</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="5540.0" y="3060.0"/> </glyph> <glyph class="macromolecule" id="s758_sa112" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575, PMID:16887996 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:20189481, PMID:22786724 NKG2D, DNAM1, 2B4 signalings induce PLCG2 phosphorylation and Ca2+ release via LCP2/VAV1 pathway. CBL inhibited Vav1-dependent activation signals in NK. Vav-deficient NK cells exhibited nearly abolished conjugate formation and cytotoxicity toward target cells. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1 (probably via LCP2),CBL. This phosphorylation is dependent on SAP adn FYN. PMID: PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Vav1 phosphorylation is induced by beta2 integrin (CD18)engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization References_end</body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="4490.0" y="2590.0"/> <glyph class="state variable" id="_c24ea4cc-eae8-4602-b475-525756603301"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4485.0" y="2605.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s759_sa113" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LCP2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:24343663, PMID:22786724, PMID:20189481 Selective phosphorylation of tyrosine 113 or tyrosine 128 in LCP2 (SLP-76) enabled binding of SLP-76 to Vav1 and induces downstream of NKG2D and 2B4 receptors and DNAM1. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs. References_end</body> </html> </notes> <label text="LCP2"/> <bbox w="80.0" h="40.0" x="5100.0" y="3050.0"/> <glyph class="state variable" id="_afbd89c9-c812-4eea-94e1-3d7642241221"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5095.0" y="3065.0"/> </glyph> </glyph> <glyph class="complex" id="s762_csa8" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP12*:NKp44* Identifiers_end References_begin: PMID:9625766 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12 References_end</body> </html> </notes> <label text="s762"/> <bbox w="100.0" h="150.0" x="2850.0" y="3425.0"/> <glyph class="macromolecule" id="s765_sa43"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="2860.0" y="3440.0"/> <glyph class="state variable" id="_e5cd5bb3-97be-4464-b513-4dca6b238e8b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2855.0" y="3460.0"/> </glyph> <glyph class="unit of information" id="_f261bd12-2039-4957-bdab-a9872f6829c1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2877.5" y="3435.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1103_sa116"> <notes> <html xmlns="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: HUGO:NCR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs. PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals. in contrast to NKp30, the expression of NKp44 on NK cells is detected only after activation. PMID:9625766 IL2‭ ‬stimulates NKp44‭ ‬surface expression in NK cells. ‭(‬NKp44‭) ‬that is absent in freshly isolated peripheral blood lymphocytes but is progressively expressed by all NK cells in vitro after culture in IL-2. References_end</body> </html> </notes> <label text="NKp44*"/> <bbox w="80.0" h="50.0" x="2860.0" y="3485.0"/> <glyph class="unit of information" id="_c73df1c7-b784-42ee-aa22-71ef25520824"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2877.5" y="3480.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s766_csa9" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP12*:NKp44* Identifiers_end</body> </html> </notes> <label text="s762"/> <bbox w="100.0" h="150.0" x="3010.0" y="3425.0"/> <glyph class="macromolecule" id="s1102_sa36"> <notes> <html xmlns="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: HUGO:NCR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs. PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals. in contrast to NKp30, the expression of NKp44 on NK cells is detected only after activation. PMID:9625766 IL2‭ ‬stimulates NKp44‭ ‬surface expression in NK cells. ‭(‬NKp44‭) ‬that is absent in freshly isolated peripheral blood lymphocytes but is progressively expressed by all NK cells in vitro after culture in IL-2. References_end</body> </html> </notes> <label text="NKp44*"/> <bbox w="80.0" h="50.0" x="3020.0" y="3485.0"/> <glyph class="unit of information" id="_7fff0f01-4b5a-4b21-a68b-a8b14dc93129"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3037.5" y="3480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s768_sa117"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="3020.0" y="3440.0"/> <glyph class="state variable" id="_845a870d-92ad-4119-9b1b-6689f3a5139a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3012.5" y="3460.0"/> </glyph> <glyph class="unit of information" id="_010851b3-72ad-4fc1-9803-fd7aecb303eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3037.5" y="3435.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s769_sa118"> <notes> <html xmlns="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: HUGO:KMT2E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23958951 NKp44L is a novel isoform of the mixed-lineage leukemia-5 protein, a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. References_end</body> </html> </notes> <label text="NKp44L*"/> <bbox w="80.0" h="40.0" x="2810.0" y="4260.0"/> <glyph class="unit of information" id="_2750fa49-bbf5-4f92-bb0b-a6f89a06b03d"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2825.0" y="4255.0"/> </glyph> </glyph> <glyph class="complex" id="s771_csa10" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP10:NKG2D* Identifiers_end</body> </html> </notes> <label text="s771"/> <bbox w="110.0" h="140.0" x="3635.0" y="3430.0"/> <glyph class="macromolecule" id="s773_sa20"> <notes> <html xmlns="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: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:17100878 NKG2D plays a major role in triggering cytotoxicity against target cells, such as the murine lymphoma line YAC-1. NKG2D detects cell surface molecules distantly related to MHC class I proteins, which are induced by viral infection and tumor transformation. As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="NKG2D*"/> <bbox w="80.0" h="50.0" x="3645.0" y="3495.0"/> <glyph class="unit of information" id="_fe81d3af-edec-4315-9a18-93bc58adaee6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3662.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s774_sa107"> <notes> <html xmlns="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: HUGO:DAP10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: PMID:17100878 As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. YINM motif of DAP10 functions as docking site for PI3K, which represents the major effector molecule downstream of NKG2D. PMID:10426994, PMID:16582911 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. Binding of DAP10 to either p85 or Grb2 alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. References_end</body> </html> </notes> <label text="DAP10"/> <bbox w="80.0" h="50.0" x="3645.0" y="3445.0"/> <glyph class="state variable" id="_7c09173a-ea81-4964-94a9-af25326c8d0a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3640.0" y="3465.0"/> </glyph> <glyph class="unit of information" id="_fe385524-b6cb-4861-bb7a-4fb454361d56"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3662.5" y="3440.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s780_sa126"> <notes> <html xmlns="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: HUGO:MICA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end</body> </html> </notes> <label text="MICA"/> <bbox w="80.0" h="40.0" x="3650.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s781_sa127"> <notes> <html xmlns="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: HUGO:MICB Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end</body> </html> </notes> <label text="MICB"/> <bbox w="80.0" h="40.0" x="3770.0" y="4240.0"/> </glyph> <glyph class="complex" id="s782_csa11" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP10:GRB2:NKG2D* Identifiers_end</body> </html> </notes> <label text="s771"/> <bbox w="115.0" h="190.0" x="3942.5" y="3465.0"/> <glyph class="macromolecule" id="s783_sa120"> <notes> <html xmlns="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: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:17100878 NKG2D plays a major role in triggering cytotoxicity against target cells, such as the murine lymphoma line YAC-1. NKG2D detects cell surface molecules distantly related to MHC class I proteins, which are induced by viral infection and tumor transformation. As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="NKG2D*"/> <bbox w="80.0" h="50.0" x="3952.5" y="3580.0"/> <glyph class="unit of information" id="_419e1a92-fdf8-4b4a-a8b4-3ee9e4d213a1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3970.0" y="3575.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s784_sa121"> <notes> <html xmlns="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: HUGO:DAP10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: PMID:17100878 As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. YINM motif of DAP10 functions as docking site for PI3K, which represents the major effector molecule downstream of NKG2D. PMID:10426994, PMID:16582911 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. Binding of DAP10 to either p85 or Grb2 alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. References_end</body> </html> </notes> <label text="DAP10"/> <bbox w="80.0" h="50.0" x="3952.5" y="3530.0"/> <glyph class="state variable" id="_0df69ea4-cc49-4ef2-8a96-6dd946f07152"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3945.0" y="3550.0"/> </glyph> <glyph class="unit of information" id="_fa619f9c-c831-423c-9000-df9ff49434f2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3970.0" y="3525.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s786_sa129"> <notes> <html xmlns="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: HUGO:GRB2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16887996, PMID:16582911 Vav1 interacts with DAP10 YxNM motifs through the adaptor protein Grb2 and is required for activation of PI3K-dependent Akt signaling. binding of DAP10‭ ‬to either p85‭ ‬or Grb2‭ ‬alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 References_end</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="3950.0" y="3480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s787_sa128" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575, PMID:16887996 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:20189481, PMID:22786724 NKG2D, DNAM1, 2B4 signalings induce PLCG2 phosphorylation and Ca2+ release via LCP2/VAV1 pathway. CBL inhibited Vav1-dependent activation signals in NK. Vav-deficient NK cells exhibited nearly abolished conjugate formation and cytotoxicity toward target cells. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1 (probably via LCP2),CBL. This phosphorylation is dependent on SAP adn FYN. PMID: PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Vav1 phosphorylation is induced by beta2 integrin (CD18)engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization References_end</body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="4492.5" y="2495.0"/> <glyph class="state variable" id="_070c1558-d3db-4c2e-a05e-9dbee2a31a5b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4485.0" y="2510.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s789_sa131" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LCP2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:24343663, PMID:22786724, PMID:20189481 Selective phosphorylation of tyrosine 113 or tyrosine 128 in LCP2 (SLP-76) enabled binding of SLP-76 to Vav1 and induces downstream of NKG2D and 2B4 receptors and DNAM1. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs. References_end</body> </html> </notes> <label text="LCP2"/> <bbox w="80.0" h="40.0" x="5100.0" y="2960.0"/> <glyph class="state variable" id="_088d8b63-5063-47db-bd25-023672840d46"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5092.5" y="2975.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s406_sa136" compartmentRef="c7_ca7"> <notes> <html xmlns="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>References_begin: PMID:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 References_end</body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="4765.0" y="2137.5"/> </glyph> <glyph class="simple chemical" id="s405_sa138" compartmentRef="c7_ca7"> <label text="PI4,5-P2"/> <bbox w="70.0" h="25.0" x="4825.0" y="2217.5"/> </glyph> <glyph class="simple chemical" id="s397_sa139" compartmentRef="c7_ca7"> <notes> <html xmlns="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>References_begin: PMID:18287025 PLCG is upstream of JNK in the pathway of NKG2D-mediated cytotoxicity PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. References_end</body> </html> </notes> <label text="IP3"/> <bbox w="70.0" h="25.0" x="4835.0" y="2067.5"/> </glyph> <glyph class="macromolecule" id="s398_sa140" compartmentRef="c5_ca5"> <notes> <html xmlns="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: HUGO:ITPR1 HGNC:6180 ENTREZ:3708 UNIPROT:Q14643 GENECARDS:ITPR1 HUGO:ITPR2 HGNC:6181 ENTREZ:3709 UNIPROT:Q14571 GENECARDS:ITPR2 HUGO:ITPR3 HGNC:6182 ENTREZ:3710 UNIPROT:Q14573 GENECARDS:ITPR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: inositol 1,4,5-trisphosphate receptor, type 1 SCA15, SCA16, “spinocerebellar ataxia 15″, “spinocerebellar ataxia 16″ REACTOME:405731 KEGG:3708 ATLASONC:GC_ITPR1 WIKI:ITPR1 inositol 1,4,5-trisphosphate receptor, type 2 “inositol 1,4,5-triphosphate receptor, type 2″ REACTOME:405722 KEGG:3709 ATLASONC:GC_ITPR2 WIKI:ITPR2 inositol 1,4,5-trisphosphate receptor, type “inositol 1,4,5-triphosphate receptor, type 3″ REACTOME:57433 KEGG:3710 ATLASONC:GC_ITPR3 WIKI:ITPR3 PMID:7890616 PCL (probably PCLG1) induces hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end</body> </html> </notes> <label text="IP3R*"/> <bbox w="80.0" h="50.0" x="4920.0" y="1925.0"/> <glyph class="unit of information" id="_5eb7eeca-808c-42b6-abca-a9f4f2aeeb9a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4937.5" y="1920.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s791_sa142" compartmentRef="c7_ca7"> <notes> <html xmlns="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>References_begin: PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PMID:12740575, PMID:15972651 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release. The calcium signal generated by PLCG is required for NKG2D-initiated killing. Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 References_end</body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="5127.5" y="1857.5"/> </glyph> <glyph class="complex" id="s632_csa13" compartmentRef="c5_ca5"> <notes> <html xmlns="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: NAME:IP3:IP3R* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end</body> </html> </notes> <label text="IP3:IP3R*"/> <bbox w="86.0" h="115.0" x="5027.0" y="1912.5"/> <glyph class="macromolecule" id="s404_sa145"> <notes> <html xmlns="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: HUGO:ITPR1 HGNC:6180 ENTREZ:3708 UNIPROT:Q14643 GENECARDS:ITPR1 HUGO:ITPR2 HGNC:6181 ENTREZ:3709 UNIPROT:Q14571 GENECARDS:ITPR2 HUGO:ITPR3 HGNC:6182 ENTREZ:3710 UNIPROT:Q14573 GENECARDS:ITPR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: inositol 1,4,5-trisphosphate receptor, type 1 SCA15, SCA16, “spinocerebellar ataxia 15″, “spinocerebellar ataxia 16″ REACTOME:405731 KEGG:3708 ATLASONC:GC_ITPR1 WIKI:ITPR1 inositol 1,4,5-trisphosphate receptor, type 2 “inositol 1,4,5-triphosphate receptor, type 2″ REACTOME:405722 KEGG:3709 ATLASONC:GC_ITPR2 WIKI:ITPR2 inositol 1,4,5-trisphosphate receptor, type “inositol 1,4,5-triphosphate receptor, type 3″ REACTOME:57433 KEGG:3710 ATLASONC:GC_ITPR3 WIKI:ITPR3 PMID:7890616 PCL (probably PCLG1) induces hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end</body> </html> </notes> <label text="IP3R*"/> <bbox w="80.0" h="50.0" x="5029.125" y="1958.0"/> <glyph class="unit of information" id="_c247a1b5-8d71-4037-b5e2-8ca3bc6900a9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5046.625" y="1953.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s403_sa146"> <label text="IP3"/> <bbox w="70.0" h="25.0" x="5034.125" y="1934.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s793_sa147" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLCG2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575, PMID:15972651, PMID:20189481 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release via VAV1. The calcium signal generated by PLCG is required for NKG2D-initiated killing. PMID:20189481, PMID:22786724, PMID:20189481 DNAM1 signaling stimulate Ca2+ mobilization provably via VAV1/PLC-GAMMA2 pathway in NK cells, PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:11169415, PMID:10072481, PMID:8649391, PMID:1281218 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. References_end</body> </html> </notes> <label text="PLCG2"/> <bbox w="80.0" h="40.0" x="4760.0" y="2370.0"/> <glyph class="state variable" id="_e6f27ad3-1910-4d9b-a00e-680af29eee81"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4755.0" y="2385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s794_sa148" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLCG2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575, PMID:15972651, PMID:20189481 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release via VAV1. The calcium signal generated by PLCG is required for NKG2D-initiated killing. PMID:20189481, PMID:22786724, PMID:20189481 DNAM1 signaling stimulate Ca2+ mobilization provably via VAV1/PLC-GAMMA2 pathway in NK cells, PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:11169415, PMID:10072481, PMID:8649391, PMID:1281218 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. References_end</body> </html> </notes> <label text="PLCG2"/> <bbox w="80.0" h="40.0" x="4760.0" y="2260.0"/> <glyph class="state variable" id="_3f64a17e-44be-486c-8169-27bc38a2ade7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4752.5" y="2275.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s795_sa149"> <notes> <html xmlns="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: HUGO:GZMA Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:16106370, PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11413196, PMID:11413196 VAV1 induces granule exocytosis of granzyme A probably via RAC1-ERK pathway. The absence of Vav1 results in defective granule exocytosis and reduced ability to lyse tumor targets. References_end</body> </html> </notes> <label text="GZMA"/> <bbox w="80.0" h="40.0" x="2060.0" y="3840.0"/> </glyph> <glyph class="macromolecule" id="s396_sa150" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. References_end</body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="4890.0" y="2370.0"/> <glyph class="state variable" id="_cb6db958-f896-4a7c-9150-8f3319d36156"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4885.0" y="2385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s408_sa151" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. References_end</body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="4890.0" y="2260.0"/> <glyph class="state variable" id="_6a5126c2-71dc-4d3b-9e7d-17ae860a01a5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4882.5" y="2275.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s796_sa152"> <notes> <html xmlns="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: HUGO:RAET1E Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:12732206 RAET1E (ULBP4) is a ligand of NKG2D. References_end</body> </html> </notes> <label text="RAET1E"/> <bbox w="80.0" h="40.0" x="3520.0" y="4180.0"/> </glyph> <glyph class="macromolecule" id="s797_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>Identifiers_begin: HUGO:ULBP1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end</body> </html> </notes> <label text="ULBP1"/> <bbox w="80.0" h="40.0" x="3880.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s798_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>Identifiers_begin: HUGO:ULBP2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end</body> </html> </notes> <label text="ULBP2"/> <bbox w="80.0" h="40.0" x="3990.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s799_sa155"> <notes> <html xmlns="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: HUGO:ULBP3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end</body> </html> </notes> <label text="ULBP3"/> <bbox w="80.0" h="40.0" x="4090.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s801_sa158" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:NCR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs. PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals. in contrast to NKp30, the expression of NKp44 on NK cells is detected only after activation. PMID:9625766 IL2‭ ‬stimulates NKp44‭ ‬surface expression in NK cells. ‭(‬NKp44‭) ‬that is absent in freshly isolated peripheral blood lymphocytes but is progressively expressed by all NK cells in vitro after culture in IL-2. References_end</body> </html> </notes> <label text="NKp44*"/> <bbox w="80.0" h="50.0" x="2790.0" y="3335.0"/> <glyph class="unit of information" id="_fa86c820-ed52-4450-93f3-39e773a830fa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2807.5" y="3330.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s802_sa159" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs. References_end</body> </html> </notes> <label text="NKp44"/> <bbox w="70.0" h="25.0" x="2785.0" y="3167.5"/> </glyph> <glyph class="nucleic acid feature" id="s803_sa160" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs. References_end</body> </html> </notes> <label text="NKp44"/> <bbox w="90.0" h="25.0" x="2775.0" y="3237.5"/> <glyph class="unit of information" id="_46c56b4c-981b-42ce-91b8-9ad02b9f4746"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2810.0" y="3232.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s742_sa163" compartmentRef="c7_ca7"> <notes> <html xmlns="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>References_begin: PMID:16713974 TLR2 activates (induses phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAPK8 HUGO:MAPK9 HUGO:MAPK10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18287025 JNK is localized to the centrosome. JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. Inhibition of JNK activity by D-JNK-1, SP600125, Or JNK-1-specific siRNA blocked polarization of granzyme B, PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. References_end</body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="4110.0" y="1360.0"/> <glyph class="state variable" id="_350d4527-2fd5-4541-ae43-ff8760f4812e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4105.0" y="1375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s805_sa164" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK8 HUGO:MAPK9 HUGO:MAPK10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18287025 JNK is localized to the centrosome. JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. Inhibition of JNK activity by D-JNK-1, SP600125, Or JNK-1-specific siRNA blocked polarization of granzyme B, PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. 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PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. 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PMID:16887996 Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. References_end</body> </html> </notes> <label text="MTOC"/> <bbox w="220.625" h="313.125" x="2269.6875" y="2373.4375"/> <glyph class="macromolecule" id="s850_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>Identifiers_begin: HUGO:PXN Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. 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References_end</body> </html> </notes> <label text="TUBGCP6"/> <bbox w="80.0" h="40.0" x="2390.3125" y="2486.5625"/> </glyph> <glyph class="macromolecule" id="s843_sa186"> <notes> <html xmlns="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: HUGO:TUBGCP5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins. References_end</body> </html> </notes> <label text="TUBGCP5"/> <bbox w="80.0" h="40.0" x="2390.3125" y="2446.5625"/> </glyph> <glyph class="macromolecule" id="s844_sa185"> <notes> <html xmlns="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: HUGO:TUBGCP4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins. References_end</body> </html> </notes> <label text="TUBGCP4"/> <bbox w="80.0" h="40.0" x="2290.3125" y="2486.5625"/> </glyph> <glyph class="macromolecule" id="s845_sa184"> <notes> <html xmlns="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: HUGO:TUBGCP3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins. References_end</body> </html> </notes> <label text="TUBGCP3"/> <bbox w="80.0" h="40.0" x="2290.3125" y="2446.5625"/> </glyph> <glyph class="macromolecule" id="s846_sa183"> <notes> <html xmlns="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: HUGO:TUBGCP2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins. References_end</body> </html> </notes> <label text="TUBGCP2"/> <bbox w="80.0" h="40.0" x="2296.5625" y="2404.0625"/> </glyph> <glyph class="macromolecule" id="s847_sa182"> <notes> <html xmlns="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: HUGO:TUBG1 HUGO:TUBG2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins. References_end</body> </html> </notes> <label text="Tubulin-γ*"/> <bbox w="80.0" h="40.0" x="2390.3125" y="2406.5625"/> </glyph> </glyph> <glyph class="phenotype" id="s837_sa192" compartmentRef="c6_ca6"> <notes> <html xmlns="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>References_begin: PMID:14612578 In NK cells actin and microtubule polymerization are required for cytotoxic function. References_end</body> </html> </notes> <label text="Granules exocytosis"/> <bbox w="160.0" h="45.0" x="2150.0" y="3347.5"/> </glyph> <glyph class="macromolecule" id="s856_sa212" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LIMK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. FcR-initiated LIMK1 phosphorylation was absent in the NK clones that had been treated with p160ROCK kinase inhibitor. Inhibition of the RhoA/p160ROCK/LIMK1 signaling pathway abrogates lipid raft polarization to the effector-target interface References_end</body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="3240.0" y="2270.0"/> <glyph class="state variable" id="_6623713a-4fae-4b63-8c9b-3140bc48f259"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3235.0" y="2285.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s857_sa213" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CFL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. LIMK1 phosphorylates CLF1 (cofilin) downstream of killer cell-activating receptors via RHOA/ROCK1 pathway. Inhibition of the p160ROCK/LIMK1 pathway results in decreased actin polymerization at the effector/target interface. References_end</body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="3060.0" y="2330.0"/> <glyph class="state variable" id="_a13ac7da-9f33-4431-9051-0a744f58bb3c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3055.0" y="2345.0"/> </glyph> </glyph> <glyph class="phenotype" id="s858_sa214" compartmentRef="c7_ca7"> <notes> <html xmlns="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>References_begin: PMID:14612578 In NK cells actin and microtubule polymerization are required for cytotoxic function. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. References_end</body> </html> </notes> <label text="Actin polymerization"/> <bbox w="160.0" h="35.0" x="2800.0" y="2482.5"/> </glyph> <glyph class="macromolecule" id="s860_sa216" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ACTB HUGO:ACTG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11698448 Inhibition of the p160ROCK/LIMK1 pathway results in decreased actin polymerization at the effector/target interface via cofilin inhibition. PMID:17395718 NKG2D regulates actin polymerization and cytotoxicity, probably via RHOA/ROCK/LIMK1 pathway in NK cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. References_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="130.0" h="50.0" x="2815.0" y="2275.0"/> </glyph> <glyph class="macromolecule" id="s861_sa218" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LIMK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. FcR-initiated LIMK1 phosphorylation was absent in the NK clones that had been treated with p160ROCK kinase inhibitor. Inhibition of the RhoA/p160ROCK/LIMK1 signaling pathway abrogates lipid raft polarization to the effector-target interface References_end</body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="3240.0" y="2370.0"/> <glyph class="state variable" id="_66457dbc-9008-49d0-a48c-e52e80742358"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3232.5" y="2385.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s862_sa220" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ACTB HUGO:ACTG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11698448 Inhibition of the p160ROCK/LIMK1 pathway results in decreased actin polymerization at the effector/target interface via cofilin inhibition. PMID:17395718 NKG2D regulates actin polymerization and cytotoxicity, probably via RHOA/ROCK/LIMK1 pathway in NK cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. References_end</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="136.0" h="56.0" x="2812.0" y="2382.0"/> <glyph class="unit of information" id="_6ca6a727-c37d-4c75-85d6-cd2f9c64f47e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2870.0" y="2377.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s863_sa219" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CFL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. LIMK1 phosphorylates CLF1 (cofilin) downstream of killer cell-activating receptors via RHOA/ROCK1 pathway. Inhibition of the p160ROCK/LIMK1 pathway results in decreased actin polymerization at the effector/target interface. References_end</body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="3060.0" y="2410.0"/> <glyph class="state variable" id="_b065352a-4cd9-497d-be42-da80cef6d072"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3052.5" y="2425.0"/> </glyph> </glyph> <glyph class="phenotype" id="s864_sa222" compartmentRef="c6_ca6"> <label text="Lipid raft polarization"/> <bbox w="190.0" h="35.0" x="2475.0" y="3322.5"/> </glyph> <glyph class="macromolecule" id="s865_sa939" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:WAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15001467, PMID:14707117 CD16 or ITGB2 (CD18) stimulation resulted in the induction of WASp tyrosine phosphorylation in NK cells, probubly by Fyn. Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation in T cells. PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. It binds actin monomers as well as the actin-related protein (ARP) 2/3 complex to catalyze branching of filamentous actin (F-actin) PMID:16606694 WIPF1 forms complex with WASP. References_end</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="3000.0" y="1850.0"/> <glyph class="state variable" id="_ca219b1c-359b-40f1-84c5-ff0df350e6fd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2995.0" y="1865.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s867_sa224" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TRIP10 Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:17785506 Cdc42-interacting protein-4 (CIP4) - TRIP10 is able to associate with Wiskott-Aldrich syndrome protein (WASp) and the actin filament-rich IS. WASP is needful for TRIP10 activation. CIP4 in NK provides cell cytotoxicity and MTOC polarization but not F-actin accumulation. TRIP10 (CIP4) functions downstream of Cdc42 to induce MTOC polarization to the IS and cytotoxicity. References_end</body> </html> </notes> <label text="TRIP10"/> <bbox w="80.0" h="40.0" x="2500.0" y="2050.0"/> </glyph> <glyph class="complex" id="s868_csa24" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:TRIP10:WASP* Identifiers_end</body> </html> </notes> <label text="s868"/> <bbox w="105.0" h="140.0" x="2557.5" y="2410.0"/> <glyph class="macromolecule" id="s1691_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:WAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15001467, PMID:14707117 CD16 or ITGB2 (CD18) stimulation resulted in the induction of WASp tyrosine phosphorylation in NK cells, probubly by Fyn. Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation in T cells. PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. It binds actin monomers as well as the actin-related protein (ARP) 2/3 complex to catalyze branching of filamentous actin (F-actin) PMID:16606694 WIPF1 forms complex with WASP. References_end</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="2567.5" y="2470.0"/> <glyph class="state variable" id="_94746ddd-6513-4ca2-b7df-02df4c53cbfc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2562.5" y="2485.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1692_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:TRIP10 Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:17785506 Cdc42-interacting protein-4 (CIP4) - TRIP10 is able to associate with Wiskott-Aldrich syndrome protein (WASp) and the actin filament-rich IS. WASP is needful for TRIP10 activation. CIP4 in NK provides cell cytotoxicity and MTOC polarization but not F-actin accumulation. TRIP10 (CIP4) functions downstream of Cdc42 to induce MTOC polarization to the IS and cytotoxicity. References_end</body> </html> </notes> <label text="TRIP10"/> <bbox w="80.0" h="40.0" x="2567.5" y="2430.0"/> </glyph> </glyph> <glyph class="phenotype" id="s871_sa227" compartmentRef="c4_ca4"> <notes> <html xmlns="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>References_begin: PMID:16887996 Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. PMID:19689731 MTOC polarization is a significant step of exocytosis References_end</body> </html> </notes> <label text="MTOC polarization"/> <bbox w="160.0" h="35.0" x="2310.0" y="2882.5"/> </glyph> <glyph class="complex" id="s879_csa22" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:ACTR2:ACTR3:ARPC1*:ARPC2:ARPC3:ARPC4:ARPC5 Identifiers_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="Arp2/3"/> <bbox w="190.0" h="210.0" x="2585.0" y="1785.0"/> <glyph class="macromolecule" id="s881_sa228"> <notes> <html xmlns="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: HUGO:ACTR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ACTR2"/> <bbox w="80.0" h="40.0" x="2595.0" y="1885.0"/> </glyph> <glyph class="macromolecule" id="s880_sa229"> <notes> <html xmlns="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: HUGO:ACTR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ACTR3"/> <bbox w="80.0" h="40.0" x="2595.0" y="1925.0"/> </glyph> <glyph class="macromolecule" id="s889_sa230"> <notes> <html xmlns="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: HUGO:ARPC2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC2"/> <bbox w="80.0" h="40.0" x="2595.0" y="1845.0"/> </glyph> <glyph class="macromolecule" id="s947_sa232"> <notes> <html xmlns="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: HUGO:ARPC3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC3"/> <bbox w="80.0" h="40.0" x="2675.0" y="1805.0"/> </glyph> <glyph class="macromolecule" id="s948_sa233"> <notes> <html xmlns="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: HUGO:ARPC4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC4"/> <bbox w="80.0" h="40.0" x="2675.0" y="1845.0"/> </glyph> <glyph class="macromolecule" id="s890_sa231"> <notes> <html xmlns="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: HUGO:ARPC1A HUGO:ARPC1B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC1*"/> <bbox w="80.0" h="40.0" x="2595.0" y="1805.0"/> </glyph> <glyph class="macromolecule" id="s1693_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ARPC5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC5"/> <bbox w="80.0" h="40.0" x="2680.0" y="1890.0"/> </glyph> </glyph> <glyph class="complex" id="s894_csa23" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:ACTR2:ACTR3:ARPC1*:ARPC2:ARPC3:ARPC4:ARPC5:WASP* Identifiers_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="..."/> <bbox w="180.0" h="190.0" x="2740.0" y="2015.0"/> <glyph class="macromolecule" id="s901_sa234"> <notes> <html xmlns="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: HUGO:ARPC5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC5"/> <bbox w="80.0" h="40.0" x="2765.0" y="2052.5"/> </glyph> <glyph class="macromolecule" id="s895_sa242"> <notes> <html xmlns="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: HUGO:ACTR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ACTR3"/> <bbox w="80.0" h="40.0" x="2750.0" y="2145.0"/> </glyph> <glyph class="macromolecule" id="s1690_sa243"> <notes> <html xmlns="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: HUGO:ACTR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ACTR2"/> <bbox w="80.0" h="40.0" x="2750.0" y="2105.0"/> </glyph> <glyph class="macromolecule" id="s1689_sa244"> <notes> <html xmlns="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: HUGO:ARPC2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC2"/> <bbox w="80.0" h="40.0" x="2750.0" y="2065.0"/> </glyph> <glyph class="macromolecule" id="s1688_sa245"> <notes> <html xmlns="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: HUGO:ARPC1A HUGO:ARPC1B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC1*"/> <bbox w="80.0" h="40.0" x="2750.0" y="2025.0"/> </glyph> <glyph class="macromolecule" id="s899_sa246"> <notes> <html xmlns="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: HUGO:ARPC3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC3"/> <bbox w="80.0" h="40.0" x="2830.0" y="2025.0"/> </glyph> <glyph class="macromolecule" id="s900_sa247"> <notes> <html xmlns="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: HUGO:ARPC4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC4"/> <bbox w="80.0" h="40.0" x="2830.0" y="2065.0"/> </glyph> <glyph class="macromolecule" id="s901_sa248"> <notes> <html xmlns="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: HUGO:ARPC5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end</body> </html> </notes> <label text="ARPC5"/> <bbox w="80.0" h="40.0" x="2830.0" y="2105.0"/> </glyph> <glyph class="macromolecule" id="s1687_sa249"> <notes> <html xmlns="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: HUGO:WAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15001467, PMID:14707117 CD16 or ITGB2 (CD18) stimulation resulted in the induction of WASp tyrosine phosphorylation in NK cells, probubly by Fyn. Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation in T cells. PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. It binds actin monomers as well as the actin-related protein (ARP) 2/3 complex to catalyze branching of filamentous actin (F-actin) PMID:16606694 WIPF1 forms complex with WASP. References_end</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="2830.0" y="2145.0"/> <glyph class="state variable" id="_a7ed4021-9df6-49ee-bd69-c7ee02bdfdd0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2825.0" y="2160.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s903_sa251" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PRKCQ Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19201850 Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression. PRKCQ upregulates granzyme A and B expression in NK cells recruited to the tumor environment. PRKCQ could be activated downstream of IL15 and TLR3 signaling. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. PMID:18784374; PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2. PMID:18784374 PKC-theta–mediated signals activate AP-1 and NFAT1. The capacity of NFAT to bind DNA was reduced in PKC-theta–deﬁcient NK cells. There is a signiﬁcant decrease in AP-1 activation in PKC-theta–deﬁcient NK cells. References_end</body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="3390.0" y="1480.0"/> <glyph class="state variable" id="_94a89ff6-977f-41d2-bea6-e58b32751a8f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3385.0" y="1495.0"/> </glyph> </glyph> <glyph class="phenotype" id="s906_sa254"> <label text="NK migration"/> <bbox w="80.0" h="30.0" x="2600.0" y="305.0"/> </glyph> <glyph class="macromolecule" id="s907_sa255" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:TLR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19201850 Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression. PRKCQ upregulates granzyme A and B expression in NK cells recruited to the tumor environment. PRKCQ could be activated downstream of IL15 and TLR3 signaling. References_end</body> </html> </notes> <label text="TLR3"/> <bbox w="80.0" h="50.0" x="2870.0" y="915.0"/> <glyph class="unit of information" id="_c0614cf8-e75e-41c1-80d4-05a093ed2ae2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2887.5" y="910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s908_sa403"> <notes> <html xmlns="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: HUGO:IL15 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7523571 Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK). Interleukin (IL) 15 activates human natural killer cells via components of the IL-2 receptor and induces cytoxic activity against tumor cells and participates in regulation of cytokine production. PMID:17398124, PMID:19913445, PMID:17459805, PMID:21307131 Dendritic cells and macrophages prime natural killer cells by trans-presenting interleukin 15. IL-15 is trans-presented on the surface of IL-15-producing cells in complex with the IL-15 receptor α chain (IL-15Rα). It results in tumoriicidal activity of NK cells. Low doses of IL-15 trigger STAT5 activation while higher concentrations are needed to activate mTOR pathway ("mTOR: A gate to NK cell maturation and activation" no PMID). PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end</body> </html> </notes> <label text="IL15"/> <bbox w="80.0" h="40.0" x="6880.0" y="750.0"/> </glyph> <glyph class="macromolecule" id="s909_sa250" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PRKCQ Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19201850 Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression. PRKCQ upregulates granzyme A and B expression in NK cells recruited to the tumor environment. PRKCQ could be activated downstream of IL15 and TLR3 signaling. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. PMID:18784374; PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2. PMID:18784374 PKC-theta–mediated signals activate AP-1 and NFAT1. The capacity of NFAT to bind DNA was reduced in PKC-theta–deﬁcient NK cells. There is a signiﬁcant decrease in AP-1 activation in PKC-theta–deﬁcient NK cells. References_end</body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="3390.0" y="1570.0"/> <glyph class="state variable" id="_4425fa7a-f567-4222-9443-a45fbbd2398f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3382.5" y="1585.0"/> </glyph> </glyph> <glyph class="complex" id="s912_csa25" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:WASP*:WIPF1 Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. 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PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. It binds actin monomers as well as the actin-related protein (ARP) 2/3 complex to catalyze branching of filamentous actin (F-actin) PMID:16606694 WIPF1 forms complex with WASP. 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References_end</body> </html> </notes> <label text="MYH9"/> <bbox w="80.0" h="40.0" x="3382.5" y="2055.0"/> </glyph> <glyph class="macromolecule" id="s918_sa263"> <notes> <html xmlns="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: HUGO:WAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15001467, PMID:14707117 CD16 or ITGB2 (CD18) stimulation resulted in the induction of WASp tyrosine phosphorylation in NK cells, probubly by Fyn. Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation in T cells. PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. 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WIPF1 (WIP) phosphorylation in NK cells is mediated by PRKCQ (PKC theta) References_end</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="3380.0" y="2150.0"/> <glyph class="state variable" id="_a7c6179e-aa75-4d62-aa63-2a0d7368f43f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3372.5" y="2164.9683"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s919_sa264" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MYH9 Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end</body> </html> </notes> <label text="MYH9"/> <bbox w="80.0" h="40.0" x="3390.0" y="1920.0"/> </glyph> <glyph class="complex" id="s920_csa27" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:WASP*:WIPF1 Identifiers_end References_begin: PMID:16606694 Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end</body> </html> </notes> <label text="WASP*:WIPF1"/> <bbox w="110.0" h="140.0" x="3250.0" y="1917.5"/> <glyph class="macromolecule" id="s921_sa266"> <notes> <html xmlns="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: HUGO:WAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15001467, PMID:14707117 CD16 or ITGB2 (CD18) stimulation resulted in the induction of WASp tyrosine phosphorylation in NK cells, probubly by Fyn. Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation in T cells. PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. It binds actin monomers as well as the actin-related protein (ARP) 2/3 complex to catalyze branching of filamentous actin (F-actin) PMID:16606694 WIPF1 forms complex with WASP. References_end</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="3270.0" y="1927.5"/> <glyph class="state variable" id="_7dc7ade7-9747-4e21-a0a9-d27d2e38094e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3265.0" y="1942.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s922_sa267"> <notes> <html xmlns="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: HUGO:WIPF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:16606694 WIPF1 forms complex with WASP. WIPF1 (WIP) phosphorylation in NK cells is mediated by PRKCQ (PKC theta) References_end</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="3265.0" y="1987.5"/> <glyph class="state variable" id="_b0bfc011-77e4-42ad-83b0-74ef9a6dc148"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3257.5" y="2002.4681"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s924_sa269" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:WIPF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:16606694 WIPF1 forms complex with WASP. WIPF1 (WIP) phosphorylation in NK cells is mediated by PRKCQ (PKC theta) References_end</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="3110.0" y="1890.0"/> <glyph class="state variable" id="_655f1484-d02f-4a11-8adf-f736c1282e2d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3105.0" y="1904.9681"/> </glyph> </glyph> <glyph class="phenotype" id="s60_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"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: PMID:21350056, PMID:16106370, PMID:23906377 Human perforin is expressed in natural killer cells. Human granzymes A, B, and K are expressed in natural killer cells.NK cytotoxicity is mediated by the directed exocytosis of cytolytic granules to release perforins and granzymes, which perforate the target cell plasma cell membrane and trigger apoptosis, respectively. PMID:11698448 A RhoA/ROCK/LIM-kinase pathway is involved in the regulation of cellular cytotoxicity. References_end</body> </html> </notes> <label text="Cytotoxicity"/> <bbox w="190.0" h="35.0" x="1705.0" y="4262.5"/> </glyph> <glyph class="complex" id="s926_csa30" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CLEC2B:NKp80* Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: PMID:20663776,PMID: 17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. PMID:20663776 Blocking of CLEC2B (AICL) partially inhibits NK cell degranulation (LAMP1/CD107a presentation). PMID:11265639 Nkp80 signaling pathway induces Ca2+ mobilization and NK cell-mediated cytolytic activity. References_end</body> </html> </notes> <label text="s926"/> <bbox w="105.0" h="140.0" x="4217.5" y="3640.0"/> <glyph class="macromolecule" id="s928_sa281"> <notes> <html xmlns="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: HUGO:CLEC2B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:20663776,PMID: PMID:17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. References_end</body> </html> </notes> <label text="CLEC2B"/> <bbox w="80.0" h="40.0" x="4232.5" y="3650.0"/> </glyph> <glyph class="macromolecule multimer" id="s934_sa282"> <notes> <html xmlns="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: HUGO:KLRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:11265639 Nkp80 is expressed at the NK cell surface as a dimer. PMID:21149606, PMID:23609447 Tyrosine 7 of NKp80 is phosphorylated by Src kinases (probably by LCK) and required for NK cytotoxicity. Cross-linking of NKp80 induces Ca 2+ mobilization and triggering of cytotoxicity in both resting and activated NK cells. References_end</body> </html> </notes> <label text="NKp80*"/> <bbox w="86.0" h="56.0" x="4229.5" y="3692.0"/> <glyph class="unit of information" id="_d21089cd-594f-42d5-ad03-53b6178d11b0"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="4262.5" y="3687.0"/> </glyph> <glyph class="state variable" id="_b133f11c-cb75-4062-9bca-1d41139f08a2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4224.5" y="3715.0"/> </glyph> <glyph class="unit of information" id="_aff511fe-5302-4bde-b8c4-e4887f335bcc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4250.0" y="3687.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s929_sa272"> <notes> <html xmlns="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: HUGO:CLEC2B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:20663776,PMID: PMID:17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. References_end</body> </html> </notes> <label text="CLEC2B"/> <bbox w="80.0" h="40.0" x="4200.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s930_sa276" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:LAMP1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15744339 LAMP1 (CD107a) surface presentation is a marker of NK cell degranulation and antitumor activity. References_end</body> </html> </notes> <label text="LAMP1"/> <bbox w="80.0" h="40.0" x="2330.0" y="3650.0"/> </glyph> <glyph class="macromolecule" id="s931_sa277"> <notes> <html xmlns="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: HUGO:LAMP1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15744339 LAMP1 (CD107a) surface presentation is a marker of NK cell degranulation and antitumor activity. References_end</body> </html> </notes> <label text="LAMP1"/> <bbox w="80.0" h="40.0" x="2240.0" y="3870.0"/> </glyph> <glyph class="macromolecule multimer" id="s933_sa279" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KLRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:11265639 Nkp80 is expressed at the NK cell surface as a dimer. PMID:21149606, PMID:23609447 Tyrosine 7 of NKp80 is phosphorylated by Src kinases (probably by LCK) and required for NK cytotoxicity. Cross-linking of NKp80 induces Ca 2+ mobilization and triggering of cytotoxicity in both resting and activated NK cells. References_end</body> </html> </notes> <label text="NKp80*"/> <bbox w="86.0" h="56.0" x="4127.0" y="3522.0"/> <glyph class="unit of information" id="_2d15bacb-235f-4ecd-9edc-4abe7608ca1f"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="4160.0" y="3517.0"/> </glyph> <glyph class="state variable" id="_b189405d-c620-413d-90fe-0407420cded8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4122.0" y="3545.0"/> </glyph> <glyph class="unit of information" id="_264eac60-9292-41b0-bca2-42dda2c0a795"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4147.5" y="3517.0"/> </glyph> </glyph> <glyph class="complex" id="s935_csa29" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CLEC2B:NKp80* Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: PMID:20663776,PMID: 17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. PMID:20663776 Blocking of CLEC2B (AICL) partially inhibits NK cell degranulation (LAMP1/CD107a presentation). PMID:11265639 Nkp80 signaling pathway induces Ca2+ mobilization and NK cell-mediated cytolytic activity. References_end</body> </html> </notes> <label text="s926"/> <bbox w="110.0" h="160.0" x="4255.0" y="3420.0"/> <glyph class="macromolecule" id="s936_sa274"> <notes> <html xmlns="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: HUGO:CLEC2B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:20663776,PMID: PMID:17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. References_end</body> </html> </notes> <label text="CLEC2B"/> <bbox w="80.0" h="40.0" x="4270.0" y="3500.0"/> </glyph> <glyph class="macromolecule multimer" id="s937_sa280"> <notes> <html xmlns="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: HUGO:KLRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:11265639 Nkp80 is expressed at the NK cell surface as a dimer. PMID:21149606, PMID:23609447 Tyrosine 7 of NKp80 is phosphorylated by Src kinases (probably by LCK) and required for NK cytotoxicity. Cross-linking of NKp80 induces Ca 2+ mobilization and triggering of cytotoxicity in both resting and activated NK cells. References_end</body> </html> </notes> <label text="NKp80*"/> <bbox w="86.0" h="56.0" x="4267.0" y="3442.0"/> <glyph class="unit of information" id="_76a04d2c-fbf2-47aa-8cad-7cafb04675d2"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="4300.0" y="3437.0"/> </glyph> <glyph class="state variable" id="_4a98631a-db71-41c3-a62e-dedd3c4deb96"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4259.5" y="3465.0"/> </glyph> <glyph class="unit of information" id="_46c578c4-7e2c-4243-8d41-e66052df0294"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4287.5" y="3437.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s938_sa283"> <notes> <html xmlns="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: HUGO:PVR Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112) [64]. Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. Level of CD155 and CD112 expression on neuroblastoma cells derived from human patients correlated with their susceptibility to NK cellmediated killing PMID:19801517 Coincubation of NK cells with ovarian carcinoma cells expressing the DNAM-1 ligand CD155 led to reduction of DNAM-1 expression. References_end</body> </html> </notes> <label text="PVR"/> <bbox w="80.0" h="40.0" x="7280.0" y="4110.0"/> </glyph> <glyph class="macromolecule" id="s939_sa284"> <notes> <html xmlns="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: HUGO:PVRL2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. PMID:21383766 In acute myeloid leukaemia an inverse correlation between CD112 expression on AML blasts and DNAM-1 expression on NK cells was described References_end</body> </html> </notes> <label text="PVRL2"/> <bbox w="80.0" h="40.0" x="7170.0" y="4110.0"/> </glyph> <glyph class="macromolecule" id="s941_sa285" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:CD226 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. DNAM-1 does not associate with any ITAM-bearing molecule but, after receptor crosslinking, its intracellular domain gets phosphorylated and delivers an intracellular signal. PKC induces phosphorylation of the Ser329 and probably FYN mediates phosphorylation of DNAM-1 at tyrosine residue 322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. References_end</body> </html> </notes> <label text="DNAM1*"/> <bbox w="80.0" h="50.0" x="7080.0" y="1985.0"/> <glyph class="state variable" id="_c44c756a-96fa-4a1f-9187-e7d210abc9e9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7075.0" y="1987.2045"/> </glyph> <glyph class="state variable" id="_0068df6f-b7b8-48fb-abc6-40067c054361"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7072.5" y="2013.554"/> </glyph> <glyph class="unit of information" id="_f66622c1-8cfe-46e7-ad89-f93b27ef561c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7097.5" y="1980.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s952_sa356" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CBL Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20189481, PMID: PMID:18835194 CBL inhibited Vav1-dependent activation signals in NK via VAV1 ubiquitination. Tyrosine phosphorylation of c-Cbl was detected after stimulation NKL cells by either NKG2D, 2B4, or the synergistic NKG2D and 2B4 combination. Cbl Limits NK Cell Activation. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. References_end</body> </html> </notes> <label text="CBL"/> <bbox w="80.0" h="40.0" x="4340.0" y="2740.0"/> <glyph class="state variable" id="_7988be9c-ce66-49b8-a9be-f7289d347233"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4335.0" y="2755.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s953_sa299"> <notes> <html xmlns="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: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:15187109 TGFB1 secreted by tumors is responsible for the poor NK lytic activity via down-regulating an NK-activating receptor, NKG2D. PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. PMID: PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="80.0" h="40.0" x="1950.0" y="420.0"/> </glyph> <glyph class="nucleic acid feature" id="s954_sa300" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CD226 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. DNAM-1 does not associate with any ITAM-bearing molecule but, after receptor crosslinking, its intracellular domain gets phosphorylated and delivers an intracellular signal. PKC induces phosphorylation of the Ser329 and probably FYN mediates phosphorylation of DNAM-1 at tyrosine residue 322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. References_end</body> </html> </notes> <label text="DNAM1"/> <bbox w="70.0" h="25.0" x="6775.0" y="1907.5"/> </glyph> <glyph class="nucleic acid feature" id="s955_sa301" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CD226 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. DNAM-1 does not associate with any ITAM-bearing molecule but, after receptor crosslinking, its intracellular domain gets phosphorylated and delivers an intracellular signal. PKC induces phosphorylation of the Ser329 and probably FYN mediates phosphorylation of DNAM-1 at tyrosine residue 322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. References_end</body> </html> </notes> <label text="DNAM1"/> <bbox w="90.0" h="25.0" x="6765.0" y="1987.5"/> <glyph class="unit of information" id="_1cd46b78-e798-447b-a050-8abc9f51ac12"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6800.0" y="1982.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s977_sa323"> <notes> <html xmlns="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: HUGO:ADAM17 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:18676862 Tumor-Associated MICA Is shed by ADAM10 and ADAM17 proteases. References_end</body> </html> </notes> <label text="ADAM17"/> <bbox w="80.0" h="40.0" x="3420.0" y="4310.0"/> </glyph> <glyph class="macromolecule" id="s979_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:MICA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:22006996, PMID:18676862 Tumor-Associated MICA Is shed by ADAM10 and ADAM17 proteases. Downstream of HIF1 and hypoxia (ADAM10). It decreases surface MICA levels and provides resistance to cytolysis. References_end</body> </html> </notes> <label text="MICAshed"/> <bbox w="80.0" h="40.0" x="3340.0" y="4240.0"/> <glyph class="unit of information" id="_516e266c-d9fb-4f7a-a751-86fd13a7694b"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3355.0" y="4235.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s944_sa288" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PRKCA HGNC:9393 ENTREZ:5578 UNIPROT:P17252 GENECARDS:PRKCA HUGO:PRKCB HGNC:9395 ENTREZ:5579 UNIPROT:P05771 GENECARDS:PRKCB HUGO:PRKCE HGNC:9401 ENTREZ:5581 UNIPROT:Q02156 GENECARDS:PRKCE HUGO:PRKCG HGNC:9402 ENTREZ:5582 UNIPROT:P05129 GENECARDS:PRKCG HUGO:PRKCZ HGNC:9412 ENTREZ:5590 UNIPROT:Q05513 GENECARDS:PRKCZ HUGO:PRKCD HGNC:9399 ENTREZ:5580 UNIPROT:Q05655 GENECARDS:PRKCD HUGO:PRKCH HGNC:9403 ENTREZ:5583 UNIPROT:P24723 GENECARDS:PRKCH HUGO:PRKCQ HGNC:9410 ENTREZ:5588 UNIPROT:Q04759 GENECARDS:PRKCQ HUGO:PRKCI HGNC:9404 ENTREZ:5584 UNIPROT:P41743 GENECARDS:PRKCI Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:58197 KEGG:5578 ATLASONC:GC_PRKCA WIKI:PRKCA REACTOME:58199 KEGG:5579 ATLASONC:GC_PRKCB WIKI:PRKCB REACTOME:58203 KEGG:5581 ATLASONC:GC_PRKCE WIKI:PRKCE REACTOME:58205 KEGG:5582 ATLASONC:GC_PRKCG WIKI:PRKCG REACTOME:58219 KEGG:5590 ATLASONC:GC_PRKCZ WIKI:PRKCZ REACTOME:58201 KEGG:5580 ATLASONC:PRKCDID42901ch3p21 WIKI:PRKCD REACTOME:58209 KEGG:5583 ATLASONC:GC_PRKCH WIKI:PRKCH REACTOME:58217 KEGG:5588 ATLASONC:GC_PRKCQ WIKI:PRKCQ REACTOME:58207 KEGG:5584 ATLASONC:PRKCIID41857ch3q26 WIKI:PRKCI PMID:24343663, PMID:9712030, PMID:10591186 The phosphorylation of the Ser329 of DNAM-1 by protein kinase C (PKC) was shown to be critical for DNAM-1-mediated intracellular signalling and functions References_end</body> </html> </notes> <label text="PKC*"/> <bbox w="80.0" h="40.0" x="6060.0" y="1920.0"/> </glyph> <glyph class="complex" id="s990_csa33" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD11a*:CD18* Identifiers_end References_begin: PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="LFA1"/> <bbox w="100.0" h="140.0" x="7080.0" y="2150.0"/> <glyph class="macromolecule" id="s992_sa293"> <notes> <html xmlns="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: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS The phosphorylation of Ser329 by PKC was later found to be critical for the association between DNAM-1 and CD18(LFA-1) in NK cells.17 This association is required for DNAM-1 signalling. PMID:19965656 Coengagement of DNAM-1 and CD18 (LFA-)1 by a Drosophila cell line transfected to express CD155 and intercellular adhesion molecule 1 triggered the IFN-g production by NK cells, while these ligands alone had no effects, reinforcing the functional link between DNAM-1 and LFA-1 in driving NK cell activation. PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. LFA-1 is required for NKG2D-mediated conjugate formation and cytotoxicity. References_end</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="7090.0" y="2155.0"/> <glyph class="unit of information" id="_a7d6b6bc-33b8-4cb2-aea4-4a9c2fabf0ec"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7107.5" y="2150.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s993_sa342"> <notes> <html xmlns="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: HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="7090.0" y="2205.0"/> <glyph class="unit of information" id="_dcbb44eb-1577-4724-9cbc-e4b8fe0f0320"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7107.5" y="2200.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s994_csa34" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD11a*:CD18*:DNAM1* Identifiers_end References_begin: PMID:10591186 LFA1 physically associates with DNAM1 in NK cells. Phosphorylated by PKC S329 probably plays a critical role in this association. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. References_end</body> </html> </notes> <label text="LFA1:DNAM1"/> <bbox w="180.0" h="175.0" x="7320.0" y="1952.5"/> <glyph class="macromolecule" id="s997_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS The phosphorylation of Ser329 by PKC was later found to be critical for the association between DNAM-1 and CD18(LFA-1) in NK cells.17 This association is required for DNAM-1 signalling. PMID:19965656 Coengagement of DNAM-1 and CD18 (LFA-)1 by a Drosophila cell line transfected to express CD155 and intercellular adhesion molecule 1 triggered the IFN-g production by NK cells, while these ligands alone had no effects, reinforcing the functional link between DNAM-1 and LFA-1 in driving NK cell activation. PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. LFA-1 is required for NKG2D-mediated conjugate formation and cytotoxicity. References_end</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="7410.0" y="1962.5"/> <glyph class="unit of information" id="_8772f315-0660-474c-bc0a-6fc8815c116b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7427.5" y="1957.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s998_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="7410.0" y="2002.5"/> <glyph class="unit of information" id="_768ee2a1-e92c-4ff6-986f-aa3762684684"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7427.5" y="1997.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s999_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CD226 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. DNAM-1 does not associate with any ITAM-bearing molecule but, after receptor crosslinking, its intracellular domain gets phosphorylated and delivers an intracellular signal. PKC induces phosphorylation of the Ser329 and probably FYN mediates phosphorylation of DNAM-1 at tyrosine residue 322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. References_end</body> </html> </notes> <label text="DNAM1*"/> <bbox w="80.0" h="50.0" x="7330.0" y="1962.5"/> <glyph class="state variable" id="_6efb1a70-200b-44a0-acf1-14d2b66ea66b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7325.0" y="1964.7045"/> </glyph> <glyph class="state variable" id="_c1947dc5-7b60-4aa6-9c79-1c7ecbb7ea73"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7322.5" y="1991.054"/> </glyph> <glyph class="unit of information" id="_04e3627c-1cd1-4722-a932-2931c5ead7e1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7347.5" y="1957.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1000_csa35" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD11a*:CD18*:DNAM1* Identifiers_end References_begin: PMID:10591186, PMID:24440149 LFA1 physically associates with DNAM1 in NK cells. Phosphorylated by PKC S329 probably plays a critical role in this association. Cross-Linking of LFA-1 induces tyrosine Phosphorylation of DNAM-,FYN probably phosphorylates DNAM1 Y322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Coengagement of LFA-1 and 2B4 led to an increase in Vav1 phosphorylation, as compared with that obtained by engagement of LFA-1 alone (Fig. 3 A). Therefore, signals through LFA-1 but not 2B4 lead to a phosphorylation of Vav1 which can be enhanced by 2B4 signals References_end</body> </html> </notes> <label text="LFA1:DNAM1"/> <bbox w="192.5" h="191.25" x="7077.5" y="1748.75"/> <glyph class="macromolecule" id="s1001_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS The phosphorylation of Ser329 by PKC was later found to be critical for the association between DNAM-1 and CD18(LFA-1) in NK cells.17 This association is required for DNAM-1 signalling. PMID:19965656 Coengagement of DNAM-1 and CD18 (LFA-)1 by a Drosophila cell line transfected to express CD155 and intercellular adhesion molecule 1 triggered the IFN-g production by NK cells, while these ligands alone had no effects, reinforcing the functional link between DNAM-1 and LFA-1 in driving NK cell activation. PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. LFA-1 is required for NKG2D-mediated conjugate formation and cytotoxicity. References_end</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="7180.0" y="1765.0"/> <glyph class="unit of information" id="_8e738f48-ca6c-462c-9b41-9365d48e2085"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7197.5" y="1760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1002_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="7182.5" y="1816.25"/> <glyph class="unit of information" id="_9a7c285e-e0d7-44f4-8218-da1fbc4cce2b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7200.0" y="1811.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s1003_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CD226 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. DNAM-1 does not associate with any ITAM-bearing molecule but, after receptor crosslinking, its intracellular domain gets phosphorylated and delivers an intracellular signal. PKC induces phosphorylation of the Ser329 and probably FYN mediates phosphorylation of DNAM-1 at tyrosine residue 322. PMID:20189481, PMID:22786724 DNAM1 induces VAV1 pathway probably via LCP2 (SLP76) . It demonstrate synergy with 2B4 in activation of vav1 pathway. DNAM1 signaling stimulate Ca2+ mobilization provably via PLC-GAMMA2 and induces ERK pathway probably via VAV1. References_end</body> </html> </notes> <label text="DNAM1*"/> <bbox w="80.0" h="50.0" x="7090.0" y="1765.0"/> <glyph class="state variable" id="_5566d979-7fef-47f3-abd8-cee85405315f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7082.5" y="1767.2045"/> </glyph> <glyph class="state variable" id="_250f8a2e-9a05-4450-b75a-93a48a3d1267"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7082.5" y="1793.554"/> </glyph> <glyph class="unit of information" id="_794ed504-0be3-4bd8-897c-bd1a11433230"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7107.5" y="1760.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1004_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="ICAM1"/> <bbox w="80.0" h="40.0" x="6840.0" y="4110.0"/> </glyph> <glyph class="macromolecule" id="s1011_sa354" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12740575, PMID:16887996 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:20189481, PMID:22786724 NKG2D, DNAM1, 2B4 signalings induce PLCG2 phosphorylation and Ca2+ release via LCP2/VAV1 pathway. CBL inhibited Vav1-dependent activation signals in NK. Vav-deficient NK cells exhibited nearly abolished conjugate formation and cytotoxicity toward target cells. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1 (probably via LCP2),CBL. This phosphorylation is dependent on SAP adn FYN. PMID: PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Vav1 phosphorylation is induced by beta2 integrin (CD18)engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization References_end</body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="4490.0" y="2670.0"/> <glyph class="state variable" id="_99cf18ee-aea4-4d0c-b1db-64c1d88b81eb"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="4480.0" y="2685.0"/> </glyph> </glyph> <glyph class="source and sink" id="s1012_sa355" compartmentRef="c7_ca7"> <label text="sa354_degraded"/> <bbox w="30.0" h="30.0" x="4635.0" y="2675.0"/> </glyph> <glyph class="macromolecule" id="s1014_sa298" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CBL Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20189481, PMID: PMID:18835194 CBL inhibited Vav1-dependent activation signals in NK via VAV1 ubiquitination. Tyrosine phosphorylation of c-Cbl was detected after stimulation NKL cells by either NKG2D, 2B4, or the synergistic NKG2D and 2B4 combination. Cbl Limits NK Cell Activation. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. References_end</body> </html> </notes> <label text="CBL"/> <bbox w="80.0" h="40.0" x="4340.0" y="2640.0"/> <glyph class="state variable" id="_7edb24f6-8a21-4a3b-9a97-c1c772497f16"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4332.5" y="2655.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1017_sa359"> <notes> <html xmlns="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: HUGO:CD48 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10359122, PMID:16081768 CD48 is a counter-receptor for 2B4 receptor, which is widely expressed on hemopoietic cells. NK cells costimulate each other through 2B4-CD48 interactions. PMID:15998796 Expression of CD48 was detected on the membrane of some tumor cells,all of which were found to be lysed by a SAP-dependent NK cell cytotoxicity. References_end</body> </html> </notes> <label text="CD48"/> <bbox w="80.0" h="40.0" x="6050.0" y="3860.0"/> </glyph> <glyph class="macromolecule" id="s1018_sa684" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTPN11 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:10358138, PMID:15713798 Human 2B4 is phosphorylated following activation and recruits PTPN11 (SHP-2). Association of SAP with h2B4 prevents recruitment of SHP-2. PMID:12707331 There is direct correlation between SHP-2 recruitment and functional inhibition of target cell conjugation and cytotoxicity downstream of KIR3DL. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) . References_end</body> </html> </notes> <label text="PTPN11"/> <clone/> <bbox w="80.0" h="40.0" x="1410.0" y="2340.0"/> </glyph> <glyph class="macromolecule" id="s1018_sa743" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTPN11 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:10358138, PMID:15713798 Human 2B4 is phosphorylated following activation and recruits PTPN11 (SHP-2). Association of SAP with h2B4 prevents recruitment of SHP-2. PMID:12707331 There is direct correlation between SHP-2 recruitment and functional inhibition of target cell conjugation and cytotoxicity downstream of KIR3DL. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) . References_end</body> </html> </notes> <label text="PTPN11"/> <clone/> <bbox w="80.0" h="40.0" x="1610.0" y="2340.0"/> </glyph> <glyph class="macromolecule" id="s1021_sa363" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15998796, PMID:15169881,PMID:15713798 SAP and FYN are required for the ability of NK cells to eliminate tumor cells in vitro and in vivo downstream of 2B4. Probably SAP couples Fyn to 2B4. PMID:22683124 Fyn-Binding Site of SH2D1A (SAP) is necessary for 2B4-Mediated NK Cell activation. NK cells, those lacking SAP displayed markedly reduced conjugate formation via inhibition of LFA1-ICAM1 association. References_end</body> </html> </notes> <label text="SH2D1A"/> <bbox w="80.0" h="40.0" x="6080.0" y="2940.0"/> </glyph> <glyph class="macromolecule" id="s1031_sa372" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:22483603 SH2-domain containing inositol-5-phosphatase (SHIP) de-phosphorylates PI(3,4,5)P3 at the D5 position of the inositol ring to create PI(3,4)P2. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. PMID:22683124 2B4-mediated inhibition was restored when SHIP-1 was reintroduced in SHIP-1-deficient cells. In the NK cells lacking SHIP-1, there was a prominent diminution of the inhibitory influence of 2B4 (to ∼25% of control). PMID:12393695 CD16 stimulation on human primary natural killer (NK) cells induces the rapid and transient translocation of SHIP-1 in the lipid-enriched plasma membrane microdomains, termed rafts, where it associates with tyrosine-phosphorylated zeta chain and shc adaptor protein. SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="1570.0" y="2240.0"/> <glyph class="state variable" id="_a444a426-87a0-48de-9b4f-dbf406d317f7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1565.0" y="2255.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1032_sa373" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CSK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. References_end</body> </html> </notes> <label text="CSK"/> <clone/> <bbox w="80.0" h="40.0" x="1560.0" y="1930.0"/> </glyph> <glyph class="macromolecule" id="s1032_sa965" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CSK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. References_end</body> </html> </notes> <label text="CSK"/> <clone/> <bbox w="80.0" h="40.0" x="1730.0" y="1930.0"/> </glyph> <glyph class="macromolecule" id="s1038_sa381" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:22483603 SH2-domain containing inositol-5-phosphatase (SHIP) de-phosphorylates PI(3,4,5)P3 at the D5 position of the inositol ring to create PI(3,4)P2. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. PMID:22683124 2B4-mediated inhibition was restored when SHIP-1 was reintroduced in SHIP-1-deficient cells. In the NK cells lacking SHIP-1, there was a prominent diminution of the inhibitory influence of 2B4 (to ∼25% of control). PMID:12393695 CD16 stimulation on human primary natural killer (NK) cells induces the rapid and transient translocation of SHIP-1 in the lipid-enriched plasma membrane microdomains, termed rafts, where it associates with tyrosine-phosphorylated zeta chain and shc adaptor protein. SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="1740.0" y="2240.0"/> <glyph class="state variable" id="_1ccd3008-8b58-4f37-aab5-4abf2a8ea3b8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1732.5" y="2255.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1039_sa382" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SH3BP2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: PMID:11390470, PMID:16177062 SH3BP2 (3BP2) is involevd in NK-activation. 3BP2 is coupled to activating receptors on NK cells.It is phosphorylated after NK stimulation. CD244 ligation induces 3BP2 phosphorylation and Vav recruitment. The adaptor protein 3BP2 binds human 2B4 (CD244) and links this receptor to Vav signaling, PLCG, ERK activation, and NK cell killing. SH2 domain of 3BP2 is required for optimal tyrosine phosphorylation of 3BP2 following FcR cross-linking and for its ability to associate with the transmembrane adaptor protein LAT. Phosphorylated tyrosine-183 of 3BP2 binds PLCG1 and PLCG2 and Vav1 during activation of NK cells through natural cytotoxicity receptors. References_end</body> </html> </notes> <label text="3BP2*"/> <bbox w="80.0" h="40.0" x="5960.0" y="2910.0"/> <glyph class="state variable" id="_5813ced8-5ac0-4808-9cb3-585d99595276"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5955.0" y="2925.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1040_sa383" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SH3BP2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: PMID:11390470, PMID:16177062 SH3BP2 (3BP2) is involevd in NK-activation. 3BP2 is coupled to activating receptors on NK cells.It is phosphorylated after NK stimulation. CD244 ligation induces 3BP2 phosphorylation and Vav recruitment. The adaptor protein 3BP2 binds human 2B4 (CD244) and links this receptor to Vav signaling, PLCG, ERK activation, and NK cell killing. SH2 domain of 3BP2 is required for optimal tyrosine phosphorylation of 3BP2 following FcR cross-linking and for its ability to associate with the transmembrane adaptor protein LAT. Phosphorylated tyrosine-183 of 3BP2 binds PLCG1 and PLCG2 and Vav1 during activation of NK cells through natural cytotoxicity receptors. References_end</body> </html> </notes> <label text="3BP2*"/> <bbox w="80.0" h="40.0" x="5960.0" y="2990.0"/> <glyph class="state variable" id="_99b3f32b-fedf-47f3-8c11-9c8fff9b5c32"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5952.5" y="3005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1042_sa384" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LAT Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10072481,PMID:16329184, PMID:11169415 LAT participate in NK-cell cytotoxicity against tumor cells downstream of CD16 and 2B4 signaling. LAT is phosphorylated downstream of 2B4 and CD16 PMID:9489702, PMID:10072481, PMID:7523143 LAT is a substrate for ZAP-70, Syk protein tyrosine kinases in T cells and probably in NK cells. PMID:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway. PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1. References_end</body> </html> </notes> <label text="LAT"/> <bbox w="80.0" h="50.0" x="5750.0" y="3185.0"/> <glyph class="state variable" id="_151a5ab3-1a4f-4262-8c9f-6f280f09b102"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5742.5" y="3205.0"/> </glyph> <glyph class="unit of information" id="_4143400c-03e3-4e5d-8774-66dccaffaa1c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5767.5" y="3180.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1043_sa385" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:FCGR3A HUGO:FCGR3B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:11449354, PMID:12393695 Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3 References_end</body> </html> </notes> <label text="FcγRIII*"/> <bbox w="80.0" h="50.0" x="5390.0" y="3355.0"/> <glyph class="unit of information" id="_a80c8c28-aff7-4598-9ab6-3b9de7c21d30"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5407.5" y="3350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1044_sa386" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="4840.0" y="3865.0"/> <glyph class="state variable" id="_1b37795a-69a0-4a99-ac66-75c797331393"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4835.0" y="3885.0"/> </glyph> <glyph class="unit of information" id="_fe81e57b-1ba5-49a4-b1e4-c1e9e6ef24ac"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4857.5" y="3860.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1057_sa50" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:1L2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:6164929 IL2 has the ability to augment the cytotoxic activity of natural killer (NK) cells agains tumor cells and potentiate effect of other cytokines (interferons). PMID: PMID:15289500 Dendric cells-derived IL-2 induces NK cell activation. DC-derived IL-2 Is Required In Vitro to Elicit IFNγ Production from NK Cells. PMID:23650441 IL-2–treated NK cells had a significantly increased contact efficiency as determined by the number of target cell contacts that cells underwent before initiating Ca2+ flux for the first time The ability of IL-2 to modulate NK cell cytotoxicity directly correlated with its ability to increase target–cell conjugation. IL-2 rapidly increases NK cell adhesion to and killing of weak targets. NK cell reactivity toward missing-self targets was enhanced in the absence of T reg cells and depended on the availability of IL-2 and activated T cells. CD4+ T cell–derived IL-2 activated NK cells in the absence of T reg cells. PMID:19528259 Nkp30‭ ‬signaling induces IL2‭ ‬release. PMID:9625766 IL2‭ ‬stimulates NKp44‭ ‬surface expression in NK cells. PMID:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end</body> </html> </notes> <label text="IL2"/> <bbox w="80.0" h="40.0" x="5390.0" y="1060.0"/> </glyph> <glyph class="macromolecule" id="s1066_sa204" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 MIP1B and IFNG secretion via PI3K pathway. PMID:21149606 Stimulation by NKp80-specific mAb induced marked IFNG production. PMID:22786724, PMID:20189481 LCP2 (SLP76) via VAV1 upregulates INFG production downstream of 2B4,NG2D signalings, probably via PI3K. PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PMID:15289500 DC-derived IL-2 Is Required In Vitro to Elicit IFNγ Production from NK Cells PMID:10843677 IL2 induces IFNG production in NK cells via MEK/ERK pathway activation. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end</body> </html> </notes> <label text="IFNG"/> <bbox w="90.0" h="40.0" x="3979.375" y="909.0625"/> </glyph> <glyph class="macromolecule" id="s1070_sa390" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:16081768, PMID:15905190, PMID:15905190 2B4 works as activator in human model and as inhibitor of NK activity in mouse model. NK cells costimulate each other through 2B4-CD48 interactions PMID: The cytoplasmic domains of murine 2B4L and human 2B4 contain three and four immunoreceptor tyrosine-based switch motifs (ITSM) Upon engagement, the receptor is recruited to lipid rafts at the target cell interface in an actin-dependent manner, and tyrosine residues in the ITSM sequences are phosphorylated . Phosphorylation of the ITSM sequences creates specific binding sites for SAP (SH2D1A). SAP is an SH2 domain-containing adaptor that links 2B4 to the Src family PTK Fyn. PMID:17171759 The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 PMID:20189481, PMID: PMID:22786724 2B4 signaling acts synergistically with NG2D and DNAM1 signalings in NK activation and tumor cells lysis. It activates LCP2/VAV1/PCLG pathway. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. DNAM1 induces VAV1 pathway probably via LCP2 (SLP76). It demonstrate synergy with 2B4 in activation of vav1 pathway. PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="2B4*"/> <bbox w="80.0" h="50.0" x="980.0" y="1825.0"/> <glyph class="state variable" id="_c3ee7aaa-d98c-464d-a9f2-a09829fdd1fa"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="972.5" y="1845.0"/> </glyph> <glyph class="unit of information" id="_efdbc405-3b88-443d-8db0-eb39a8208435"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="997.5" y="1820.0"/> </glyph> </glyph> <glyph class="complex" id="s1081_csa105" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD247:Fc_gamma_RIII* Identifiers_end References_begin: PMID:18768831 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. References_end</body> </html> </notes> <label text="s1081"/> <bbox w="100.0" h="140.0" x="5450.0" y="3470.0"/> <glyph class="macromolecule" id="s1556_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="5460.0" y="3495.0"/> <glyph class="state variable" id="_fcac3df1-6214-4dcd-ae3c-ef943793580c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5455.0" y="3515.0"/> </glyph> <glyph class="unit of information" id="_58caf0b7-88e1-41e4-beb8-fe48219e04a1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5477.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1557_sa819"> <notes> <html xmlns="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: HUGO:FCGR3A HUGO:FCGR3B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:11449354, PMID:12393695 Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3 References_end</body> </html> </notes> <label text="FcγRIII*"/> <bbox w="80.0" h="50.0" x="5460.0" y="3545.0"/> <glyph class="unit of information" id="_bb5d62b8-1062-4d51-ab91-2d6761e311c0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5477.5" y="3540.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1084_sa395" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals. PMID:10562324 NKp30 is involeded in the Induction of natural cytotoxicity against tumor cells. References_end</body> </html> </notes> <label text="NKp30*"/> <bbox w="80.0" h="50.0" x="4510.0" y="3425.0"/> <glyph class="unit of information" id="_a0a6d3d9-007f-468a-9af1-87332d9c8602"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4527.5" y="3420.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1085_sa396" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:FCER1G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . References_end</body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="4520.0" y="3895.0"/> <glyph class="state variable" id="_948b4718-7371-4c56-83ea-0128daa7d0e9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4515.0" y="3915.0"/> </glyph> <glyph class="unit of information" id="_329c1c01-c090-4ea1-b582-f41ff940be15"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4537.5" y="3890.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1086_sa398" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:NCR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . Ncr1 knockout mice exhibit an increase in tumour metastasis. PMID:22267813 NK cells with defective cell-surface expression of NKp46 are hyperreactive in responses to the prototypic NK cell tumor target cell line. But Ncr1 knockout mice have been reported to be highly susceptible to the infections. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="NKp46*"/> <bbox w="80.0" h="50.0" x="4930.0" y="3385.0"/> <glyph class="unit of information" id="_3f3aa392-3aca-4d50-8c2e-752f09d2b1e9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4947.5" y="3380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1087_sa156"> <notes> <html xmlns="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: HUGO:1L2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:6164929 IL2 has the ability to augment the cytotoxic activity of natural killer (NK) cells agains tumor cells and potentiate effect of other cytokines (interferons). PMID: PMID:15289500 Dendric cells-derived IL-2 induces NK cell activation. DC-derived IL-2 Is Required In Vitro to Elicit IFNγ Production from NK Cells. PMID:23650441 IL-2–treated NK cells had a significantly increased contact efficiency as determined by the number of target cell contacts that cells underwent before initiating Ca2+ flux for the first time The ability of IL-2 to modulate NK cell cytotoxicity directly correlated with its ability to increase target–cell conjugation. IL-2 rapidly increases NK cell adhesion to and killing of weak targets. NK cell reactivity toward missing-self targets was enhanced in the absence of T reg cells and depended on the availability of IL-2 and activated T cells. CD4+ T cell–derived IL-2 activated NK cells in the absence of T reg cells. PMID:19528259 Nkp30‭ ‬signaling induces IL2‭ ‬release. PMID:9625766 IL2‭ ‬stimulates NKp44‭ ‬surface expression in NK cells. PMID:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end</body> </html> </notes> <label text="IL2"/> <bbox w="80.0" h="40.0" x="5900.0" y="340.0"/> </glyph> <glyph class="complex" id="s1088_csa40" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:FCER1G:HLA-G:KIR2DL4 Identifiers_end</body> </html> </notes> <label text="s1088"/> <bbox w="200.0" h="130.0" x="4250.0" y="3845.0"/> <glyph class="macromolecule" id="s1092_sa402"> <notes> <html xmlns="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: HUGO:FCER1G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . References_end</body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="4350.0" y="3895.0"/> <glyph class="state variable" id="_9c36930a-dd92-4087-b26d-838ad2c5abac"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4345.0" y="3915.0"/> </glyph> <glyph class="unit of information" id="_9ee0ccbc-62aa-4054-9416-d73c747d8978"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4367.5" y="3890.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1447_sa739"> <notes> <html xmlns="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: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end</body> </html> </notes> <label text="HLA-G"/> <bbox w="80.0" h="40.0" x="4350.0" y="3850.0"/> </glyph> <glyph class="macromolecule" id="s1089_sa399"> <notes> <html xmlns="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: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="4260.0" y="3895.0"/> <glyph class="state variable" id="_c3775fbb-70f6-4dad-a3b4-5615b7a523e3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4255.0" y="3915.0"/> </glyph> <glyph class="unit of information" id="_18b6309a-5879-43bd-b794-0d76c0de4214"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4277.5" y="3890.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s23_sa738" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="1530.0" y="3325.0"/> <glyph class="state variable" id="_06f967c7-df6f-4242-ae6e-96d8ceb1d5a8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1525.0" y="3345.0"/> </glyph> <glyph class="unit of information" id="_c2d1c504-69e9-41c5-b2b6-17db5641ecb3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1547.5" y="3320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1093_sa69" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PIK3R1 HUGO:PIK3R2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:10426994, PMID:16582911 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:21149606 NKp80-mediated cytotoxicity is PI3K-dependent. PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. References_end</body> </html> </notes> <label text="PI3KR(p85)*"/> <clone/> <bbox w="80.0" h="40.0" x="5885.0" y="2680.0"/> </glyph> <glyph class="macromolecule" id="s1093_sa70" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PIK3R1 HUGO:PIK3R2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:10426994, PMID:16582911 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:21149606 NKp80-mediated cytotoxicity is PI3K-dependent. PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. References_end</body> </html> </notes> <label text="PI3KR(p85)*"/> <clone/> <bbox w="80.0" h="40.0" x="5880.0" y="2600.0"/> </glyph> <glyph class="macromolecule" id="s1094_sa73" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end</body> </html> </notes> <label text="VAV2"/> <clone/> <bbox w="80.0" h="40.0" x="4840.0" y="2490.0"/> </glyph> <glyph class="macromolecule" id="s1094_sa86" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end</body> </html> </notes> <label text="VAV2"/> <clone/> <bbox w="80.0" h="40.0" x="4840.0" y="2590.0"/> </glyph> <glyph class="macromolecule" id="s1095_sa74" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end</body> </html> </notes> <label text="VAV3"/> <clone/> <bbox w="80.0" h="40.0" x="4660.0" y="2500.0"/> </glyph> <glyph class="macromolecule" id="s1095_sa87" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:VAV3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end</body> </html> </notes> <label text="VAV3"/> <clone/> <bbox w="80.0" h="40.0" x="4660.0" y="2600.0"/> </glyph> <glyph class="macromolecule" id="s1096_sa75" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11907067, PMID:11062502 RAC1 activates PAK1 downstream of SYK and PI3K and upstream of ERK and MEK. PMID:12885870 Engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK1. PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end</body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="80.0" h="40.0" x="4250.0" y="2240.0"/> </glyph> <glyph class="macromolecule" id="s1096_sa80" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11907067, PMID:11062502 RAC1 activates PAK1 downstream of SYK and PI3K and upstream of ERK and MEK. PMID:12885870 Engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK1. PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end</body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="80.0" h="40.0" x="4250.0" y="2140.0"/> </glyph> <glyph class="macromolecule" id="s1097_sa90" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG PMID:12040186 The regulatory subunit maintains the p110 catalytic subunit in a low-activity state in quiescent cells and mediates its activation by direct interaction with phosphotyrosine residues of activated growth factor receptors or adaptor proteins. Direct binding of p110 to activated Ras protein (also induced by growth factor stimulation) further stimulates PI3K activity. The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:11062502, PMID:11385609 PI3K /RAC1/PAK1/MEK /ERK pathway controls NK cytolitic activity downstream of NKp30 and NKp46. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:8294866 Phosphatidylinositol-3 kinase activation induced upon Fc gamma RIIIA-ligand interaction in NK cells References_end</body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="5770.0" y="2550.0"/> </glyph> <glyph class="macromolecule" id="s1097_sa91" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG PMID:12040186 The regulatory subunit maintains the p110 catalytic subunit in a low-activity state in quiescent cells and mediates its activation by direct interaction with phosphotyrosine residues of activated growth factor receptors or adaptor proteins. Direct binding of p110 to activated Ras protein (also induced by growth factor stimulation) further stimulates PI3K activity. The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:11062502, PMID:11385609 PI3K /RAC1/PAK1/MEK /ERK pathway controls NK cytolitic activity downstream of NKp30 and NKp46. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:8294866 Phosphatidylinositol-3 kinase activation induced upon Fc gamma RIIIA-ligand interaction in NK cells References_end</body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="5770.0" y="2640.0"/> </glyph> <glyph class="simple chemical" id="s1098_sa92" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="4515.0" y="2377.5"/> </glyph> <glyph class="simple chemical" id="s1098_sa170" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="4095.0" y="2607.5"/> </glyph> <glyph class="simple chemical" id="s1098_sa695" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="3785.0" y="2727.5"/> </glyph> <glyph class="simple chemical" id="s1098_sa935" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="4085.0" y="2397.5"/> </glyph> <glyph class="simple chemical" id="s1098_sa1045" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="5335.0" y="2397.5"/> </glyph> <glyph class="simple chemical" id="s1098_sa1047" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="5875.0" y="1957.5"/> </glyph> <glyph class="simple chemical" id="s1098_sa1060" compartmentRef="c7_ca7"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="5375.0" y="2017.5"/> </glyph> <glyph class="simple chemical" id="s1099_sa93" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="4438.75" y="2376.875"/> </glyph> <glyph class="simple chemical" id="s1099_sa171" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="3998.75" y="2606.875"/> </glyph> <glyph class="simple chemical" id="s1099_sa694" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="3708.75" y="2726.875"/> </glyph> <glyph class="simple chemical" id="s1099_sa934" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="4008.75" y="2396.875"/> </glyph> <glyph class="simple chemical" id="s1099_sa1046" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="5258.75" y="2396.875"/> </glyph> <glyph class="simple chemical" id="s1099_sa1048" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="5788.75" y="1956.875"/> </glyph> <glyph class="simple chemical" id="s1099_sa1061" compartmentRef="c7_ca7"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="5288.75" y="2016.875"/> </glyph> <glyph class="macromolecule" id="s1100_sa369" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTPN6 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID: PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). Additionally probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 (demonstrated in T cells). PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1in NK cells. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs PMID:8986721 SHP-1 participates in ZAP-70, PLC-G dephosphorylation (inactivation) downstream of KIRs. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. References_end</body> </html> </notes> <label text="PTPN6"/> <clone/> <bbox w="80.0" h="40.0" x="1410.0" y="2470.0"/> </glyph> <glyph class="macromolecule" id="s1100_sa368" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTPN6 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID: PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). Additionally probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 (demonstrated in T cells). PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1in NK cells. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs PMID:8986721 SHP-1 participates in ZAP-70, PLC-G dephosphorylation (inactivation) downstream of KIRs. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. References_end</body> </html> </notes> <label text="PTPN6"/> <clone/> <bbox w="80.0" h="40.0" x="1620.0" y="2470.0"/> </glyph> <glyph class="macromolecule" id="s1101_sa211" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ROCK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12778124 The kinase activity of ROCKs is moderately enhanced after Rho binding. PMID:11698448 p160ROCK plays a fundamental role in the development of cellular cytotoxicity via LIMK1 phosphorylation. But it does not affect conjugate formation. References_end</body> </html> </notes> <label text="ROCK1"/> <clone/> <bbox w="80.0" h="40.0" x="3570.0" y="2180.0"/> </glyph> <glyph class="macromolecule" id="s1101_sa217" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ROCK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12778124 The kinase activity of ROCKs is moderately enhanced after Rho binding. PMID:11698448 p160ROCK plays a fundamental role in the development of cellular cytotoxicity via LIMK1 phosphorylation. But it does not affect conjugate formation. References_end</body> </html> </notes> <label text="ROCK1"/> <clone/> <bbox w="80.0" h="40.0" x="3570.0" y="2260.0"/> </glyph> <glyph class="macromolecule" id="s1045_sa387" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="3270.0" y="3315.0"/> <glyph class="state variable" id="_4cc66b0c-e49c-4e88-a62c-a566a752e52e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3265.0" y="3335.0"/> </glyph> <glyph class="unit of information" id="_95f159d4-2d92-48b5-92b6-89b203fddcd6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3287.5" y="3310.0"/> </glyph> </glyph> <glyph class="complex" id="s1107_csa41" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL15RA:IL2RB:IL2RG Identifiers_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. References_end</body> </html> </notes> <label text="s1107"/> <bbox w="190.0" h="160.0" x="6505.0" y="1090.0"/> <glyph class="macromolecule" id="s1109_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL15RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. http://cancerres.aacrjournals.org/content/72/8_Supplement/3506.short IL-15/IL-15Rα complexes activates natural killer cells and enhances anti-GD2 monoclonal antibody-mediated antibody-dependent cellular cytotoxicity in vitro and in vivo. References_end</body> </html> </notes> <label text="IL15RA"/> <bbox w="80.0" h="50.0" x="6515.0" y="1175.0"/> <glyph class="unit of information" id="_0eb37dfc-51fc-463d-ae04-01614932623d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6532.5" y="1170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1110_sa405"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="6605.0" y="1175.0"/> <glyph class="state variable" id="_010d536d-02de-4564-8419-584430303b2d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6600.0" y="1195.0"/> </glyph> <glyph class="unit of information" id="_bac1c4aa-7814-4de0-a6c2-1358ef308d2b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6622.5" y="1170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1111_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="6605.0" y="1115.0"/> <glyph class="unit of information" id="_f0d45be1-dfcf-472d-8691-036fc0a498d9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6622.5" y="1110.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1108_csa42" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL15:IL15RA:IL2RB:IL2RG Identifiers_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. http://cancerres.aacrjournals.org/content/72/8_Supplement/3506.short IL-15/IL-15Rα complexes activates natural killer cells and enhances anti-GD2 monoclonal antibody-mediated antibody-dependent cellular cytotoxicity in vitro and in vivo. References_end</body> </html> </notes> <label text="s1107"/> <bbox w="190.0" h="160.0" x="6545.0" y="1280.0"/> <glyph class="macromolecule" id="s1104_sa407"> <notes> <html xmlns="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: HUGO:IL15RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. http://cancerres.aacrjournals.org/content/72/8_Supplement/3506.short IL-15/IL-15Rα complexes activates natural killer cells and enhances anti-GD2 monoclonal antibody-mediated antibody-dependent cellular cytotoxicity in vitro and in vivo. References_end</body> </html> </notes> <label text="IL15RA"/> <bbox w="80.0" h="50.0" x="6557.5" y="1375.0"/> <glyph class="unit of information" id="_178abb28-c7f0-4f56-90e9-d6d2321ad4f6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6575.0" y="1370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1105_sa408"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="6647.5" y="1375.0"/> <glyph class="state variable" id="_598dda10-5525-4e67-bf48-adf7799290a4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6640.0" y="1395.0"/> </glyph> <glyph class="unit of information" id="_2f463d34-730a-4894-821b-b110f48ada62"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6665.0" y="1370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1106_sa409"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="6647.5" y="1315.0"/> <glyph class="unit of information" id="_3ba76516-b3a0-4e8c-849e-c6856a4c4148"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6665.0" y="1310.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1125_sa419"> <notes> <html xmlns="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: HUGO:IL15 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7523571 Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK). Interleukin (IL) 15 activates human natural killer cells via components of the IL-2 receptor and induces cytoxic activity against tumor cells and participates in regulation of cytokine production. PMID:17398124, PMID:19913445, PMID:17459805, PMID:21307131 Dendritic cells and macrophages prime natural killer cells by trans-presenting interleukin 15. IL-15 is trans-presented on the surface of IL-15-producing cells in complex with the IL-15 receptor α chain (IL-15Rα). It results in tumoriicidal activity of NK cells. Low doses of IL-15 trigger STAT5 activation while higher concentrations are needed to activate mTOR pathway ("mTOR: A gate to NK cell maturation and activation" no PMID). PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end</body> </html> </notes> <label text="IL15"/> <bbox w="80.0" h="40.0" x="6557.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1112_sa410" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MTOR Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:24973821, PMID:24795729 mTOR activity in NK cells is mainly under the control of IL-15. mTOR deficiency profoundly impaired the early cytokine-driven activation of NK cells at multiple levels. Inhibition of mTOR abrogates inflammation-induced priming. mTOR controls the maturation and homeostasis of NK cells. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. mTOR has positive influence on GZMA level in the NK cells. and NK cells from rapamycin-treated mice (mTOR-inhibition) had attenuated lytic activities toward target tumor cells. IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="5560.0" y="1950.0"/> <glyph class="state variable" id="_f02925a8-b8c8-49a2-8b7c-902d4dd2ff41"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5555.0" y="1965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1113_sa411" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:AKT1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="5920.0" y="2390.0"/> <glyph class="state variable" id="_bee58b12-f0f3-422f-81e1-f92576e00bc2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5915.0" y="2405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1114_sa412" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PDK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). References_end</body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="5860.0" y="2480.0"/> </glyph> <glyph class="complex" id="s1115_csa43" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:PDPK1:PIP3* Identifiers_end</body> </html> </notes> <label text="s1115"/> <bbox w="100.0" h="120.0" x="5770.0" y="2310.0"/> <glyph class="macromolecule" id="s1116_sa413"> <notes> <html xmlns="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: HUGO:PDK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). References_end</body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="5780.0" y="2320.0"/> </glyph> <glyph class="simple chemical" id="s1117_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"> <head> <title/> </head> <body>MODULE:NK PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:9438848 PI3K product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav proteins</body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="5785.0" y="2377.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1118_sa415" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:AKT1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="5920.0" y="2320.0"/> <glyph class="state variable" id="_1537bef3-19cd-4bed-96d9-fa0eb907dcca"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5912.5" y="2335.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1119_sa417" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="2925.0" y="3017.5"/> <glyph class="unit of information" id="_39a41c15-e65d-4fef-a362-ecc64359459c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2960.0" y="3012.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1120_sa416" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MTOR Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:24973821, PMID:24795729 mTOR activity in NK cells is mainly under the control of IL-15. mTOR deficiency profoundly impaired the early cytokine-driven activation of NK cells at multiple levels. Inhibition of mTOR abrogates inflammation-induced priming. mTOR controls the maturation and homeostasis of NK cells. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. mTOR has positive influence on GZMA level in the NK cells. and NK cells from rapamycin-treated mice (mTOR-inhibition) had attenuated lytic activities toward target tumor cells. IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="5560.0" y="2090.0"/> <glyph class="state variable" id="_636cfeaf-b0f3-405f-9737-76e9fc38b494"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5552.5" y="2105.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1121_sa208"> <notes> <html xmlns="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: HUGO:CCL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway. References_end</body> </html> </notes> <label text="CCL4"/> <bbox w="80.0" h="40.0" x="7350.0" y="1340.0"/> </glyph> <glyph class="macromolecule" id="s1122_sa205"> <notes> <html xmlns="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: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 MIP1B and IFNG secretion via PI3K pathway. PMID:21149606 Stimulation by NKp80-specific mAb induced marked IFNG production. PMID:22786724, PMID:20189481 LCP2 (SLP76) via VAV1 upregulates INFG production downstream of 2B4,NG2D signalings, probably via PI3K. PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PMID:15289500 DC-derived IL-2 Is Required In Vitro to Elicit IFNγ Production from NK Cells PMID:10843677 IL2 induces IFNG production in NK cells via MEK/ERK pathway activation. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end</body> </html> </notes> <label text="IFNG"/> <bbox w="80.0" h="40.0" x="3970.0" y="210.0"/> </glyph> <glyph class="macromolecule" id="s1123_sa203"> <notes> <html xmlns="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: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway via NKG2D. PMID:11015446 Cross-linking of the KIR2DS2/DAP12 receptor on NKL cells resulted in the dose-dependent secretion of IFNG and GM-CSF References_end</body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="7410.0" y="1440.0"/> </glyph> <glyph class="macromolecule" id="s1126_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL12A HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. PMID:8700208 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production, probably via STAT4. PMID:12372421 The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells PMID:22077060 Prolonged and repeated IL-12 stimulation may also activate an additional negative feedback mechanism to control and terminate the IL-12–induced proinflammatory immune response, representing a unique example of cytokine signaling auto-regulation. The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. PMID: PMID:9834059 NK cells stimulated by IL12 accumulate much higher levels of the IL-12Rbeta2-chain mRNA and are significantly more responsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor References_end</body> </html> </notes> <label text="IL12*"/> <bbox w="80.0" h="40.0" x="5060.0" y="210.0"/> </glyph> <glyph class="macromolecule" id="s1136_sa428" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GAB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16212621, PMID: PMID:10982827 Phosphorylation of Gab2 was enhanced by both IL-2 and IL-15 in T cells. IL-2- and IL-15-induced Gab2-PI3K association and downstream AKT activation in T cells and B cells. PMID:10849428 IL-2 but not IL-4, IL-12, or IFN-α/β, was able to induce the phosphorylation of Gab2 in NK cells and induces its association with PI3K (p85). JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. References_end</body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="5640.0" y="2810.0"/> <glyph class="state variable" id="_0cc2fdf9-59e7-4086-acf9-e0a81c2f5d85"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5635.0" y="2825.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1137_sa429" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GAB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16212621, PMID: PMID:10982827 Phosphorylation of Gab2 was enhanced by both IL-2 and IL-15 in T cells. IL-2- and IL-15-induced Gab2-PI3K association and downstream AKT activation in T cells and B cells. PMID:10849428 IL-2 but not IL-4, IL-12, or IFN-α/β, was able to induce the phosphorylation of Gab2 in NK cells and induces its association with PI3K (p85). JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. References_end</body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="5640.0" y="2720.0"/> <glyph class="state variable" id="_a337e10d-b8ea-48c3-ac8e-53b361e61613"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5632.5" y="2735.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1139_sa431" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2Rβ are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:10849428 JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="JAK3"/> <clone/> <bbox w="80.0" h="40.0" x="6270.0" y="1550.0"/> </glyph> <glyph class="macromolecule" id="s1139_sa450" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2Rβ are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:10849428 JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="JAK3"/> <clone/> <bbox w="80.0" h="40.0" x="6400.0" y="1550.0"/> </glyph> <glyph class="macromolecule" id="s1140_sa432" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). PMID:12759422 IL15 and IL21 induces STAT4 and STAT1 phosphorylation and binding to IFNG promotor, probably via JAK1 References_end</body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="6130.0" y="1440.0"/> </glyph> <glyph class="macromolecule" id="s1140_sa449" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). PMID:12759422 IL15 and IL21 induces STAT4 and STAT1 phosphorylation and binding to IFNG promotor, probably via JAK1 References_end</body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="6280.0" y="1440.0"/> </glyph> <glyph class="macromolecule" id="s1140_sa590" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). PMID:12759422 IL15 and IL21 induces STAT4 and STAT1 phosphorylation and binding to IFNG promotor, probably via JAK1 References_end</body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="3172.5" y="970.0"/> </glyph> <glyph class="macromolecule" id="s1140_sa591" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). PMID:12759422 IL15 and IL21 induces STAT4 and STAT1 phosphorylation and binding to IFNG promotor, probably via JAK1 References_end</body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="3172.5" y="1060.0"/> </glyph> <glyph class="macromolecule" id="s1140_sa1122" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). PMID:12759422 IL15 and IL21 induces STAT4 and STAT1 phosphorylation and binding to IFNG promotor, probably via JAK1 References_end</body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="1500.0" y="1570.0"/> </glyph> <glyph class="macromolecule" id="s1141_sa433" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:12759422 IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="STAT3"/> <bbox w="80.0" h="40.0" x="6100.0" y="1690.0"/> <glyph class="state variable" id="_13004e95-8bcd-4f29-a693-c8ace4b46871"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6095.0" y="1705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1142_sa434" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT5A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:10072525 STAT5a/b and not STAT3 were binding to the STAT element downstream of IL2 in NK cells. PMID:10358173, PMID:7479881 IL2 signaling induces IRF1 expression in NK cells, probably via STAT5. PMID:12759422 IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="STAT5A"/> <bbox w="80.0" h="40.0" x="6110.0" y="1770.0"/> <glyph class="state variable" id="_8e6ffedd-c10c-4854-80f6-605653dff35c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6105.0" y="1785.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1150_sa438" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:12759422 IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="STAT3"/> <bbox w="80.0" h="40.0" x="5940.0" y="1690.0"/> <glyph class="state variable" id="_c547d66a-aeb0-4ce8-946d-6c26ae1cfcf9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5932.5" y="1705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1151_sa440" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT5A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:10072525 STAT5a/b and not STAT3 were binding to the STAT element downstream of IL2 in NK cells. PMID:10358173, PMID:7479881 IL2 signaling induces IRF1 expression in NK cells, probably via STAT5. PMID:12759422 IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="STAT5A"/> <bbox w="80.0" h="40.0" x="5940.0" y="1770.0"/> <glyph class="state variable" id="_214618ca-f9c6-471b-b876-d508baf3653d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5932.5" y="1785.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1152_sa443" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT5B Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:9841920 Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity downstrea of IL2 and IL15. PMID:10072525 STAT5a/b and not STAT3 were binding to the STAT element downstream of IL2 in NK cells. PMID:12759422 IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="STAT5B"/> <bbox w="80.0" h="40.0" x="6100.0" y="1840.0"/> <glyph class="state variable" id="_1ab209c9-5d65-4c7a-a0a1-e58b5e84dcec"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6095.0" y="1855.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1153_sa444" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT5B Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:9841920 Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity downstrea of IL2 and IL15. PMID:10072525 STAT5a/b and not STAT3 were binding to the STAT element downstream of IL2 in NK cells. PMID:12759422 IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="STAT5B"/> <bbox w="80.0" h="40.0" x="5940.0" y="1840.0"/> <glyph class="state variable" id="_c3386b9e-5543-45b1-ad18-6e91afb35bb1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5932.5" y="1855.0"/> </glyph> </glyph> <glyph class="complex" id="s1154_csa45" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL2RA:IL2RB:IL2RG Identifiers_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2Rβ are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation References_end</body> </html> </notes> <label text="s1154"/> <bbox w="190.0" h="130.0" x="5745.0" y="755.0"/> <glyph class="macromolecule" id="s1156_sa435"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="5845.0" y="770.0"/> <glyph class="unit of information" id="_ea5728c9-6e05-4540-998c-10665cb95dc7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5862.5" y="765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1157_sa436"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="5845.0" y="820.0"/> <glyph class="state variable" id="_6a38d627-3b17-4e24-9cb3-d427d5ee10ba"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5840.0" y="840.0"/> </glyph> <glyph class="unit of information" id="_097d9c7c-9814-42f2-85a1-809fbf0b80f5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5862.5" y="815.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1158_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL2RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. References_end</body> </html> </notes> <label text="IL2RA"/> <bbox w="80.0" h="50.0" x="5755.0" y="820.0"/> <glyph class="unit of information" id="_6f3093d9-14b9-467b-a4b3-4210a151f1a6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5772.5" y="815.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1159_csa46" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL2:IL2RA:IL2RB:IL2RG Identifiers_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2Rβ are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:11489965, PMID:10843677 The IFN-γ secretion by NK cells induced by IL-2 depends on an ERK mitogen-activated protein kinase pathway References_end</body> </html> </notes> <label text="s1154"/> <bbox w="202.5" h="140.0" x="5818.75" y="980.0"/> <glyph class="macromolecule" id="s1160_sa445"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="5931.25" y="1005.0"/> <glyph class="unit of information" id="_7a6376a9-7699-4f4a-b819-31361a7f4b34"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5948.75" y="1000.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1161_sa446"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="5933.75" y="1052.5"/> <glyph class="state variable" id="_8245dcc1-943d-40e6-ba8e-80f0383fcfa9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5928.75" y="1072.5"/> </glyph> <glyph class="unit of information" id="_5edf8b91-1b5d-4f03-8e75-75bd9a8af9a8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5951.25" y="1047.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1162_sa447"> <notes> <html xmlns="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: HUGO:IL2RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. References_end</body> </html> </notes> <label text="IL2RA"/> <bbox w="80.0" h="50.0" x="5833.75" y="1052.5"/> <glyph class="unit of information" id="_a92ea18a-2931-496e-a2fa-200596d963b9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5851.25" y="1047.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1163_sa448"> <notes> <html xmlns="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: HUGO:1L2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:6164929 IL2 has the ability to augment the cytotoxic activity of natural killer (NK) cells agains tumor cells and potentiate effect of other cytokines (interferons). PMID: PMID:15289500 Dendric cells-derived IL-2 induces NK cell activation. DC-derived IL-2 Is Required In Vitro to Elicit IFNγ Production from NK Cells. PMID:23650441 IL-2–treated NK cells had a significantly increased contact efficiency as determined by the number of target cell contacts that cells underwent before initiating Ca2+ flux for the first time The ability of IL-2 to modulate NK cell cytotoxicity directly correlated with its ability to increase target–cell conjugation. IL-2 rapidly increases NK cell adhesion to and killing of weak targets. NK cell reactivity toward missing-self targets was enhanced in the absence of T reg cells and depended on the availability of IL-2 and activated T cells. CD4+ T cell–derived IL-2 activated NK cells in the absence of T reg cells. PMID:19528259 Nkp30‭ ‬signaling induces IL2‭ ‬release. PMID:9625766 IL2‭ ‬stimulates NKp44‭ ‬surface expression in NK cells. PMID:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end</body> </html> </notes> <label text="IL2"/> <bbox w="80.0" h="40.0" x="5831.25" y="1010.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1167_sa452" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:10544201, PMID:12372421 Perforin enhancers contain tandem Stat-like elements that are required for their IL-2 response and transactivation by Stat5. PMID:10072525 STAT5a/b and not STAT3 were binding to the STAT element downstream of IL2. IL-6 stimulation results in the detection of a complex on perforin promoter that can be blocked by the addition of anti-STAT1A antiserum. PMID:12372421 Activated STAT1, STAT3, STAT4, and STAT5 bound human perforin promoter in vitro. PMID:12133954 IL-2R signals can activate a pathway leading to NF-κB p50/p65 activation in NK cells, NF-κB binds to the upstream enhancer of the perforin gene and that this pathway is involved in the activation of perforin expression. PMID:12967644 IFNA induces perforin expression via STAT1 in NK cells. PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="70.0" h="25.0" x="3067.5" y="2937.5"/> </glyph> <glyph class="nucleic acid feature" id="s1168_sa453" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="3065.0" y="3017.5"/> <glyph class="unit of information" id="_e172a795-e76f-4a7d-8ac4-a3fc93976552"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3100.0" y="3012.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1169_sa454"> <notes> <html xmlns="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: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18760876 Combined immunogene therapy of IL-6 and IL-15 effectively relieved the inhibitory effect of TGF-beta and activated NK cell cytotoxicity. PMID:10072525 IL-6 stimulation results in the detection of a complex on perforin promoter that can be blocked by the addition of anti-STAT1A antiserum in NK cells. References_end</body> </html> </notes> <label text="IL6"/> <bbox w="80.0" h="40.0" x="3550.0" y="210.0"/> </glyph> <glyph class="macromolecule" id="s1170_sa519" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10072525, PMID:9715265, PMID:2143209 L-6 induces homo- and heterodimerized STAT1 alpha and STAT3 in NK cells. IL-6 stimulation results in the detection of a complex on perforin promoter that can be blocked by the addition of anti-STAT1A antiserum in NK cells. IL6 induces perphorin expression in T cells, and probably in NK cells. PMID:8683106, PMID:12967644 IFNA signaling induces STAT1 phosphorylation in NK cells. IFNalpha regulates NK cell cytotoxicity through STAT1 pathway. IFNA induces perforin, FASL and IRF1 expression via STAT1 in NK cells. PMID:8683106 IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3. References_end</body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="3270.0" y="1130.0"/> <glyph class="state variable" id="_731b9de5-a2f3-4b5f-b0b2-73a4b762f795"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3265.0" y="1145.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1171_sa456" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GZMA Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:24973821 mTOR has positive influence on GZMA level in the NK cells. References_end</body> </html> </notes> <label text="GZMA"/> <bbox w="90.0" h="25.0" x="2935.0" y="3077.5"/> <glyph class="unit of information" id="_123c4cdb-b617-46c7-a66d-54e529da4978"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2970.0" y="3072.5"/> </glyph> </glyph> <glyph class="complex" id="s1172_csa47" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:TSC1:TSC2 Identifiers_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="TSC1:TSC2"/> <bbox w="100.0" h="140.0" x="5810.0" y="2120.0"/> <glyph class="macromolecule" id="s1173_sa457"> <notes> <html xmlns="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: HUGO:TSC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="TSC1"/> <bbox w="80.0" h="40.0" x="5820.0" y="2140.0"/> </glyph> <glyph class="macromolecule" id="s1174_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:TSC2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="TSC2"/> <bbox w="80.0" h="40.0" x="5820.0" y="2180.0"/> <glyph class="state variable" id="_dfcf076e-76da-42d5-989b-121f1b647775"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5815.0" y="2195.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1176_csa48" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GDP:RHEB Identifiers_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. 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References_end</body> </html> </notes> <label text="RHEB"/> <bbox w="80.0" h="40.0" x="5700.0" y="1990.0"/> </glyph> <glyph class="simple chemical" id="s1180_sa462"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="5705.0" y="2047.5"/> </glyph> </glyph> <glyph class="complex" id="s1185_csa50" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:TSC1:TSC2 Identifiers_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="TSC1:TSC2"/> <bbox w="100.0" h="140.0" x="6030.0" y="2120.0"/> <glyph class="macromolecule" id="s1186_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>Identifiers_begin: HUGO:TSC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="TSC1"/> <bbox w="80.0" h="40.0" x="6040.0" y="2130.0"/> </glyph> <glyph class="macromolecule" id="s1187_sa465"> <notes> <html xmlns="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: HUGO:TSC2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end</body> </html> </notes> <label text="TSC2"/> <bbox w="80.0" h="40.0" x="6040.0" y="2170.0"/> <glyph class="state variable" id="_3aac52c9-1eeb-4ce1-b94c-34f37e9bdda8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6032.5" y="2185.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1189_sa470" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:WASF2 Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:21383498 IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function. References_end</body> </html> </notes> <label text="WASF2"/> <bbox w="80.0" h="40.0" x="3230.0" y="2080.0"/> <glyph class="state variable" id="_1e5f42b3-0de8-4baa-81f4-a92e7c89259b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3225.0" y="2095.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1190_sa471"> <notes> <html xmlns="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: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:9469432 IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells PMID: PMID:11449378 IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. PMID: PMID:10679398 The role of IL-18 in innate immunity. PMID: PMID:10925275 IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells. IFN-alpha and IL-12 strongly up-regulate mRNA expression of the IL-18R components, accessory protein-like (AcPL) and IL-1R-related protein (IL-1Rrp). In addition, IFN-alpha enhanced the expression of MyD88, an adaptor molecule involved in IL-18 signaling. References_end</body> </html> </notes> <label text="IL18"/> <bbox w="80.0" h="40.0" x="4600.0" y="160.0"/> </glyph> <glyph class="macromolecule" id="s113_sa473" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12133954 IL2R signaling induces IkBa degradation and formation of heterodimeric p50/p65 NFkB complexes References_end</body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="4330.0" y="2030.0"/> <glyph class="state variable" id="_4bca7671-e5d7-4609-983a-5fe43a1508f4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4325.0" y="2045.0"/> </glyph> </glyph> <glyph class="source and sink" id="s345_sa474" compartmentRef="c7_ca7"> <label text="s345"/> <bbox w="30.0" h="30.0" x="4405.0" y="1965.0"/> </glyph> <glyph class="macromolecule" id="s1194_sa475" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12133954 IL2R signaling induces IkBa degradation and formation of heterodimeric p50/p65 NFkB complexes References_end</body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="4190.0" y="1980.0"/> <glyph class="state variable" id="_d3fe59f4-b234-4c00-8fa3-369087c09f43"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4182.5" y="1995.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1195_sa476" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages References_end</body> </html> </notes> <label text="RELA"/> <bbox w="96.25" h="51.125" x="3821.875" y="1794.4375"/> </glyph> <glyph class="macromolecule" id="s1196_sa477" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="97.5" h="47.75" x="3821.25" y="1916.125"/> <glyph class="unit of information" id="_b00ede11-53a0-4edd-b2be-b141bc22c134"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3845.0" y="1911.125"/> </glyph> </glyph> <glyph class="complex" id="s291_csa53" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:NFKB1_p50*:NFKBIA:RELA Identifiers_end</body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="4332.5" y="1752.5"/> <glyph class="macromolecule" id="s293_sa481"> <notes> <html xmlns="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: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="4347.5" y="1859.5"/> <glyph class="unit of information" id="_8b0a4b40-94b4-40e4-8c92-c4df72256351"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4362.5" y="1854.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s292_sa482"> <notes> <html xmlns="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: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="4347.5" y="1814.5"/> </glyph> <glyph class="macromolecule" id="s1197_sa483"> <notes> <html xmlns="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: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12133954 IL2R signaling induces IkBa degradation and formation of heterodimeric p50/p65 NFkB complexes References_end</body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="4346.0" y="1768.5"/> <glyph class="state variable" id="_166580c7-7796-4888-b53e-6abd9e74ec9f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4341.0" y="1783.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s305_csa54" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:NFKB1_p50*:NFKBIA:RELA Identifiers_end</body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="4172.5" y="1762.5"/> <glyph class="macromolecule" id="s307_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="4187.5" y="1869.5"/> <glyph class="unit of information" id="_4a520382-b33f-4609-921f-51378374a191"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4202.5" y="1864.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s306_sa485"> <notes> <html xmlns="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: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="4187.5" y="1827.5"/> </glyph> <glyph class="macromolecule" id="s101_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12133954 IL2R signaling induces IkBa degradation and formation of heterodimeric p50/p65 NFkB complexes References_end</body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="4186.0" y="1778.5"/> <glyph class="state variable" id="_d3b8ce5e-2e75-4345-a2da-a551cf580128"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4178.5" y="1793.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s647_csa55" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CHUK:IKBKG:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: complex PMID‭:15145317 The activated IKK complex, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription References_end</body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="4340.0" y="1578.0"/> <glyph class="macromolecule" id="s1200_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IKBKG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end</body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="4348.0" y="1585.0"/> <glyph class="state variable" id="_e0073bef-6368-43b6-8fef-2d6e157c30bb"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="4418.0" y="1600.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1201_sa488"> <notes> <html xmlns="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: HUGO:IKBKB Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end</body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="4349.0" y="1631.0"/> <glyph class="state variable" id="_d003d582-c5c4-4fa7-928e-a841245da2fe"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4341.5" y="1646.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1202_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end</body> </html> </notes> <label text="CHUK"/> <bbox w="80.0" h="40.0" x="4350.0" y="1676.0"/> </glyph> </glyph> <glyph class="complex" id="s174_csa56" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CHUK:IKBKG:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: complex PMID‭:15145317 The activated IKK complex, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription References_end</body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="4170.0" y="1578.0"/> <glyph class="macromolecule" id="s1203_sa490"> <notes> <html xmlns="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: HUGO:IKBKG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end</body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="4178.0" y="1585.0"/> <glyph class="state variable" id="_fec37429-e81c-4968-9fd0-5c4a80149521"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4253.0" y="1600.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1204_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end</body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="4180.0" y="1630.0"/> <glyph class="state variable" id="_240ed0a5-5161-4dd8-bf44-d2b4d07da3c8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4175.0" y="1645.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1711_sa492"> <notes> <html xmlns="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: HUGO:CHUK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end</body> </html> </notes> <label text="CHUK"/> <bbox w="80.0" h="40.0" x="4180.0" y="1670.0"/> </glyph> </glyph> <glyph class="complex" id="s178_csa52" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:NFKB1_p50*:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:12133954 IL2R signaling induces IkBa degradation and formation of heterodimeric p50/p65 NFkB complexes NF-κB binds to the upstream enhancer of the perforin gene and that this pathway is involved in the activation of perforin expression downstream of NFkB PMID:12759422, PMID:10679398 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. Probably via NIK pathway. PMID:21224476, PMID:12759422 NFKBIZ binds to the IFNG promoter in response to IL-12 and IL-18 and encreases promoter activity. NFKBIZ regulates IFNG expression by bindingof NF-κB p65/p50 on IFNG promoter . References_end</body> </html> </notes> <label text="RELA:p50"/> <bbox w="100.0" h="127.25" x="3990.0" y="1836.375"/> <glyph class="macromolecule" id="s235_sa480"> <notes> <html xmlns="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>HUGO:NFKB1 MODULE:MACROPHAGE PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="86.75" h="50.0" x="3996.625" y="1888.625"/> <glyph class="unit of information" id="_8e925372-282a-4449-8ff9-5dd37c5f1a1f"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4015.0" y="1883.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s20_sa479"> <notes> <html xmlns="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: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages References_end</body> </html> </notes> <label text="RELA"/> <bbox w="87.5" h="37.25" x="3996.25" y="1845.0"/> </glyph> </glyph> <glyph class="phenotype" id="s1206_sa513"> <notes> <html xmlns="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>References_begin: PMID:22683124 PLCG2-deficient NK cells avd VAV1-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:19454690 Stimulation through either FcR or NKG2D increases β1 and β2 integrin-mediated adhesion of human NK cells. References_end</body> </html> </notes> <label text="Conjugate formation"/> <bbox w="260.0" h="75.0" x="7350.0" y="3602.5"/> </glyph> <glyph class="complex" id="s128_csa62" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL6R:gp130* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:9620640 IL6 receptor contains two subunits IL6R and gp130. References_end</body> </html> </notes> <label text="IL6R"/> <bbox w="176.5" h="80.0" x="3631.75" y="490.0"/> <glyph class="macromolecule" id="s1208_sa514"> <notes> <html xmlns="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: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end</body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="3718.25" y="505.0"/> <glyph class="state variable" id="_83494b37-86cf-46cf-9d5b-ff556849a92b"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="3780.75" y="502.54102"/> </glyph> <glyph class="unit of information" id="_16588a9b-3c38-4f92-9a79-52ed4cb2cbfe"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3735.75" y="500.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1209_sa515"> <notes> <html xmlns="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: HUGO:IL6R Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end</body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="3638.25" y="505.0"/> <glyph class="unit of information" id="_b0b548c6-4b21-4710-8d29-a3c0cca08e82"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3655.75" y="500.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1210_csa63" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL6:IL6R:gp130* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:9620640 IL6 receptor contains two subunits IL6R and gp130. References_end</body> </html> </notes> <label text="IL6R"/> <bbox w="226.5" h="157.25" x="3656.75" y="701.375"/> <glyph class="macromolecule" id="s1211_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end</body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="3763.25" y="786.375"/> <glyph class="state variable" id="_caec22e4-4b79-4e23-b395-a2409b3cdde8"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="3825.75" y="783.916"/> </glyph> <glyph class="unit of information" id="_58c6b946-3fd8-4c48-8548-d581fffae0c0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3780.75" y="781.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1212_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end</body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="3676.75" y="783.625"/> <glyph class="unit of information" id="_ba7abc40-dcc8-4e63-9d54-ba45fb08b08d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3694.25" y="778.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s1213_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18760876 Combined immunogene therapy of IL-6 and IL-15 effectively relieved the inhibitory effect of TGF-beta and activated NK cell cytotoxicity. PMID:10072525 IL-6 stimulation results in the detection of a complex on perforin promoter that can be blocked by the addition of anti-STAT1A antiserum in NK cells. References_end</body> </html> </notes> <label text="IL6"/> <bbox w="80.0" h="40.0" x="3680.0" y="720.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1214_sa455" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10072525, PMID:9715265, PMID:2143209 L-6 induces homo- and heterodimerized STAT1 alpha and STAT3 in NK cells. IL-6 stimulation results in the detection of a complex on perforin promoter that can be blocked by the addition of anti-STAT1A antiserum in NK cells. IL6 induces perphorin expression in T cells, and probably in NK cells. PMID:8683106, PMID:12967644 IFNA signaling induces STAT1 phosphorylation in NK cells. IFNalpha regulates NK cell cytotoxicity through STAT1 pathway. IFNA induces perforin, FASL and IRF1 expression via STAT1 in NK cells. PMID:8683106 IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3. References_end</body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="3270.0" y="1220.0"/> <glyph class="state variable" id="_2787c652-959e-45f9-9b90-348f2192792c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3262.5" y="1235.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1215_sa520" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10358173 IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells via STAT4. PMID:8920893 The transcription factor interferon regulatory factor-1 is essential for natural killer cell function. IRF-1-deficient mice displayed a normal frequency of NK marker-positive cells, but exhibited greatly reduced NK cell-mediated cytotoxicity after both virus infection and stimulation with the IFN inducer polyinosinic:polycytidilic acid in vivo. In vitro, cytolytic activity in IRF-1-deficient NK cells remained defective after stimulation with IFN-beta, IL-2, and IL-12. References_end</body> </html> </notes> <label text="IRF1"/> <bbox w="80.0" h="40.0" x="3400.0" y="1340.0"/> </glyph> <glyph class="macromolecule" id="s1216_sa521" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:14581002 IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. IFN-alpha and IL-12 induce Stat4 DNA binding to the IRF-4 promoter GAS element References_end</body> </html> </notes> <label text="IRF4"/> <bbox w="80.0" h="40.0" x="4840.0" y="1640.0"/> </glyph> <glyph class="macromolecule" id="s1127_sa421" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="80.0" h="40.0" x="5000.0" y="1360.0"/> <glyph class="state variable" id="_ae94df2a-6558-47fe-9582-b2333a5e1027"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5075.0" y="1371.385"/> </glyph> <glyph class="state variable" id="_bb7a4c27-3aa9-465b-85c7-214cd4b814dc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4992.5" y="1375.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1219_sa524" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22888135 IL12 upregulates IL2RA (CD25) expression via STAT4. PMID:12244150 IL-15 induces STAT5 DNA binding to the IL-2Rα GAS-c/GAS-n element and upregulates IL2RA expression. Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL2RA"/> <bbox w="90.0" h="25.0" x="5765.0" y="1447.5"/> <glyph class="unit of information" id="_19f46761-72a8-4405-9a56-fc44e8b6afb9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5800.0" y="1442.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1220_sa525" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22888135 IL12 upregulates IL2RA (CD25) expression via STAT4. PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL2RA"/> <bbox w="70.0" h="25.0" x="5655.0" y="1447.5"/> </glyph> <glyph class="macromolecule" id="s1221_sa526" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. References_end</body> </html> </notes> <label text="IL2RA"/> <bbox w="80.0" h="50.0" x="5890.0" y="1435.0"/> <glyph class="unit of information" id="_ef4c790b-d876-41d6-a53a-876b863d8721"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5907.5" y="1430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s133_sa530" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK11 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 GENECARDS:MAPK11 HUGO:MAPK12 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 GENECARDS:MAPK12 HUGO:MAPK13 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 GENECARDS:MAPK13 HUGO:MAPK14 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 GENECARDS:MAPK14 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 PMID:10961885, PMID:15345584, PMID:10903731 IL-12 and IL18 activate p38 in NK cells. IFNG mRNA is stabilized by MAPK p38. MAPK p38 signaling downstream of IL18 and IL 12 increases IFNG production. PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="4570.0" y="1350.0"/> <glyph class="state variable" id="_6ce20f7f-3121-4bb8-a918-2bcdf0d73948"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4565.0" y="1364.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s134_sa531" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK11 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 GENECARDS:MAPK11 HUGO:MAPK12 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 GENECARDS:MAPK12 HUGO:MAPK13 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 GENECARDS:MAPK13 HUGO:MAPK14 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 GENECARDS:MAPK14 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 PMID:10961885, PMID:15345584, PMID:10903731 IL-12 and IL18 activate p38 in NK cells. IFNG mRNA is stabilized by MAPK p38. MAPK p38 signaling downstream of IL18 and IL 12 increases IFNG production. PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="4570.0" y="1430.0"/> <glyph class="state variable" id="_1fa60ab4-c449-4ec3-a620-11fde2197600"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4562.5" y="1444.9681"/> </glyph> </glyph> <glyph class="complex" id="s1225_csa64" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL12RB1:IL12RB2 Identifiers_end References_begin: PMID: 15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="s1225"/> <bbox w="175.0" h="102.5" x="4892.5" y="538.75"/> <glyph class="macromolecule" id="s1709_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL12RB1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB1"/> <bbox w="80.0" h="50.0" x="4897.5" y="566.25"/> <glyph class="unit of information" id="_46bf63cb-1b47-48f6-9f6e-fa035d94c0b1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4915.0" y="561.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s1230_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB2"/> <bbox w="80.0" h="50.0" x="4980.0" y="565.0"/> <glyph class="unit of information" id="_7d758e84-8ca4-428e-96f8-d43bf629286c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4997.5" y="560.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1232_csa65" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL12*:IL12RB1:IL12RB2 Identifiers_end</body> </html> </notes> <label text="s1225"/> <bbox w="210.0" h="135.0" x="4985.0" y="782.5"/> <glyph class="macromolecule" id="s1233_sa534"> <notes> <html xmlns="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: HUGO:IL12RB1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB1"/> <bbox w="80.0" h="50.0" x="5005.0" y="842.5"/> <glyph class="unit of information" id="_7a71e82e-b069-4388-8c15-e27ca2099cb2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5022.5" y="837.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1234_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB2"/> <bbox w="80.0" h="50.0" x="5095.0" y="842.5"/> <glyph class="unit of information" id="_207719ed-f209-4310-a55c-e2aabc6f97d8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5112.5" y="837.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1231_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL12A HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. PMID:8700208 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production, probably via STAT4. PMID:12372421 The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells PMID:22077060 Prolonged and repeated IL-12 stimulation may also activate an additional negative feedback mechanism to control and terminate the IL-12–induced proinflammatory immune response, representing a unique example of cytokine signaling auto-regulation. The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. PMID: PMID:9834059 NK cells stimulated by IL12 accumulate much higher levels of the IL-12Rbeta2-chain mRNA and are significantly more responsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor References_end</body> </html> </notes> <label text="IL12*"/> <bbox w="80.0" h="40.0" x="5005.0" y="792.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1235_sa539" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="JAK2"/> <clone/> <bbox w="80.0" h="40.0" x="4990.0" y="1010.0"/> <glyph class="state variable" id="_1d1b5502-90e9-45bb-828d-f6c978f74bef"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4985.0" y="1025.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1235_sa1124" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="JAK2"/> <clone/> <bbox w="80.0" h="40.0" x="1420.0" y="1640.0"/> <glyph class="state variable" id="_885b2453-e6d1-42e8-afbe-231ca8843513"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1415.0" y="1655.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1236_sa540" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="TYK2"/> <clone/> <bbox w="80.0" h="40.0" x="5120.0" y="1010.0"/> <glyph class="state variable" id="_1e6a78d4-4d3e-412b-aa79-30a50331e85c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5115.0" y="1025.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1236_sa592" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="TYK2"/> <clone/> <bbox w="80.0" h="40.0" x="3342.5" y="970.0"/> <glyph class="state variable" id="_022dcfa2-fe0e-4eea-b900-8494e8469197"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3337.5" y="985.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1236_sa593" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="TYK2"/> <clone/> <bbox w="80.0" h="40.0" x="3342.5" y="1060.0"/> <glyph class="state variable" id="_b4cdfddf-98f0-4828-9251-c76efbed21fa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3337.5" y="1075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1236_sa1123" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="TYK2"/> <clone/> <bbox w="80.0" h="40.0" x="1370.0" y="1710.0"/> <glyph class="state variable" id="_0a78353d-da55-46c4-bbad-c7dc91954b4c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1365.0" y="1725.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1240_sa522" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="80.0" h="40.0" x="5000.0" y="1240.0"/> <glyph class="state variable" id="_e78a201b-b27e-420b-8c28-1c61616d27b5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5075.0" y="1251.385"/> </glyph> <glyph class="state variable" id="_084e71d4-e4bc-452c-892d-3387fedade79"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4995.0" y="1255.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1241_sa541" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="80.0" h="40.0" x="5000.0" y="1430.0"/> <glyph class="state variable" id="_b38ed9b0-cc50-44ac-bc63-e0d3c9061ceb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5072.5" y="1441.385"/> </glyph> <glyph class="state variable" id="_1e356c55-1580-491c-a61b-1b7aecb3d1da"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4992.5" y="1445.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1242_sa542" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAP2K6 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of Il12.. References_end</body> </html> </notes> <label text="MAP2K6"/> <clone/> <bbox w="80.0" h="40.0" x="4690.0" y="1350.0"/> </glyph> <glyph class="macromolecule" id="s1242_sa543" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAP2K6 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of Il12.. References_end</body> </html> </notes> <label text="MAP2K6"/> <clone/> <bbox w="80.0" h="40.0" x="4690.0" y="1260.0"/> </glyph> <glyph class="nucleic acid feature" id="s1243_sa544" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:8700208, PMID:9715265, PMID:11449378 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. PMID:12759422 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:18768831, PMID:16713975 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. PMID:12244150, PMID:12759422 Both IL-15 and IL-21 induced the expression of the IFN-γ gene via STATs and IL18 via NF-kB. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-gamma gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-gamma gene regulatory sites. IL-18, however, activated the binding of NF-kappa B to the IFN-gamma promoter NF-kappa B site. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IFNG"/> <bbox w="78.75" h="38.125" x="3990.625" y="1090.9375"/> </glyph> <glyph class="nucleic acid feature" id="s1244_sa545" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:8700208, PMID:9715265, PMID:11449378 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. PMID:12759422 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:18768831, PMID:16713975 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end</body> </html> </notes> <label text="IFNG"/> <bbox w="115.0" h="32.5" x="3974.375" y="989.0625"/> <glyph class="unit of information" id="_e09aebdd-956b-4383-bd8c-35ad7b2bf9bc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4021.875" y="984.0625"/> </glyph> </glyph> <glyph class="macromolecule" id="s1245_sa546" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JUN Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11801649 IL18 induces accumulation of serine-phosphorylated c-Jun capable of activating c-Jun N-terminal kinase in T cells. References_end</body> </html> </notes> <label text="JUN"/> <bbox w="80.0" h="40.0" x="4238.0" y="1450.0"/> <glyph class="state variable" id="_6c5b5637-4022-4186-876d-5cfdcf1b2471"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4230.5" y="1465.0"/> </glyph> </glyph> <glyph class="complex" id="s1246_csa66" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:JUN:STAT4 Identifiers_end References_begin: PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. References_end</body> </html> </notes> <label text="s1246"/> <bbox w="100.0" h="140.0" x="3960.0" y="1440.0"/> <glyph class="macromolecule" id="s1247_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"> <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: HUGO:JUN Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11801649 IL18 induces accumulation of serine-phosphorylated c-Jun capable of activating c-Jun N-terminal kinase in T cells. 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Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="80.0" h="40.0" x="3970.0" y="1510.0"/> <glyph class="state variable" id="_3811062b-9fa2-44e9-8f0b-02f2011186a3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4042.5" y="1521.385"/> </glyph> <glyph class="state variable" id="_0282650d-9195-41ea-b77b-66dd2468725f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3962.5" y="1525.0"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1253_sa553" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10358173 IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells via STAT4. References_end</body> </html> </notes> <label text="IRF1"/> <bbox w="90.0" h="25.0" x="3395.0" y="1277.5"/> <glyph class="unit of information" id="_b780fe0d-70ee-489d-8d69-93535c66e2b6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3430.0" y="1272.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1255_sa555" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF8 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:14581002, PMID:19710469 IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. Probably wia STAT4 References_end</body> </html> </notes> <label text="IRF8"/> <bbox w="80.0" h="40.0" x="4940.0" y="1640.0"/> </glyph> <glyph class="nucleic acid feature" id="s1256_sa556" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:14581002 IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. IFN-alpha and IL-12 induce Stat4 DNA binding to the IRF-4 promoter GAS element References_end</body> </html> </notes> <label text="IRF4"/> <bbox w="70.0" h="25.0" x="4845.0" y="1497.5"/> </glyph> <glyph class="nucleic acid feature" id="s1257_sa557" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF8 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:14581002, PMID:19710469 IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. Probably wia STAT4 References_end</body> </html> </notes> <label text="IRF8"/> <bbox w="70.0" h="25.0" x="4945.0" y="1497.5"/> </glyph> <glyph class="nucleic acid feature" id="s1258_sa558" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:14581002 IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. IFN-alpha and IL-12 induce Stat4 DNA binding to the IRF-4 promoter GAS element References_end</body> </html> </notes> <label text="IRF4"/> <bbox w="90.0" h="25.0" x="4835.0" y="1577.5"/> <glyph class="unit of information" id="_aa4051e5-b128-4857-bbdb-fa1dddca28f3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4870.0" y="1572.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1259_sa559" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF8 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:14581002, PMID:19710469 IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells. Probably wia STAT4 References_end</body> </html> </notes> <label text="IRF8"/> <bbox w="90.0" h="25.0" x="4935.0" y="1577.5"/> <glyph class="unit of information" id="_7c9f46a1-b5cb-4f1e-b762-4ef8152d07fc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4970.0" y="1572.5"/> </glyph> </glyph> <glyph class="complex" id="s1260_csa67" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL18R1:IL18RAP Identifiers_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="s1260"/> <bbox w="180.0" h="100.0" x="4430.0" y="490.0"/> <glyph class="macromolecule" id="s1264_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL18R1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18R1"/> <bbox w="80.0" h="50.0" x="4440.0" y="515.0"/> <glyph class="unit of information" id="_d9c15ea1-f1bc-47b5-bfcd-56c479e3730f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4457.5" y="510.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1265_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: HUGO:IL18RAP Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18RAP"/> <bbox w="80.0" h="50.0" x="4520.0" y="515.0"/> <glyph class="unit of information" id="_42d62740-fcb8-461b-8e0d-fcf05aff2664"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4537.5" y="510.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1263_csa68" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL18:IL18R1:IL18RAP:MYD88 Identifiers_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:10903731 IL-18-binding complex is constitutively expressed in the human NK cell line and cytotoxic activity is augmented by IL-18 References_end</body> </html> </notes> <label text="s1260"/> <bbox w="187.5" h="172.5" x="4632.5" y="677.5"/> <glyph class="macromolecule" id="s1261_sa562"> <notes> <html xmlns="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: HUGO:IL18R1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18R1"/> <bbox w="80.0" h="50.0" x="4640.0" y="735.0"/> <glyph class="unit of information" id="_5e9e50e3-48f0-49e6-b3b1-721846bbef20"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4657.5" y="730.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1262_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: HUGO:IL18RAP Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18RAP"/> <bbox w="80.0" h="50.0" x="4730.0" y="735.0"/> <glyph class="unit of information" id="_018476d0-3d31-428a-b7cc-9900c8c14937"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4747.5" y="730.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1266_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:9469432 IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells PMID: PMID:11449378 IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. PMID: PMID:10679398 The role of IL-18 in innate immunity. PMID: PMID:10925275 IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells. IFN-alpha and IL-12 strongly up-regulate mRNA expression of the IL-18R components, accessory protein-like (AcPL) and IL-1R-related protein (IL-1Rrp). In addition, IFN-alpha enhanced the expression of MyD88, an adaptor molecule involved in IL-18 signaling. References_end</body> </html> </notes> <label text="IL18"/> <bbox w="80.0" h="40.0" x="4640.0" y="690.0"/> </glyph> <glyph class="macromolecule" id="s1277_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:9697844 MyD88-deficient mice also had defects in IL-18-mediated functions including NK cell activity. Dominant negativ MyD88 bloks IL18 induced activation of NFkB and AP1 (via JNK) PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:20876105, PMID:17027520, PMID:15241416 IL18 induces IκB‐ζ expression in NK cells. the induction of IκB‐ζ depends on MyD88 as the induction was not observed in MyD88‐deficient cells References_end</body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="4640.0" y="790.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1267_sa565" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:9697844 MyD88-deficient mice also had defects in IL-18-mediated functions including NK cell activity. Dominant negativ MyD88 bloks IL18 induced activation of NFkB and AP1 (via JNK) PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:20876105, PMID:17027520, PMID:15241416 IL18 induces IκB‐ζ expression in NK cells. the induction of IκB‐ζ depends on MyD88 as the induction was not observed in MyD88‐deficient cells References_end</body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="4440.0" y="710.0"/> </glyph> <glyph class="macromolecule" id="s1269_sa567" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TRAF6 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. References_end</body> </html> </notes> <label text="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="4520.0" y="1100.0"/> </glyph> <glyph class="macromolecule" id="s1269_sa580" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TRAF6 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. References_end</body> </html> </notes> <label text="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="4520.0" y="1180.0"/> </glyph> <glyph class="macromolecule" id="s1270_sa568" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11801649 IL18 induces accumulation of serine-phosphorylated c-Jun capable of activating c-Jun N-terminal kinase in T cells. PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 References_end</body> </html> </notes> <label text="AP1*"/> <clone/> <bbox w="80.0" h="40.0" x="4378.0" y="1360.0"/> </glyph> <glyph class="macromolecule" id="s1270_sa569" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11801649 IL18 induces accumulation of serine-phosphorylated c-Jun capable of activating c-Jun N-terminal kinase in T cells. PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 References_end</body> </html> </notes> <label text="AP1*"/> <clone/> <bbox w="80.0" h="40.0" x="4378.0" y="1450.0"/> </glyph> <glyph class="macromolecule" id="s1271_sa570" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JUN Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11801649 IL18 induces accumulation of serine-phosphorylated c-Jun capable of activating c-Jun N-terminal kinase in T cells. References_end</body> </html> </notes> <label text="JUN"/> <bbox w="80.0" h="40.0" x="4238.0" y="1360.0"/> <glyph class="state variable" id="_5b4e95d6-0aa6-4a67-a16a-bca85ada38a3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4233.0" y="1375.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1273_sa574" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:17100878 NKG2D plays a major role in triggering cytotoxicity against target cells, such as the murine lymphoma line YAC-1. NKG2D detects cell surface molecules distantly related to MHC class I proteins, which are induced by viral infection and tumor transformation. As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:22491735 MiR-1245 is a direct negative regulator of NKG2D in NK cells downstream of TGFB. Knocking down microRNA-1245 in natural killer cells resulted in higher NKG2D expression and relative resistance to the effect of TGFB1. PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. References_end</body> </html> </notes> <label text="NKG2D*"/> <bbox w="90.0" h="25.0" x="3617.5" y="3287.5"/> <glyph class="unit of information" id="_19273659-b8b5-46f4-876b-5ef1f64f1c3f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3652.5" y="3282.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1274_sa575" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK3K14 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10679398 TRAF6 relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation downstream of IL18.. References_end</body> </html> </notes> <label text="MAP3K14"/> <clone/> <bbox w="80.0" h="40.0" x="4490.0" y="1560.0"/> </glyph> <glyph class="macromolecule" id="s1274_sa581" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAPK3K14 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10679398 TRAF6 relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation downstream of IL18.. References_end</body> </html> </notes> <label text="MAP3K14"/> <clone/> <bbox w="80.0" h="40.0" x="4490.0" y="1480.0"/> </glyph> <glyph class="macromolecule" id="s1275_sa576" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRAK4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID: PMID:12682231 IL-1 receptor-associated kinase 4 is essential for IL-18-mediated NK and Th1 cell responses. IRAK-4 is essential for the induction of IFNG by IL-18 stimulations. Although wild-type cells showed a typical course of IκB degradation peaking at 15 min, almost no IκB degradation was observable in IRAK-4-deficient Th1 cells following IL-18 stimulation. IL-18-induced AP-1 is completely abolished in IRAK-4-deficient cells. References_end</body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="4450.0" y="930.0"/> <glyph class="state variable" id="_267efed5-88b0-413b-87d2-09425b657184"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4445.0" y="944.96814"/> </glyph> </glyph> <glyph class="simple chemical" id="s1276_sa141" compartmentRef="c5_ca5"> <notes> <html xmlns="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>References_begin: PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PMID:12740575, PMID:15972651 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release. The calcium signal generated by PLCG is required for NKG2D-initiated killing. Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:11265639 Cross-linking of NKp80 induces Ca 2+ mobilization and triggering of cytotoxicity in both resting and activated NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. References_end</body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="5127.5" y="1977.5"/> </glyph> <glyph class="macromolecule" id="s1278_sa579" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRAK4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID: PMID:12682231 IL-1 receptor-associated kinase 4 is essential for IL-18-mediated NK and Th1 cell responses. IRAK-4 is essential for the induction of IFNG by IL-18 stimulations. Although wild-type cells showed a typical course of IκB degradation peaking at 15 min, almost no IκB degradation was observable in IRAK-4-deficient Th1 cells following IL-18 stimulation. IL-18-induced AP-1 is completely abolished in IRAK-4-deficient cells. References_end</body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="4450.0" y="1000.0"/> <glyph class="state variable" id="_3424a727-f968-42bb-af92-43c799fdc4dc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4442.5" y="1014.96814"/> </glyph> </glyph> <glyph class="macromolecule" id="s1268_sa566" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRAK1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:10190904 induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. References_end</body> </html> </notes> <label text="IRAK1"/> <clone/> <bbox w="80.0" h="40.0" x="4600.0" y="920.0"/> <glyph class="state variable" id="_5ec1929b-4384-4798-bc8d-6317665a3d9e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4592.5" y="935.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1268_sa578" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRAK1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:10190904 induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. References_end</body> </html> </notes> <label text="IRAK1"/> <clone/> <bbox w="80.0" h="40.0" x="4600.0" y="990.0"/> <glyph class="state variable" id="_8b538f66-30e1-4566-9966-9babd50c6535"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4592.5" y="1005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1280_sa583" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:HMGB1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:15802534 Activated NK cells release HMGB1, which promotes inflammation and induces DC maturation. IL-18 induces HMGB1 secretion by NK cells References_end</body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="4167.5" y="910.0"/> </glyph> <glyph class="macromolecule" id="s1281_sa584"> <notes> <html xmlns="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: HUGO:HMGB1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:15802534 Activated NK cells release HMGB1, which promotes inflammation and induces DC maturation. IL-18 induces HMGB1 secretion by NK cells References_end</body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="4190.0" y="200.0"/> </glyph> <glyph class="complex" id="s1282_csa69" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IFNAR1:IFNAR2 Identifiers_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. References_end</body> </html> </notes> <label text="s1282"/> <bbox w="120.0" h="175.0" x="3190.0" y="512.5"/> <glyph class="macromolecule" id="s1297_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IFNAR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. References_end</body> </html> </notes> <label text="IFNAR1"/> <bbox w="80.0" h="50.0" x="3210.0" y="542.5"/> <glyph class="unit of information" id="_d86e5853-2533-4872-a854-2c52a62f852f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3227.5" y="537.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1298_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IFNAR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs References_end</body> </html> </notes> <label text="IFNAR2"/> <bbox w="80.0" h="50.0" x="3210.0" y="602.5"/> <glyph class="unit of information" id="_857a7e9e-9ddb-4b5e-87d6-3719ee9c0eef"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3227.5" y="597.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1286_csa70" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IFNA:IFNAR1:IFNAR2 Identifiers_end References_begin: PMID:25333658 IFNAR−/− NK cells produce significantly less granzyme B than wild-type competitor NK cells PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. References_end</body> </html> </notes> <label text="s1282"/> <bbox w="119.75" h="221.75" x="3050.125" y="709.125"/> <glyph class="macromolecule" id="s1285_sa587"> <notes> <html xmlns="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: HUGO:IFNA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. PMID:11449378 IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. IFN-α and IL-12 induce tyrosine phosphorylation and DNA binding of Stat4 to IFN-γ promoter GAS element PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. http://www.tandfonline.com/doi/abs/10.4161/21624011.2014.948705#.VJLI5efuK2s IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells. References_end</body> </html> </notes> <label text="IFNA"/> <bbox w="80.0" h="40.0" x="3069.125" y="736.125"/> </glyph> <glyph class="macromolecule" id="s1287_sa588"> <notes> <html xmlns="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: HUGO:IFNAR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. References_end</body> </html> </notes> <label text="IFNAR1"/> <bbox w="80.0" h="50.0" x="3070.125" y="794.125"/> <glyph class="unit of information" id="_5dca0c6e-92bc-47bc-aef9-be9add154579"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3087.625" y="789.125"/> </glyph> </glyph> <glyph class="macromolecule" id="s1288_sa589"> <notes> <html xmlns="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: HUGO:IFNAR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs References_end</body> </html> </notes> <label text="IFNAR2"/> <bbox w="80.0" h="50.0" x="3070.125" y="854.125"/> <glyph class="unit of information" id="_48b56107-f6a3-4be6-a157-ea6627a1a6c2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3087.625" y="849.125"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1289_sa594" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:FASLG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. References_end</body> </html> </notes> <label text="FASL*"/> <bbox w="90.0" h="25.0" x="2085.0" y="2777.5"/> <glyph class="unit of information" id="_bbf81f2c-8709-468c-b8f7-26dd73d43456"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2120.0" y="2772.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1290_sa595" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:FASLG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. PMID:8892629 IFN-gamma-inducing factor (IL18) up-regulates Fas ligand-mediated cytotoxic activity (via upregulation of FASL expression) of murine natural killer cell clones PMID:15120186 2B4 and LFA1 signalings upregulates FasL mRNA and surface expression in NK cells. FasL transcription is inhibited by NKG2A/CD94 References_end</body> </html> </notes> <label text="FASL*"/> <bbox w="70.0" h="25.0" x="2095.0" y="2707.5"/> </glyph> <glyph class="macromolecule" id="s1291_sa596" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:FASLG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. PMID:9858524 Mature CD56(+) NK cells mediate TRAIL-dependent and FasL-dependent cytotoxicity of tumor cells. PMID:8892629 IFN-gamma-inducing factor (IL18) up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones References_end</body> </html> </notes> <label text="FASL*"/> <bbox w="80.0" h="40.0" x="2090.0" y="2840.0"/> </glyph> <glyph class="nucleic acid feature" id="s1254_sa554" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10358173, PMID:14581002 IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells via STAT4. IL2 signaling induces IRF1 expression in NK cells, probably via STAT5. IL-12 and IL-2 synergistically induce IRF-1 expression. IL-4 does not up-regulate IRF-1 expression and fails to inhibit IL-12-dependent up-regulation of IRF-1. PMID:12967644 IFNA induces IRF1 expression via STAT1 in NK cells. References_end</body> </html> </notes> <label text="IRF1"/> <bbox w="70.0" h="25.0" x="3405.0" y="1207.5"/> </glyph> <glyph class="macromolecule" id="s1292_sa597" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:9858524 Mature CD56(+) NK cells mediate TRAIL-dependent and FasL-dependent cytotoxicity of tumor cells. PMID:11257133 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. References_end</body> </html> </notes> <label text="TRAIL*"/> <bbox w="80.0" h="40.0" x="1980.0" y="2840.0"/> </glyph> <glyph class="nucleic acid feature" id="s1293_sa598" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11257133 Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. References_end</body> </html> </notes> <label text="TRAIL*"/> <bbox w="90.0" h="25.0" x="1985.0" y="2777.5"/> <glyph class="unit of information" id="_333418f9-75ac-47bb-9fac-b78c262d2b66"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2020.0" y="2772.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1294_sa599" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:11257133 Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. References_end</body> </html> </notes> <label text="TRAIL*"/> <bbox w="70.0" h="25.0" x="1995.0" y="2707.5"/> </glyph> <glyph class="macromolecule" id="s1295_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IFNB Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. References_end</body> </html> </notes> <label text="IFNB"/> <bbox w="80.0" h="40.0" x="3310.0" y="210.0"/> </glyph> <glyph class="complex" id="s1300_csa71" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:IFNAR1:IFNAR2:IFNB Identifiers_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. References_end</body> </html> </notes> <label text="s1282"/> <bbox w="120.0" h="230.0" x="3360.0" y="685.0"/> <glyph class="macromolecule" id="s1301_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IFNAR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. References_end</body> </html> </notes> <label text="IFNAR1"/> <bbox w="80.0" h="50.0" x="3380.0" y="770.0"/> <glyph class="unit of information" id="_bbae8767-79fd-4c84-aa17-01f12992ede4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3397.5" y="765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1302_sa602"> <notes> <html xmlns="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: HUGO:IFNAR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs References_end</body> </html> </notes> <label text="IFNAR2"/> <bbox w="80.0" h="50.0" x="3380.0" y="830.0"/> <glyph class="unit of information" id="_bbb40a46-3878-46da-abe1-c9b3b397d66f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3397.5" y="825.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1299_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IFNB Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. References_end</body> </html> </notes> <label text="IFNB"/> <bbox w="80.0" h="40.0" x="3380.0" y="720.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1303_sa538" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="5120.0" y="1080.0"/> <glyph class="state variable" id="_4cad0ba5-2abf-4e67-a4c8-31b5b6f2eb6a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5112.5" y="1095.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1304_sa537" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="4990.0" y="1090.0"/> <glyph class="state variable" id="_acc68dad-48ed-43ed-8276-0211cb4a5ded"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4982.5" y="1105.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1305_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:9637476, PMID:10878343 MIF prevented the release of perforin granules by NK cells but not CTLs. Tumor cells produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells. PMID:18490733 MIF inhibits NK cell activity through a transcriptional down-regulation of NKG2D References_end</body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="1570.0" y="640.0"/> </glyph> <glyph class="nucleic acid feature" id="s1306_sa605" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFKBIZ Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17027520 A promoter region of NFKBIZ (IκB‐ζ) gene harbors three NF‐κB binding site within 300‐bp upstream of the transcription initiation site PMID:20876105, PMID:17027520, IL18 induces expression of NFKBIZ in NK cells provavly via NFkB pathway or via increasing of mRNA stability.. References_end</body> </html> </notes> <label text="NFKBIZ"/> <bbox w="70.0" h="25.0" x="3815.0" y="1477.5"/> </glyph> <glyph class="nucleic acid feature" id="s1307_sa606" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFKBIZ Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17027520 NFkB p65/p50 induces expression of NFKBIZ downstream of IL18. References_end</body> </html> </notes> <label text="NFKBIZ"/> <bbox w="90.0" h="25.0" x="3805.0" y="1567.5"/> <glyph class="unit of information" id="_d221a882-39da-49b9-8800-d2086cce1cb0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3840.0" y="1562.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1308_sa607" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFKBIZ Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:20876105 NFKBIZ induced by IL18 together with STAT4 induced by IL12 activates IFNG expression in NK cells. STAT4 was not recruited to the Ifng gene regions in Nfkbiz−/− NK cells. NFKBIZ is Required for change in histone 3 lysine 9 acetylation in response to IL-12 and IL-18 in NK Cells. PMID:21224476 NFKBIZ binds to the IFNG promoter in response to IL-12 and IL-18 and encreases promoter activity. NFKBIZ regulates IFNG expression by binding to NF-κB p65/p50. References_end</body> </html> </notes> <label text="NFKBIZ"/> <bbox w="80.0" h="40.0" x="3810.0" y="1630.0"/> </glyph> <glyph class="macromolecule" id="s1311_sa611" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:15187109 TGFB1 secreted by tumors is responsible for the poor NK lytic activity via down-regulating an NK-activating receptor, NKG2D. PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. PMID: PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFB1"/> <bbox w="80.0" h="40.0" x="2090.0" y="1240.0"/> </glyph> <glyph class="macromolecule" id="s1312_sa612" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11792802, PMID: PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:16713975 TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="2500.0" y="1120.0"/> <glyph class="state variable" id="_63ceec18-915d-48b8-8241-cb90be21bece"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2495.0" y="1135.0"/> </glyph> </glyph> <glyph class="phenotype" id="s1313_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"> <head> <title/> </head> <body>References_begin: PMID:22863752, PMID:24132110 TGFβ has been identified as a factor that inhibits the functional maturation of this cell population. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. References_end</body> </html> </notes> <label text="Immaturity_of_NK_cells"/> <bbox w="170.0" h="35.0" x="1795.0" y="562.5"/> </glyph> <glyph class="macromolecule" id="s1317_sa617" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TBX21 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:10761931, PMID: PMID:12055627, PMID:18768831 The pattern of T-bet expression correlates well with the production of IFNG in NK cells. The induction of T-bet expression and secretion of IFNγ in NK cells that produce IFNγ exists only upon treatment with IL-2 and IL-12 and CD16 pathway activation.. T-bet regulates IFNG expression in NK cells, probably via chromatin remodeling. PMID:14614857 T-bet expression was approximately 4-fold reduced in GATA-3 deficient NK cells compared to controls, while Hlx expression was about 10-fold reduced. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end</body> </html> </notes> <label text="TBX21"/> <bbox w="80.0" h="40.0" x="3680.0" y="1650.0"/> </glyph> <glyph class="macromolecule" id="s1319_sa619" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:HLX Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12055627,PMID:14614857 T-Bet induces HLX in T cells, and probably in NK cells. HLX activates IFNG expression. T-bet expression was approximately 4-fold reduced in GATA-3 deficient NK cells compared to controls, while Hlx expression was about 10-fold reduced References_end</body> </html> </notes> <label text=" HLX"/> <bbox w="80.0" h="40.0" x="3550.0" y="1750.0"/> </glyph> <glyph class="macromolecule" id="s548_sa620" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="1960.0" y="930.0"/> <glyph class="unit of information" id="_d284be6c-e6fe-45e6-9fbd-feff9dbdaf56"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1977.5" y="925.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s851_sa621" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:TGFBR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="1960.0" y="860.0"/> <glyph class="unit of information" id="_cf88b19b-3f0f-4047-919c-188df79f0708"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1977.5" y="855.0"/> </glyph> </glyph> <glyph class="complex" id="s1320_csa72" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:TGFB*:TGFBR1:TGFBR2 Identifiers_end References_begin: PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation References_end</body> </html> </notes> <label text="s1320"/> <bbox w="120.0" h="170.0" x="2180.0" y="855.0"/> <glyph class="macromolecule" id="s1322_sa622"> <notes> <html xmlns="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: HUGO:TGFBR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="2190.0" y="910.0"/> <glyph class="unit of information" id="_94a0f782-ccef-4ff3-b57c-35ff64f48730"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2207.5" y="905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1321_sa623"> <notes> <html xmlns="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: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="2190.0" y="950.0"/> <glyph class="unit of information" id="_5a329107-7439-4406-81f0-91948f7cd54c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2207.5" y="945.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1339_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:17070508, PMID:18490733 TGFB downregulates NKG2D expression. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-β in NK cells via the c-Jun N-terminal kinase (JNK) pathway PMID:2871107 Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. PMID: PMID:20538542 TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. The roles of TGFβ in the tumour microenvironment. PMID:20616810 The polarization of immune cells in the tumour environment by TGFbeta. References_end</body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="2190.0" y="865.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1325_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. PMID:18768831 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end</body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="7310.0" y="1270.0"/> </glyph> <glyph class="macromolecule" id="s1326_sa627" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11792802, PMID: PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:16713975 TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="2500.0" y="1190.0"/> <glyph class="state variable" id="_04defd92-3ca9-4cd1-9916-c5dec275cbee"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2492.5" y="1205.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1327_sa628" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TBX1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:10761931, PMID: PMID:12055627, PMID:18768831, PMID:16713975 The pattern of T-bet expression correlates well with the production of IFNG in NK cells. The induction of T-bet expression and secretion of IFNγ in NK cells that produce IFNγ exists only upon treatment with IL-2, IL15,IL18 and IL-12 and CD16 pathway activation.. T-bet regulates IFNG expression in NK cells, probably via chromatin remodeling. References_end</body> </html> </notes> <label text="TBX21"/> <bbox w="90.0" h="25.0" x="3675.0" y="1597.5"/> <glyph class="unit of information" id="_c4a25d26-026c-4e7f-9d67-7ced9694ead5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3710.0" y="1592.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1329_sa630" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:HLX Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:14614857 GATA-3-deficient NK cells produced less IFN-γ compared to control NK cells. T-bet expression was approximately 4-fold reduced in GATA-3° NK cells compared to controls, while Hlx expression was about 10-fold reduced (provavly via T-bet). References_end</body> </html> </notes> <label text="HLX"/> <bbox w="90.0" h="25.0" x="3545.0" y="1677.5"/> <glyph class="unit of information" id="_a61e9123-e820-4c4d-a17f-290e6d381bee"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3580.0" y="1672.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1330_sa631" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:HLX Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12055627,PMID:14614857 T-Bet induces HLX in T cells, and probably in NK cells. GATA-3-deficient NK cells produced less IFN-γ compared to control NK cells. T-bet expression was approximately 4-fold reduced in GATA-3° NK cells compared to controls, while Hlx expression was about 10-fold reduced (provavly via T-bet). References_end</body> </html> </notes> <label text="HLX"/> <bbox w="70.0" h="25.0" x="3555.0" y="1617.5"/> </glyph> <glyph class="macromolecule" id="s1331_sa632" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11792802, PMID: PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. References_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="2400.0" y="1230.0"/> </glyph> <glyph class="complex" id="s1332_csa73" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:SMAD3:SMAD4 Identifiers_end References_begin: PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocatio References_end</body> </html> </notes> <label text="s1332"/> <bbox w="100.0" h="120.0" x="2480.0" y="1270.0"/> <glyph class="macromolecule" id="s1334_sa633"> <notes> <html xmlns="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: HUGO:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11792802, PMID: PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:16713975 TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="2490.0" y="1280.0"/> <glyph class="state variable" id="_2e7064a8-b6ed-4548-ac93-0ee300777d57"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2482.5" y="1295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1333_sa634"> <notes> <html xmlns="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: HUGO:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11792802, PMID: PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. References_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="2490.0" y="1330.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1336_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:17070508, PMID:18490733 TGFB downregulates NKG2D expression. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-β in NK cells via the c-Jun N-terminal kinase (JNK) pathway PMID:2871107 Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. PMID: PMID:20538542 TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. The roles of TGFβ in the tumour microenvironment. PMID:20616810 The polarization of immune cells in the tumour environment by TGFbeta. References_end</body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="2040.0" y="570.0"/> </glyph> <glyph class="macromolecule" id="s1337_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:TGFB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFB2"/> <bbox w="80.0" h="40.0" x="2070.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s1338_sa638"> <notes> <html xmlns="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: HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end</body> </html> </notes> <label text="TGFB3"/> <bbox w="80.0" h="40.0" x="2210.0" y="420.0"/> </glyph> <glyph class="nucleic acid feature" id="s1340_sa644" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR1245A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:22491735 TGFB1-induced miR-1245 over-expression occurs at the level of post-transcriptional processing. Human microRNA-1245 downregulates the NKG2D receptor in NK cells and impairs NKG2D-mediated functions downstream of TGFB. References_end</body> </html> </notes> <label text="MIR1245A"/> <bbox w="90.0" h="25.0" x="2175.0" y="1547.5"/> <glyph class="unit of information" id="_39aafad0-cf83-4add-9946-570d5537642d"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2205.0" y="1542.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1341_sa641" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR183 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells. References_end</body> </html> </notes> <label text="MIR183"/> <bbox w="90.0" h="25.0" x="1957.5" y="1547.5"/> <glyph class="unit of information" id="_43aa83d8-94dc-4732-901f-eb6473d15168"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1987.5" y="1542.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1342_sa642" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:17100878 NKG2D plays a major role in triggering cytotoxicity against target cells, such as the murine lymphoma line YAC-1. NKG2D detects cell surface molecules distantly related to MHC class I proteins, which are induced by viral infection and tumor transformation. As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:12646700, PMID:15187109, PMID: PMID:18490724 [ TGFB1 downderulates NKp30 and NKG2D mRNA and protein level.. References_end</body> </html> </notes> <label text="NKG2D*"/> <bbox w="70.0" h="25.0" x="3627.5" y="3227.5"/> </glyph> <glyph class="macromolecule" id="s1343_sa643" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:DAP10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: PMID:17100878 As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. YINM motif of DAP10 functions as docking site for PI3K, which represents the major effector molecule downstream of NKG2D. PMID:10426994, PMID:16582911 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. Binding of DAP10 to either p85 or Grb2 alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. References_end</body> </html> </notes> <label text="DAP10"/> <bbox w="80.0" h="50.0" x="3490.0" y="3445.0"/> <glyph class="state variable" id="_978742d8-cca7-40cb-ba63-1640292aff0f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3485.0" y="3465.0"/> </glyph> <glyph class="unit of information" id="_e202055e-7006-4d20-86ad-730f09a74424"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3507.5" y="3440.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1344_sa645" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR1245A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:22491735 TGFB1-induced miR-1245 over-expression occurs at the level of post-transcriptional processing. Human microRNA-1245 downregulates the NKG2D receptor in NK cells and impairs NKG2D-mediated functions downstream of TGFB. References_end</body> </html> </notes> <label text="MIR1245A"/> <bbox w="70.0" h="25.0" x="2175.0" y="1477.5"/> </glyph> <glyph class="complex" id="s1345_csa74" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MIR1245A:NKG2D* Identifiers_end References_begin: PMID: 22491735 TGFB1-induced miR-1245 over-expression occurs at the level of post-transcriptional processing. Human microRNA-1245 downregulates the NKG2D receptor in NK cells and impairs NKG2D-mediated functions downstream of TGFB. References_end</body> </html> </notes> <label text="s1345"/> <bbox w="100.0" h="100.0" x="3480.0" y="3290.0"/> <glyph class="nucleic acid feature" id="s1346_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:17100878 NKG2D plays a major role in triggering cytotoxicity against target cells, such as the murine lymphoma line YAC-1. NKG2D detects cell surface molecules distantly related to MHC class I proteins, which are induced by viral infection and tumor transformation. As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:22491735 MiR-1245 is a direct negative regulator of NKG2D in NK cells downstream of TGFB. Knocking down microRNA-1245 in natural killer cells resulted in higher NKG2D expression and relative resistance to the effect of TGFB1. PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. References_end</body> </html> </notes> <label text="NKG2D*"/> <bbox w="90.0" h="25.0" x="3485.0" y="3307.5"/> <glyph class="unit of information" id="_84d37562-0658-40bf-8663-e87f90164934"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3520.0" y="3302.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1347_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:MIR1245A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:22491735 TGFB1-induced miR-1245 over-expression occurs at the level of post-transcriptional processing. Human microRNA-1245 downregulates the NKG2D receptor in NK cells and impairs NKG2D-mediated functions downstream of TGFB. References_end</body> </html> </notes> <label text="MIR1245A"/> <bbox w="90.0" h="25.0" x="3485.0" y="3337.5"/> <glyph class="unit of information" id="_782ea3eb-19de-4bad-aac6-690b59be92bd"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3515.0" y="3332.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1348_sa648" compartmentRef="c7_ca7"> <label text="csa74_degraded"/> <bbox w="30.0" h="30.0" x="3415.0" y="3295.0"/> </glyph> <glyph class="nucleic acid feature" id="s1349_sa649" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR183 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells. References_end</body> </html> </notes> <label text="MIR183"/> <bbox w="70.0" h="25.0" x="1967.5" y="1477.5"/> </glyph> <glyph class="nucleic acid feature" id="s1350_sa651" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells and interupts DAP12 dependent signaling (at least via NKp44 and KIR2DS4 receptors) . References_end</body> </html> </notes> <label text="DAP12"/> <bbox w="70.0" h="25.0" x="3275.0" y="3157.5"/> </glyph> <glyph class="nucleic acid feature" id="s1351_sa652" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells and interupts DAP12 dependent signaling (at least via NKp44 and KIR2DS4 receptors) . References_end</body> </html> </notes> <label text="DAP12"/> <bbox w="90.0" h="25.0" x="3265.0" y="3237.5"/> <glyph class="unit of information" id="_0cb4fbb9-ab67-47de-adb8-d5f163596119"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3300.0" y="3232.5"/> </glyph> </glyph> <glyph class="complex" id="s1352_csa75" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:DAP12:MIR183 Identifiers_end References_begin: PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells and interupts DAP12 dependent signaling (at least via NKp44 and KIR2DS4 receptors) . References_end</body> </html> </notes> <label text="s1352"/> <bbox w="100.0" h="90.0" x="3120.0" y="3195.0"/> <glyph class="nucleic acid feature" id="s1354_sa653"> <notes> <html xmlns="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: HUGO:MIR183 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells. References_end</body> </html> </notes> <label text="MIR183"/> <bbox w="90.0" h="25.0" x="3125.0" y="3202.5"/> <glyph class="unit of information" id="_77cdbac6-aaf8-405a-bf96-c494784361e3"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3155.0" y="3197.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1353_sa654"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:24586048 Suppression of NK cells is a result of TGF-β induction of microRNA (miR)-183, which binds and represses DNAX activating protein 12 kDa (DAP12), a signal adaptor for lytic function in NK cells and interupts DAP12 dependent signaling (at least via NKp44 and KIR2DS4 receptors) . References_end</body> </html> </notes> <label text="DAP12"/> <bbox w="90.0" h="25.0" x="3125.0" y="3232.5"/> <glyph class="unit of information" id="_e77a2d20-1ce8-4d90-bbe8-20e09ae86067"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3160.0" y="3227.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1355_sa655" compartmentRef="c7_ca7"> <label text="csa75_degraded"/> <bbox w="30.0" h="30.0" x="3185.0" y="3305.0"/> </glyph> <glyph class="nucleic acid feature" id="s1356_sa656" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR185 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24586048 TGFB induces MIR185 expression in NK cells. References_end</body> </html> </notes> <label text="MIR185"/> <bbox w="70.0" h="25.0" x="2067.5" y="1477.5"/> </glyph> <glyph class="nucleic acid feature" id="s1357_sa657" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR185 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24586048 TGFB induces MIR185 expression in NK cells. References_end</body> </html> </notes> <label text="MIR185"/> <bbox w="90.0" h="25.0" x="2057.5" y="1547.5"/> <glyph class="unit of information" id="_5bbc8e74-2583-4829-81e0-746c9b77484a"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2087.5" y="1542.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1328_sa629" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TBX21 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10761931, PMID: PMID:12055627, PMID:18768831, PMID:16713975, PMID:15084276, PMID:12244150 The pattern of T-bet expression correlates well with the production of IFNG in NK cells. The induction of T-bet expression and secretion of IFNγ in NK cells that produce IFNγ exists only upon treatment with IL-2, IL15,IL18, IL21 and IL-12 and CD16 pathway activation.. T-bet regulates IFNG expression in NK cells, probably via chromatin remodeling. PMID:18768831, PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. TBX21 is involeved in IFNG gene activation. References_end</body> </html> </notes> <label text="TBX21"/> <bbox w="70.0" h="25.0" x="3682.5" y="1517.5"/> </glyph> <glyph class="macromolecule" id="s1358_sa659" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="2280.0" y="1250.0"/> <glyph class="state variable" id="_6d4e6942-46a7-4957-93f3-66123ca05704"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2272.5" y="1264.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s1359_sa658" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="2280.0" y="1170.0"/> <glyph class="state variable" id="_e63cded2-6607-4d5b-a8cb-e41780c4426b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2275.0" y="1184.9681"/> </glyph> </glyph> <glyph class="complex" id="s1360_csa76" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:SMAD2:SMAD4 Identifiers_end</body> </html> </notes> <label text="s1360"/> <bbox w="100.0" h="120.0" x="2340.0" y="1320.0"/> <glyph class="macromolecule" id="s1361_sa660"> <notes> <html xmlns="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: HUGO:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11792802, PMID: PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. References_end</body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="2350.0" y="1370.0"/> </glyph> <glyph class="macromolecule" id="s1362_sa661"> <notes> <html xmlns="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: HUGO:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="2350.0" y="1330.0"/> <glyph class="state variable" id="_e5f4fc71-38da-4c75-a545-3753b476356f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2342.5" y="1344.9681"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1363_sa662" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="70.0" h="25.0" x="2935.0" y="2947.5"/> </glyph> <glyph class="macromolecule" id="s1364_sa663" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RUNX1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15084276 Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. PMID:18003603 ???? RUNX1 down-regulates IFNG expression in NK cells and upregulates expression of CD122 (IL-2/IL-15 common receptor beta subunit) via direct binding to its promoter in development. NK cells in Runx dominant negative form Tg mice have immature surface phenotype. References_end</body> </html> </notes> <label text="RUNX1"/> <bbox w="80.0" h="40.0" x="3240.0" y="1630.0"/> </glyph> <glyph class="nucleic acid feature" id="s1365_sa664" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RUNX1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15084276 Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end</body> </html> </notes> <label text="RUNX1"/> <bbox w="70.0" h="25.0" x="3245.0" y="1527.5"/> </glyph> <glyph class="nucleic acid feature" id="s1366_sa665" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RUNX1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15084276 Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end</body> </html> </notes> <label text="RUNX1"/> <bbox w="90.0" h="25.0" x="3235.0" y="1577.5"/> <glyph class="unit of information" id="_bd34eb6e-1ab3-4723-9a99-a71664d21ea6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3270.0" y="1572.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1367_sa666" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="5890.0" y="1485.0"/> <glyph class="state variable" id="_02ecc1b9-dd55-4f88-bd5c-3d5acfb83d0d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5885.0" y="1505.0"/> </glyph> <glyph class="unit of information" id="_18ef25fc-a53c-48cf-bdf7-5a3c753ece1d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5907.5" y="1480.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1368_sa667" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18003603 RUNX1 down-regulates IFNG expression in NK cells and upregulates expression of CD122 (IL-2/IL-15 common receptor beta subunit) via direct binding to its promoter. PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="70.0" h="25.0" x="5655.0" y="1497.5"/> </glyph> <glyph class="nucleic acid feature" id="s1369_sa668" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18003603 RUNX proteins down-regulates IFNG expression in NK cells and upregulates expression of CD122 (IL-2/IL-15 common receptor beta subunit) via direct binding to its promoter. PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="90.0" h="25.0" x="5765.0" y="1497.5"/> <glyph class="unit of information" id="_5861651a-5ad8-42e9-bc5e-6efd3f436621"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5800.0" y="1492.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1371_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>Identifiers_begin: HUGO:IL21 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:24751819 Interleukin-21 (IL-21) is produced by CD4+ T cell populations, with the highest production by T follicular helper (TFH) cells and TH17 cells, and slightly lower levels produced by natural killer T (NKT) cells. IL-21 signals via heterodimers of the IL-21 receptor (IL-21R) and the common cytokine receptor γ-chain, (encoded by IL2RG) Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). IL-21 binding to IL-21R can also activate the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways. PMID:12244150 IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. PMID:16081783 IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. PMID:16785506 Interleukin-21 enhances NK cell activation in response to antibody-coated targets (CD16 dependent). References_end</body> </html> </notes> <label text="IL21"/> <bbox w="80.0" h="40.0" x="6420.0" y="520.0"/> </glyph> <glyph class="nucleic acid feature" id="s1372_sa671" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 IL12,IL15 and IL18 significantly suppresse TGF-BRII mRNA expression and inhibit downstream signaling. References_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="70.0" h="25.0" x="1995.0" y="1377.5"/> </glyph> <glyph class="nucleic acid feature" id="s1373_sa672" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 IL12,IL15 and IL18 significantly suppresse TGF-BRII mRNA expression. References_end</body> </html> </notes> <label text="TGFBR2"/> <bbox w="90.0" h="25.0" x="1985.0" y="1317.5"/> <glyph class="unit of information" id="_b15be1e1-4e28-49a9-9c17-bb4438194d2b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2020.0" y="1312.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1374_sa673" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="90.0" h="25.0" x="2185.0" y="1317.5"/> <glyph class="unit of information" id="_6ffaf721-a018-4279-9352-a8695a82d608"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2220.0" y="1312.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1375_sa674" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end</body> </html> </notes> <label text="SMAD2"/> <bbox w="70.0" h="25.0" x="2195.0" y="1377.5"/> </glyph> <glyph class="nucleic acid feature" id="s1376_sa675" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="90.0" h="25.0" x="2615.0" y="1117.5"/> <glyph class="unit of information" id="_b45fec34-c9ff-4683-abd8-e884a20addaa"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2650.0" y="1112.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1377_sa676" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 or with IL12 and IL15 downregulated SMAD3 transcript and protein level. References_end</body> </html> </notes> <label text="SMAD3"/> <bbox w="70.0" h="25.0" x="2625.0" y="1177.5"/> </glyph> <glyph class="macromolecule" id="s1378_sa573" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:17100878 NKG2D plays a major role in triggering cytotoxicity against target cells, such as the murine lymphoma line YAC-1. NKG2D detects cell surface molecules distantly related to MHC class I proteins, which are induced by viral infection and tumor transformation. As with many other activating NK cell receptors, NKG2D does not signal on its own but requires a unique signaling adapter, called DAP10. PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:18490724,PMID:11777960 IL15 upregulates NKG2D surface expression in NK cells. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="NKG2D*"/> <bbox w="80.0" h="50.0" x="3620.0" y="3335.0"/> <glyph class="unit of information" id="_144e90bc-f3b2-4db3-bddd-b6bb764ba0ad"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3637.5" y="3330.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1379_sa677" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: ACTIVATING_RECEPTORS PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level.. References_end</body> </html> </notes> <label text="NKp30*"/> <bbox w="90.0" h="25.0" x="4505.0" y="3337.5"/> <glyph class="unit of information" id="_9204aa72-f61e-4a17-a7af-11ea8bbb1ee8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4540.0" y="3332.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1380_sa678" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: ACTIVATING_RECEPTORS PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. References_end</body> </html> </notes> <label text="NKp30*"/> <bbox w="70.0" h="25.0" x="4505.0" y="3237.5"/> </glyph> <glyph class="macromolecule" id="s1381_sa679" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SP1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17705132 SP1 directly activate TBX21 (T-Bet) promoter in NK cells downstream of IL12, IL15. Mithramycin A inhibits while monokines increase Sp1 binding to T-BET promoter and downregulates T-BET and IFNG expression in NK cells. References_end</body> </html> </notes> <label text="SP1"/> <bbox w="80.0" h="40.0" x="3680.0" y="1400.0"/> </glyph> <glyph class="macromolecule" id="s1318_sa618" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GATA3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:14614857 GATA-3-deficient NK cells produced less IFN-γ compared to control NK cells. T-bet expression was approximately 4-fold reduced in GATA-3° NK cells compared to controls, while Hlx expression was about 10-fold reduced (provavly via T-bet). References_end</body> </html> </notes> <label text="GATA3"/> <bbox w="80.0" h="40.0" x="3550.0" y="1400.0"/> </glyph> <glyph class="macromolecule" id="s1149_sa441"> <notes> <html xmlns="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: HUGO:IFNA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. PMID:11449378 IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. IFN-α and IL-12 induce tyrosine phosphorylation and DNA binding of Stat4 to IFN-γ promoter GAS element PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. http://www.tandfonline.com/doi/abs/10.4161/21624011.2014.948705#.VJLI5efuK2s IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells. References_end</body> </html> </notes> <label text="IFNA"/> <bbox w="80.0" h="40.0" x="3010.0" y="230.0"/> </glyph> <glyph class="macromolecule" id="s904_sa252" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CRLK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:18835194 CrkL suppression resulted in a significant decrease in cytotoxicity against P815 tumor targets coated with either anti-NKG2D or anti-FcR, and against MICA-expressing BaF3 cells. But at the same time,CrkL was shown to be phosphorylated in an Abl-dependent manner upon ligation of inhibitory killer Ig-related receptors (KIRs) to terminate signaling from activating receptors. References_end</body> </html> </notes> <label text="CRKL"/> <bbox w="80.0" h="40.0" x="3930.0" y="3060.0"/> <glyph class="state variable" id="_520337e4-cc54-4436-9c7b-28deba6a8cd9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3925.0" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1384_sa681" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CRK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity. PMID:22464172 The intensity of p-Vav1 in Crk-silenced NK cells was decreased References_end</body> </html> </notes> <label text="CRK"/> <bbox w="80.0" h="40.0" x="4040.0" y="3060.0"/> <glyph class="state variable" id="_cb02be5f-3725-4e56-839a-31bb1ab2ffbb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4035.0" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1385_sa682" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CRK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity. PMID:22464172 The intensity of p-Vav1 in Crk-silenced NK cells was decreased References_end</body> </html> </notes> <label text="CRK"/> <bbox w="80.0" h="40.0" x="3460.0" y="3060.0"/> <glyph class="state variable" id="_082297eb-6e9e-474b-8990-1c8e1c4e7f48"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3452.5" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1386_sa683" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ABL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:18835194 Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity downstream of KIR2DL1 and NKG2A/CD94 pathway.. References_end</body> </html> </notes> <label text="ABL1"/> <clone/> <bbox w="80.0" h="40.0" x="3730.0" y="2790.0"/> </glyph> <glyph class="macromolecule" id="s1386_sa690" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ABL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:18835194 Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity downstream of KIR2DL1 and NKG2A/CD94 pathway.. References_end</body> </html> </notes> <label text="ABL1"/> <clone/> <bbox w="80.0" h="40.0" x="1760.0" y="2340.0"/> </glyph> <glyph class="macromolecule" id="s1387_sa685" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RAPGEF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. RAPGEF1(C3G) activates the GTPase Rap1 References_end</body> </html> </notes> <label text="RAPGEF1"/> <bbox w="80.0" h="40.0" x="3810.0" y="3060.0"/> </glyph> <glyph class="macromolecule" id="s1388_sa687" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:BCAR1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18835194 Several YxxP motifs for binding of (CrkII) are also present in the scaffold protein BCAR1 (p130CAS). Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. References_end</body> </html> </notes> <label text="BCAR1"/> <bbox w="80.0" h="40.0" x="3710.0" y="3060.0"/> <glyph class="state variable" id="_6521c8e6-4069-4808-b610-b6f211755452"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3705.0" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1390_sa693" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CRLK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:18835194 CrkL suppression resulted in a significant decrease in cytotoxicity against P815 tumor targets coated with either anti-NKG2D or anti-FcR, and against MICA-expressing BaF3 cells. But at the same time,CrkL was shown to be phosphorylated in an Abl-dependent manner upon ligation of inhibitory killer Ig-related receptors (KIRs) to terminate signaling from activating receptors. References_end</body> </html> </notes> <label text="CRKL"/> <bbox w="80.0" h="40.0" x="3590.0" y="3060.0"/> <glyph class="state variable" id="_e0237809-e158-47ff-ba8d-1da19afb26e3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3582.5" y="3075.0"/> </glyph> </glyph> <glyph class="complex" id="s1391_csa77" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GDP:RAP1A Identifiers_end</body> </html> </notes> <label text="s1391"/> <bbox w="100.0" h="120.0" x="3830.0" y="2600.0"/> <glyph class="macromolecule" id="s1392_sa253"> <notes> <html xmlns="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: HUGO:RAP1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19454690 Ligation of either the FcR or NKG2D results in activation of Rap1and induces Rap1-RAPL-MST1 signaling cascade. Rap1 is activated following FcR and NKG2D ligation in a PI3K- and CrkL-dependent manner. Rap1 regulates NKG2D-mediated adhesion and MTOC polarization leading to NK cell cytotoxicity. References_end</body> </html> </notes> <label text="RAP1A"/> <bbox w="80.0" h="40.0" x="3840.0" y="2620.0"/> </glyph> <glyph class="simple chemical" id="s1393_sa696"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="3851.75" y="2666.875"/> </glyph> </glyph> <glyph class="complex" id="s1394_csa78" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GTP:RAP1A Identifiers_end</body> </html> </notes> <label text="s1394"/> <bbox w="100.0" h="120.0" x="3610.0" y="2600.0"/> <glyph class="macromolecule" id="s905_sa686"> <notes> <html xmlns="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: HUGO:RAP1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19454690 Ligation of either the FcR or NKG2D results in activation of Rap1and induces Rap1-RAPL-MST1 signaling cascade. Rap1 is activated following FcR and NKG2D ligation in a PI3K- and CrkL-dependent manner. Rap1 regulates NKG2D-mediated adhesion and MTOC polarization leading to NK cell cytotoxicity. References_end</body> </html> </notes> <label text="RAP1A"/> <bbox w="80.0" h="40.0" x="3620.0" y="2620.0"/> </glyph> <glyph class="simple chemical" id="s1395_sa697"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="3628.0" y="2667.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1403_sa705" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="6990.0" y="2095.0"/> <glyph class="unit of information" id="_02b90e4d-eca3-4fcc-bd18-b90b0ac461b0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7007.5" y="2090.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1405_sa707"> <notes> <html xmlns="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: HUGO:VCAM1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="VCAM1"/> <bbox w="80.0" h="40.0" x="6570.0" y="4110.0"/> </glyph> <glyph class="macromolecule" id="s1406_sa708" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="80.0" h="50.0" x="6480.0" y="2715.0"/> <glyph class="unit of information" id="_d2705a5e-4a12-46e9-acf8-cdb5ab5d19a8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6497.5" y="2710.0"/> </glyph> </glyph> <glyph class="complex" id="s1407_csa79" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:ITGA4:ITGB1 Identifiers_end References_begin: PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. References_end</body> </html> </notes> <label text="s1407"/> <bbox w="110.0" h="140.0" x="6605.0" y="3050.0"/> <glyph class="macromolecule" id="s1410_sa711"> <notes> <html xmlns="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: HUGO:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="6620.0" y="3055.0"/> <glyph class="unit of information" id="_afc9438b-f52c-409c-99a3-5a1aa5d32584"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6637.5" y="3050.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1411_sa712"> <notes> <html xmlns="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: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="80.0" h="50.0" x="6620.0" y="3105.0"/> <glyph class="unit of information" id="_f1dfe08e-9920-4724-9079-c6ac55b63a01"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6637.5" y="3100.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1412_csa80" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:ITGA4:ITGB1:VCAM1 Identifiers_end References_begin: PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="s1407"/> <bbox w="112.5" h="205.0" x="6653.75" y="2757.5"/> <glyph class="macromolecule" id="s1413_sa713"> <notes> <html xmlns="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: HUGO:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="6673.75" y="2767.5"/> <glyph class="unit of information" id="_bd7a3a2a-645f-4a63-99e5-d5ae0251703e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6691.25" y="2762.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1414_sa714"> <notes> <html xmlns="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: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="80.0" h="50.0" x="6673.75" y="2817.5"/> <glyph class="unit of information" id="_aa077502-f946-496f-b5a5-80312987c6ac"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6691.25" y="2812.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1415_sa715"> <notes> <html xmlns="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: HUGO:VCAM1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="VCAM1"/> <bbox w="80.0" h="40.0" x="6673.75" y="2882.5"/> </glyph> </glyph> <glyph class="complex" id="s1416_csa81" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CRKL:PI3KR Identifiers_end References_begin: PMID:19454690 IP of p85 indicated constitutive p85-CrkL association. Disruption of this p85-CrkL complex would lead to impaired killing downstream of NKG2D. References_end</body> </html> </notes> <label text="s1416"/> <bbox w="120.0" h="130.0" x="4110.0" y="2705.0"/> <glyph class="macromolecule" id="s1418_sa716"> <notes> <html xmlns="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: HUGO:PIK3R1 HUGO:PIK3R2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:10426994, PMID:16582911 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:21149606 NKp80-mediated cytotoxicity is PI3K-dependent. PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. References_end</body> </html> </notes> <label text="PI3KR(p85)*"/> <bbox w="80.0" h="40.0" x="4130.0" y="2715.0"/> </glyph> <glyph class="macromolecule" id="s1417_sa717"> <notes> <html xmlns="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: HUGO:CRLK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:18835194 CrkL suppression resulted in a significant decrease in cytotoxicity against P815 tumor targets coated with either anti-NKG2D or anti-FcR, and against MICA-expressing BaF3 cells. But at the same time,CrkL was shown to be phosphorylated in an Abl-dependent manner upon ligation of inhibitory killer Ig-related receptors (KIRs) to terminate signaling from activating receptors. References_end</body> </html> </notes> <label text="CRKL"/> <bbox w="80.0" h="40.0" x="4130.0" y="2765.0"/> <glyph class="state variable" id="_fb574123-9615-4dbe-bb8f-8b14bee60793"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4125.0" y="2780.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1420_sa719" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MTS1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:16892067 Ligation of either FcR or NKG2D increased phosphorylation of MST1 in NK cells. Probably via RAPL. NKG2D signaling increases integrin-dependent NK cell adgesion, promably via MST1 which can upregulate LFA-1/ICAM1 adhesion References_end</body> </html> </notes> <label text="MST1"/> <bbox w="80.0" h="40.0" x="3480.0" y="2570.0"/> <glyph class="state variable" id="_1bed9852-13e7-4676-9289-9118d049b367"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3475.0" y="2585.0"/> </glyph> </glyph> <glyph class="complex" id="s1421_csa83" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:KLRD1:NKG2A* Identifiers_end</body> </html> </notes> <label text="s1421"/> <bbox w="110.0" h="140.0" x="1090.0" y="2905.0"/> <glyph class="macromolecule" id="s12_sa722"> <notes> <html xmlns="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: HUGO:KLRC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. CD3 zeta (associated with NKp46 and NKp30) and KARAP/DAP12 (associated with NKp44). PMID:22464172 NKG2A induces CRK phosphorylation downstream of HLA-E. PMID:9485206 NKG2A inhibits NK cells via direct association with SHP-1 and SHP-2 PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. References_end</body> </html> </notes> <label text="NKG2A*"/> <bbox w="80.0" h="50.0" x="1100.0" y="2910.0"/> <glyph class="unit of information" id="_635870c1-8d01-40df-a754-f12da40f8ec6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1117.5" y="2905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1389_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. KLRD1 (CD94). References_end</body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="1100.0" y="2970.0"/> <glyph class="unit of information" id="_a7dd6698-6d21-4a0d-9b3d-966f8f008ebc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1117.5" y="2965.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1423_sa721"> <notes> <html xmlns="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: HUGO:HLA-E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:2731048 HLA-E is a ligand of inhibitory receptor NKG2A. PMID:9486650, PMID: PMID:9655483, PMID:11015446 KLRC2 (D94/NKG2C), an activating NK cell receptor of the C-type lectin superfamily that binds to HLA-E, noncovalently associates with DAP12. References_end</body> </html> </notes> <label text="HLA-E"/> <bbox w="80.0" h="40.0" x="900.0" y="4230.0"/> </glyph> <glyph class="complex" id="s1425_csa82" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-E:KLRD1:NKG2A* Identifiers_end References_begin: PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. References_end</body> </html> </notes> <label text="s1421"/> <bbox w="110.0" h="210.0" x="1225.0" y="2895.0"/> <glyph class="macromolecule" id="s1426_sa12"> <notes> <html xmlns="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: HUGO:KLRC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. CD3 zeta (associated with NKp46 and NKp30) and KARAP/DAP12 (associated with NKp44). PMID:22464172 NKG2A induces CRK phosphorylation downstream of HLA-E. PMID:9485206 NKG2A inhibits NK cells via direct association with SHP-1 and SHP-2 PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. References_end</body> </html> </notes> <label text="NKG2A*"/> <bbox w="80.0" h="50.0" x="1230.0" y="2905.0"/> <glyph class="unit of information" id="_ff8e1132-1e19-42fa-97ad-4bc3bc4c9f63"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1247.5" y="2900.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1427_sa692"> <notes> <html xmlns="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: HUGO:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. KLRD1 (CD94). References_end</body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="1230.0" y="2965.0"/> <glyph class="unit of information" id="_011ec5f1-44eb-4bc7-85cd-f5262f2286ea"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1247.5" y="2960.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1428_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: HUGO:HLA-E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:2731048 HLA-E is a ligand of inhibitory receptor NKG2A. PMID:9486650, PMID: PMID:9655483, PMID:11015446 KLRC2 (D94/NKG2C), an activating NK cell receptor of the C-type lectin superfamily that binds to HLA-E, noncovalently associates with DAP12. References_end</body> </html> </notes> <label text="HLA-E"/> <bbox w="80.0" h="40.0" x="1230.0" y="3020.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1432_sa729"> <notes> <html xmlns="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: HUGO:HLA-B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. References_end</body> </html> </notes> <label text="HLA-B"/> <bbox w="80.0" h="40.0" x="1190.0" y="4230.0"/> </glyph> <glyph class="macromolecule" id="s1433_sa730"> <notes> <html xmlns="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: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="760.0" y="4220.0"/> </glyph> <glyph class="macromolecule" id="s1434_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end</body> </html> </notes> <label text="HLA-G"/> <bbox w="80.0" h="40.0" x="1410.0" y="4220.0"/> </glyph> <glyph class="complex" id="s1435_csa84" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-C:KIR2DL2 Identifiers_end</body> </html> </notes> <label text="s1435"/> <bbox w="100.0" h="130.0" x="1010.0" y="2425.0"/> <glyph class="macromolecule" id="s1436_sa9"> <notes> <html xmlns="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: HUGO:KIR2DL2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:21339333 KIR2DL2 signaling blocks the initiation of activating responses downstream of HLA-C via SHP-1,SHP-2. KIR2DL2 signaling inhibits IFNG secretion and Ca2+ mobilization, probably via inhibition of NKG2D-DAP10 signaling. PMID:9605119 Interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3) with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor cell lysis. References_end</body> </html> </notes> <label text="KIR2DL2"/> <bbox w="80.0" h="50.0" x="1020.0" y="2480.0"/> <glyph class="unit of information" id="_88bc1821-7c74-45b3-8a6f-49d01074c6ad"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1037.5" y="2475.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1441_sa735"> <notes> <html xmlns="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: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="1020.0" y="2435.0"/> </glyph> </glyph> <glyph class="complex" id="s1437_csa92" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-C:KIR2DL1 Identifiers_end</body> </html> </notes> <label text="s1437"/> <bbox w="100.0" h="120.0" x="960.0" y="2600.0"/> <glyph class="macromolecule" id="s1438_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor PMID:12917349, PMID:18835194 Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DL1"/> <bbox w="80.0" h="50.0" x="970.0" y="2655.0"/> <glyph class="state variable" id="_b543a54c-8c34-4ed3-b188-8710b6ae146f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="965.0" y="2675.0"/> </glyph> <glyph class="unit of information" id="_622f6731-2e9e-4075-8a6d-f95252b1602b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="987.5" y="2650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1442_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="970.0" y="2610.0"/> </glyph> </glyph> <glyph class="complex" id="s1439_csa90" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-C:KIR2DL3 Identifiers_end</body> </html> </notes> <label text="s1439"/> <bbox w="100.0" h="120.0" x="1080.0" y="2740.0"/> <glyph class="macromolecule" id="s1440_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8574854 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. KIR2DL3 inhibits NK cells downstream of HLA-C via SHP-1 binding and activation. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DL3"/> <bbox w="80.0" h="50.0" x="1090.0" y="2795.0"/> <glyph class="state variable" id="_5663c1aa-54de-4ece-abdf-901e04785221"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1085.0" y="2815.0"/> </glyph> <glyph class="unit of information" id="_01341d30-51be-4634-bb4c-8dde9b9aab04"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1107.5" y="2790.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1443_sa749"> <notes> <html xmlns="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: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="1090.0" y="2750.0"/> </glyph> </glyph> <glyph class="complex" id="s1445_csa87" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-G:KIR2DL4 Identifiers_end References_begin: PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. References_end</body> </html> </notes> <label text="s1445"/> <clone/> <bbox w="100.0" h="120.0" x="1550.0" y="2970.0"/> <glyph class="macromolecule" id="s1446_sa23"> <notes> <html xmlns="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: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="KIR2DL4"/> <clone/> <bbox w="80.0" h="50.0" x="1560.0" y="3025.0"/> <glyph class="state variable" id="_e07c927c-0c22-40a7-b71c-6b2a6dc2cd29"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1552.5" y="3045.0"/> </glyph> <glyph class="unit of information" id="_0d0994ce-ef18-49cc-b45c-dad74145b159"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1577.5" y="3020.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1448_sa740"> <notes> <html xmlns="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: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end</body> </html> </notes> <label text="HLA-G"/> <clone/> <bbox w="80.0" h="40.0" x="1560.0" y="2980.0"/> </glyph> </glyph> <glyph class="complex" id="s1445_csa93" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-G:KIR2DL4 Identifiers_end References_begin: PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. References_end</body> </html> </notes> <label text="s1445"/> <clone/> <bbox w="100.0" h="120.0" x="1550.0" y="3140.0"/> <glyph class="macromolecule" id="s1448_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end</body> </html> </notes> <label text="HLA-G"/> <clone/> <bbox w="80.0" h="40.0" x="1560.0" y="3150.0"/> </glyph> <glyph class="macromolecule" id="s1446_sa755"> <notes> <html xmlns="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: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="KIR2DL4"/> <clone/> <bbox w="80.0" h="50.0" x="1560.0" y="3195.0"/> <glyph class="state variable" id="_cee82a4d-a4a1-4033-a56e-99460e888433"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1552.5" y="3215.0"/> </glyph> <glyph class="unit of information" id="_329ad663-f45e-44bb-8697-93964c9c2be7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1577.5" y="3190.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1449_csa88" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-B:KIR3DL1 Identifiers_end</body> </html> </notes> <label text="s1449"/> <bbox w="100.0" h="120.0" x="1420.0" y="2880.0"/> <glyph class="macromolecule" id="s1450_sa741"> <notes> <html xmlns="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: HUGO:KIR3LD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. Recognition of Inhibitory HLA-B Allotypes (Bw4+) by the KIR NKB1 Alters Stimulatory Signal Transduction Pathways in NK Cells via inhibition of PI3K pathway and Ca2+ mobilization. Probably it acts via LAT inhibition.KIR recognition of inhibitory class I molecules disrupted the ability of pp36 (LAT) to associate with Grb2 in vitro. PTP-1C (SHP-1) activated by KIR3DL1 binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2. PMID:11994457 Tyrosine-phosphorylated KIR3DL1 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2, SHP-1.3DL1-mediated inhibition of cytotoxicity was abolished upon overexpression of SHP-1. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end</body> </html> </notes> <label text="KIR3DL1"/> <bbox w="80.0" h="50.0" x="1430.0" y="2935.0"/> <glyph class="state variable" id="_48709b49-2d4d-4633-b934-9976be079408"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1422.5" y="2955.0"/> </glyph> <glyph class="unit of information" id="_388245cd-d76c-4613-a4b8-1ef5a9adb308"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1447.5" y="2930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1451_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:HLA-B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. References_end</body> </html> </notes> <label text="HLA-B"/> <bbox w="80.0" h="40.0" x="1430.0" y="2890.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1454_sa744" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LCK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:12740575 Src kinaze LCK participate in activation of NKG2D signaling and induction of PLCG phosphorylation, probably via DAP10 phosphorylation. PMID:9751747, PMID:8986721 LCK phosphorylates KIR receptors in NK cells downstream of HLA binding. PMID:22513334 Probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 in NK cells (demonstrated in T cells). PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK. References_end</body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="4300.0" y="3120.0"/> <glyph class="state variable" id="_c703b944-e925-472c-8a36-bd50f02441b1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4295.0" y="3135.0"/> </glyph> </glyph> <glyph class="complex" id="s1458_csa89" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-B:KIR3DL1 Identifiers_end</body> </html> </notes> <label text="s1449"/> <bbox w="100.0" h="120.0" x="1420.0" y="3070.0"/> <glyph class="macromolecule" id="s1459_sa746"> <notes> <html xmlns="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: HUGO:HLA-B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. References_end</body> </html> </notes> <label text="HLA-B"/> <bbox w="80.0" h="40.0" x="1430.0" y="3080.0"/> </glyph> <glyph class="macromolecule" id="s1460_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KIR3LD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. Recognition of Inhibitory HLA-B Allotypes (Bw4+) by the KIR NKB1 Alters Stimulatory Signal Transduction Pathways in NK Cells via inhibition of PI3K pathway and Ca2+ mobilization. Probably it acts via LAT inhibition.KIR recognition of inhibitory class I molecules disrupted the ability of pp36 (LAT) to associate with Grb2 in vitro. PTP-1C (SHP-1) activated by KIR3DL1 binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2. PMID:11994457 Tyrosine-phosphorylated KIR3DL1 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2, SHP-1.3DL1-mediated inhibition of cytotoxicity was abolished upon overexpression of SHP-1. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end</body> </html> </notes> <label text="KIR3DL1"/> <bbox w="80.0" h="50.0" x="1430.0" y="3125.0"/> <glyph class="state variable" id="_0b923f63-f089-46fb-9178-544880296d7e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1425.0" y="3145.0"/> </glyph> <glyph class="unit of information" id="_eb7a0433-964a-47a8-9e8a-18da0f4d025a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1447.5" y="3120.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1461_csa86" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-C:KIR2DL3 Identifiers_end</body> </html> </notes> <label text="s1439"/> <bbox w="100.0" h="120.0" x="1240.0" y="2690.0"/> <glyph class="macromolecule" id="s1463_sa10"> <notes> <html xmlns="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: HUGO:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144, PMID:8574854 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. KIR2DL3 inhibits NK cells downstream of HLA-C via SHP-1 binding and activation. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DL3"/> <bbox w="80.0" h="50.0" x="1250.0" y="2745.0"/> <glyph class="state variable" id="_4c831cf4-46f5-4358-9dd1-cb802a9006b2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1242.5" y="2765.0"/> </glyph> <glyph class="unit of information" id="_7e692249-e0c4-41ac-81aa-949438e4264b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1267.5" y="2740.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1462_sa737"> <notes> <html xmlns="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: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="1250.0" y="2700.0"/> </glyph> </glyph> <glyph class="complex" id="s1467_csa85" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-C:KIR2DL1 Identifiers_end</body> </html> </notes> <label text="s1437"/> <bbox w="100.0" h="120.0" x="1110.0" y="2600.0"/> <glyph class="macromolecule" id="s1469_sa8"> <notes> <html xmlns="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: HUGO:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor PMID:12917349, PMID:18835194 Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DL1"/> <bbox w="80.0" h="50.0" x="1120.0" y="2655.0"/> <glyph class="state variable" id="_57367eb5-3b02-4410-bd94-f84fa54cf6ae"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1112.5" y="2675.0"/> </glyph> <glyph class="unit of information" id="_f9c141ee-32f5-47c6-af64-093882d102cc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1137.5" y="2650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1468_sa736"> <notes> <html xmlns="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: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="1120.0" y="2610.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1475_sa759" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KIR2DL5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:15187115; PMID:17371997 KIR2DL5 can inhibit human NK cell activation via recruitment of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2). References_end</body> </html> </notes> <label text="KIR2DL5"/> <bbox w="80.0" h="50.0" x="1090.0" y="2335.0"/> <glyph class="unit of information" id="_05a51de9-4889-4202-b5ae-afd27644dff4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1107.5" y="2330.0"/> </glyph> </glyph> <glyph class="complex" id="s1478_csa94" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP12*:HLA-E:KLRC2:KLRD1 Identifiers_end</body> </html> </notes> <label text="s1478"/> <bbox w="190.0" h="180.0" x="3135.0" y="3570.0"/> <glyph class="macromolecule" id="s1476_sa760"> <notes> <html xmlns="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: HUGO:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. KLRD1 (CD94). References_end</body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="3145.0" y="3675.0"/> <glyph class="unit of information" id="_92e5b1e2-4cf4-42d9-ada0-72ecef6ce71e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3162.5" y="3670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1477_sa761"> <notes> <html xmlns="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: HUGO:HLA-E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:2731048 HLA-E is a ligand of inhibitory receptor NKG2A. PMID:9486650, PMID: PMID:9655483, PMID:11015446 KLRC2 (D94/NKG2C), an activating NK cell receptor of the C-type lectin superfamily that binds to HLA-E, noncovalently associates with DAP12. References_end</body> </html> </notes> <label text="HLA-E"/> <bbox w="80.0" h="40.0" x="3145.0" y="3580.0"/> </glyph> <glyph class="macromolecule" id="s1482_sa765"> <notes> <html xmlns="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: HUGO:KLRC2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:9486650, PMID: PMID:9655483, PMID:11015446 KLRC2 (D94/NKG2C), an activating NK cell receptor of the C-type lectin superfamily that binds to HLA-E, noncovalently associates with DAP12. Activation of CD94/NKG2C/DAP12 complexes caused tyrosine phosphorylation of numerous cellular proteins, including DAP12 and Syk CD94/NKG2C can fully activate the cell to divide and produce cytokines, whereas NKG2D costimulates in a manner similar to CD28 (Groh et al. 2001; Roberts et al. 2001) The ligand of CD94/NKG2A and CD94/NKG2C receptors is the nonclassic MHC class I molecule HLA-E (Braud et al. 1998; Llano et al. 1998) References_end</body> </html> </notes> <label text="KLRC2"/> <bbox w="80.0" h="50.0" x="3145.0" y="3625.0"/> <glyph class="unit of information" id="_697498b0-8c03-407a-bce4-c2b3989009aa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3162.5" y="3620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1483_sa766"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="3240.0" y="3675.0"/> <glyph class="state variable" id="_3d1f89c6-0a1a-4a8c-9e02-b74497813ae4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3235.0" y="3695.0"/> </glyph> <glyph class="unit of information" id="_2a814558-abae-4510-91c2-dc3f0cc5c08c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3257.5" y="3670.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1484_csa95" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP12*:KIR2DS2 Identifiers_end</body> </html> </notes> <label text="s1484"/> <bbox w="120.0" h="170.0" x="3360.0" y="3565.0"/> <glyph class="macromolecule" id="s1047_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KIR2DS2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:11015446, PMID: PMID:9655483, PMID:9490415 KIR2DS2 interacts with DAP12. Ligation of KIR2DS2 in transfectants expressing KIR2DS2/DAP12 complexes results in the tyrosine phosphorylation of DAP12 and other cellular substrates and the association of phosphorylated DAP12 with Syk and ZAP70. Cross-linking of the KIR2DS2/DAP12 receptor on NKL cells resulted in the dose-dependent secretion of IFN-γ and GM-CSF References_end</body> </html> </notes> <label text="KIR2DS2"/> <bbox w="80.0" h="50.0" x="3380.0" y="3630.0"/> <glyph class="unit of information" id="_4d4ad938-7ec6-4645-9e04-f99b1360e878"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3397.5" y="3625.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1485_sa767"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="3380.0" y="3580.0"/> <glyph class="state variable" id="_dacc207e-01fa-4536-9105-fb0b1f26b230"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3375.0" y="3600.0"/> </glyph> <glyph class="unit of information" id="_ac66d070-04c0-4bc8-8e3d-2584874d0553"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3397.5" y="3575.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1486_csa96" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP12*:KIR3DS1 Identifiers_end</body> </html> </notes> <label text="s1486"/> <bbox w="100.0" h="150.0" x="3540.0" y="3565.0"/> <glyph class="macromolecule" id="s21_sa21"> <notes> <html xmlns="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: HUGO:KIR3DS1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:17202323 KIR3DS1 is expressed on NK cells, ligand for this receptor is unknown. KIR3DS1 associates with the ITAM-bearing adaptor, DAP12 and triggers cytolysis and IFN-γ production. References_end</body> </html> </notes> <label text="KIR3DS1"/> <bbox w="80.0" h="50.0" x="3550.0" y="3630.0"/> <glyph class="unit of information" id="_59018c72-39b9-406e-8080-7f7425fb1e40"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3567.5" y="3625.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1487_sa768"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="3550.0" y="3580.0"/> <glyph class="state variable" id="_49b8cd9d-b7e1-4e9c-8b68-c09f51c469d9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3545.0" y="3600.0"/> </glyph> <glyph class="unit of information" id="_2ee40c55-e709-4e7b-bcf2-3974e9a77fec"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3567.5" y="3575.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1490_csa97" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:DAP12*:HLA-E:KLRC3:KLRD1 Identifiers_end</body> </html> </notes> <label text="s1490"/> <bbox w="210.0" h="190.0" x="3345.0" y="3755.0"/> <glyph class="macromolecule" id="s1080_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KLRC3 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:15728498 NKG2E/CD94 receptors bind HLA-E PMID: PMID:15884055, PMID:24935923 (NKG2E) provably acts via DAP12, but his action si not clear. References_end</body> </html> </notes> <label text="KLRC3"/> <bbox w="80.0" h="50.0" x="3355.0" y="3820.0"/> <glyph class="unit of information" id="_b501ade1-3185-40a2-bc8a-2ee6cb15e708"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3372.5" y="3815.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1488_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. KLRD1 (CD94). References_end</body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="3355.0" y="3870.0"/> <glyph class="unit of information" id="_e59d9481-dec0-49d9-a42e-cbc443f88d7c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3372.5" y="3865.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1491_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:HLA-E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:2731048 HLA-E is a ligand of inhibitory receptor NKG2A. PMID:9486650, PMID: PMID:9655483, PMID:11015446 KLRC2 (D94/NKG2C), an activating NK cell receptor of the C-type lectin superfamily that binds to HLA-E, noncovalently associates with DAP12. References_end</body> </html> </notes> <label text="HLA-E"/> <bbox w="80.0" h="40.0" x="3355.0" y="3765.0"/> </glyph> <glyph class="macromolecule" id="s1489_sa771"> <notes> <html xmlns="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: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9625766, PMID:12731048 NKp44 is coupled to the intracytoplasmic transduction machinery via the association with KARAP/DAP12. DAP12 becomes phosphorylated after NKp44 activation. PMID:23715743, PMID:24586048 DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors (KIR2DS4, KIR2DS, NKp44 )on natural killer cells. References_end</body> </html> </notes> <label text="DAP12*"/> <bbox w="80.0" h="50.0" x="3455.0" y="3870.0"/> <glyph class="state variable" id="_b6f9deb5-0201-456c-a0f2-3a31f69cb365"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3447.5" y="3890.0"/> </glyph> <glyph class="unit of information" id="_faf29eba-9ead-4061-b659-c256010c3181"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3472.5" y="3865.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1492_sa772" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. KLRD1 (CD94). References_end</body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="3000.0" y="3755.0"/> <glyph class="unit of information" id="_6ed4ffc9-9801-4aaf-856f-cd9f036c2862"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3017.5" y="3750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1493_sa773" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KLRC2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:9486650, PMID: PMID:9655483, PMID:11015446 KLRC2 (D94/NKG2C), an activating NK cell receptor of the C-type lectin superfamily that binds to HLA-E, noncovalently associates with DAP12. Activation of CD94/NKG2C/DAP12 complexes caused tyrosine phosphorylation of numerous cellular proteins, including DAP12 and Syk CD94/NKG2C can fully activate the cell to divide and produce cytokines, whereas NKG2D costimulates in a manner similar to CD28 (Groh et al. 2001; Roberts et al. 2001) The ligand of CD94/NKG2A and CD94/NKG2C receptors is the nonclassic MHC class I molecule HLA-E (Braud et al. 1998; Llano et al. 1998) References_end</body> </html> </notes> <label text="KLRC2"/> <bbox w="80.0" h="50.0" x="2990.0" y="3655.0"/> <glyph class="unit of information" id="_33dc498e-3dcd-478f-b607-d2969e1e710f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3007.5" y="3650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1494_sa774" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:KLRC3 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:15728498 NKG2E/CD94 receptors bind HLA-E PMID: PMID:15884055, PMID:24935923 (NKG2E) provably acts via DAP12, but his action si not clear. References_end</body> </html> </notes> <label text="KLRC3"/> <bbox w="80.0" h="50.0" x="3120.0" y="3835.0"/> <glyph class="unit of information" id="_a70edf60-8b53-4e0c-8a3f-5ebc4b4c9d33"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3137.5" y="3830.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1495_sa28" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:16081768, PMID:15905190, PMID:15905190 2B4 works as activator in human model and as inhibitor of NK activity in mouse model. NK cells costimulate each other through 2B4-CD48 interactions PMID: The cytoplasmic domains of murine 2B4L and human 2B4 contain three and four immunoreceptor tyrosine-based switch motifs (ITSM) Upon engagement, the receptor is recruited to lipid rafts at the target cell interface in an actin-dependent manner, and tyrosine residues in the ITSM sequences are phosphorylated . Phosphorylation of the ITSM sequences creates specific binding sites for SAP (SH2D1A). SAP is an SH2 domain-containing adaptor that links 2B4 to the Src family PTK Fyn. PMID:17171759 The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 PMID:20189481, PMID: PMID:22786724 2B4 signaling acts synergistically with NG2D and DNAM1 signalings in NK activation and tumor cells lysis. It activates LCP2/VAV1/PCLG pathway. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. DNAM1 induces VAV1 pathway probably via LCP2 (SLP76). It demonstrate synergy with 2B4 in activation of vav1 pathway. PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="2B4*"/> <clone/> <bbox w="80.0" h="50.0" x="6110.0" y="3355.0"/> <glyph class="state variable" id="_06548da7-6397-4995-a3c3-df96a2775193"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6105.0" y="3375.0"/> </glyph> <glyph class="unit of information" id="_276deb83-d622-48cc-8c38-f08d25a2ec80"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6127.5" y="3350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1495_sa391" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:16081768, PMID:15905190, PMID:15905190 2B4 works as activator in human model and as inhibitor of NK activity in mouse model. NK cells costimulate each other through 2B4-CD48 interactions PMID: The cytoplasmic domains of murine 2B4L and human 2B4 contain three and four immunoreceptor tyrosine-based switch motifs (ITSM) Upon engagement, the receptor is recruited to lipid rafts at the target cell interface in an actin-dependent manner, and tyrosine residues in the ITSM sequences are phosphorylated . Phosphorylation of the ITSM sequences creates specific binding sites for SAP (SH2D1A). SAP is an SH2 domain-containing adaptor that links 2B4 to the Src family PTK Fyn. PMID:17171759 The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 PMID:20189481, PMID: PMID:22786724 2B4 signaling acts synergistically with NG2D and DNAM1 signalings in NK activation and tumor cells lysis. It activates LCP2/VAV1/PCLG pathway. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. DNAM1 induces VAV1 pathway probably via LCP2 (SLP76). It demonstrate synergy with 2B4 in activation of vav1 pathway. PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="2B4*"/> <clone/> <bbox w="80.0" h="50.0" x="820.0" y="1825.0"/> <glyph class="state variable" id="_075ea6d7-3c1a-44bc-aaff-0beec4ccb7ec"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="815.0" y="1845.0"/> </glyph> <glyph class="unit of information" id="_8528430b-d211-4732-90ee-a01980fc9311"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="837.5" y="1820.0"/> </glyph> </glyph> <glyph class="complex" id="s1499_csa98" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CDH1:CDH2:CDH4:KLRG1 Identifiers_end References_begin: PMID:17307799 References_end</body> </html> </notes> <label text="s1499"/> <bbox w="120.0" h="220.0" x="680.0" y="2220.0"/> <glyph class="macromolecule" id="s1500_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:KLRG1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end</body> </html> </notes> <label text="KLRG1"/> <bbox w="80.0" h="50.0" x="700.0" y="2355.0"/> <glyph class="state variable" id="_5efbde27-5976-4a6c-9944-55079db7081f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="692.5" y="2375.0"/> </glyph> <glyph class="unit of information" id="_f2f35bee-cc62-4623-ae41-dd0c2d4e7481"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="717.5" y="2350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1501_sa779"> <notes> <html xmlns="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: HUGO:CDH1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH1"/> <bbox w="80.0" h="40.0" x="700.0" y="2310.0"/> </glyph> <glyph class="macromolecule" id="s1502_sa780"> <notes> <html xmlns="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: HUGO:CDH2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:17307799 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH2"/> <bbox w="80.0" h="40.0" x="700.0" y="2270.0"/> </glyph> <glyph class="macromolecule" id="s1503_sa781"> <notes> <html xmlns="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: HUGO:CDH4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH4"/> <bbox w="80.0" h="40.0" x="700.0" y="2230.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1510_sa788"> <notes> <html xmlns="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: HUGO:CLEC2D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="CLEC2D"/> <bbox w="80.0" h="40.0" x="320.0" y="2110.0"/> </glyph> <glyph class="complex" id="s1513_csa99" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CLEC2D:KLRB1 Identifiers_end</body> </html> </notes> <label text="s1513"/> <bbox w="100.0" h="120.0" x="720.0" y="1980.0"/> <glyph class="macromolecule" id="s1518_sa789"> <notes> <html xmlns="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: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:18159636 Transcription of the KLRB1 gene is suppressed in human cancer tissues PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:22378844, PMID:24227772 miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. IL15 and KLRB1 (NK1.1) ligation also induce MIR155 expression. References_end</body> </html> </notes> <label text="KLRB1"/> <bbox w="80.0" h="50.0" x="730.0" y="2035.0"/> <glyph class="unit of information" id="_74aab172-31c9-47f1-9104-bb3fa4566e0d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="747.5" y="2030.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1514_sa790"> <notes> <html xmlns="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: HUGO:CLEC2D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="CLEC2D"/> <bbox w="80.0" h="40.0" x="720.0" y="1990.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1516_sa791" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation References_end</body> </html> </notes> <label text="KLRB1"/> <bbox w="70.0" h="25.0" x="1205.0" y="2067.5"/> </glyph> <glyph class="nucleic acid feature" id="s1517_sa792" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. References_end</body> </html> </notes> <label text="KLRB1"/> <bbox w="90.0" h="25.0" x="1205.0" y="2137.5"/> <glyph class="unit of information" id="_cbc33d86-a46f-47df-aa2b-c17eb324db5d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1240.0" y="2132.5"/> </glyph> </glyph> <glyph class="complex" id="s1519_csa100" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-G:LILRB1 Identifiers_end</body> </html> </notes> <label text="s1519"/> <bbox w="100.0" h="120.0" x="1730.0" y="3140.0"/> <glyph class="macromolecule" id="s1520_sa793"> <notes> <html xmlns="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: HUGO:LILRB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:15771571, PMID:10591185, PMID:9933109 LILRB1 binds with low afﬁnity to a conserved region in the α3 domain of essentially all HLA class I glycoproteins, including HLA-A, -B, -C, -E, -F, and -G. LILRB1 receptors on NK cells can suppress their activation (cytotoxicity) upon encountering HLA classI–bearing targets (demonstrated for HLA-G, only). References_end</body> </html> </notes> <label text="LILRB1"/> <bbox w="80.0" h="50.0" x="1740.0" y="3195.0"/> <glyph class="unit of information" id="_ae3db847-416f-4efa-9133-ee336b8df0ed"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1757.5" y="3190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1521_sa794"> <notes> <html xmlns="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: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end</body> </html> </notes> <label text="HLA-G"/> <bbox w="80.0" h="40.0" x="1740.0" y="3150.0"/> </glyph> </glyph> <glyph class="complex" id="s1522_csa101" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:HLA-C:KIR2DS4 Identifiers_end</body> </html> </notes> <label text="s1522"/> <bbox w="100.0" h="130.0" x="2730.0" y="3645.0"/> <glyph class="macromolecule" id="s1523_sa795"> <notes> <html xmlns="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: HUGO:HLA-C Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. References_end</body> </html> </notes> <label text="HLA-C"/> <bbox w="80.0" h="40.0" x="2740.0" y="3655.0"/> </glyph> <glyph class="macromolecule" id="s1524_sa796"> <notes> <html xmlns="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: HUGO:KIR2DS4 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:11390475, PMID:15265913 KIR2DS4 interacts with HLA-Cw4, but not with HLA-Cw6. Additionally it is involeved in MHC class I-independent recognition of target cells. KIR2DS4 signaling is involved in the killing of melanoma cells PMID:9521070 KIR2DS4 (NKAT8) signaling induces significant intracellular calcium mobilization, and phosphorylation of the MAP kinases ERK1 and ERK2.Recognition of HLA-Cw3 on target cells by NKAT8 resulted in enhanced cytotoxicity. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end</body> </html> </notes> <label text="KIR2DS4"/> <bbox w="80.0" h="50.0" x="2740.0" y="3700.0"/> <glyph class="unit of information" id="_716b0d7f-f801-44a3-aa87-9be3a0d36580"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2757.5" y="3695.0"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1525_sa816" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:23422749 The enhanced NK-cell survival, expansion, activation, and tumor control result from overexpression of miR-155 in NK cells. PMID:19359473, PMID:22378844, PMID:24227772 Inositol phosphatase SHIP1 is a primary and direct target of miR-155. miR-155 upregulates IFNG production in natural killer cells via SHIP1 downregulation. Inhibition of either calcineurin or PI3Kled to a dose-responsive decrease in the differential between 155−/− and WT NK cell PMID:24227772 But an the same time mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. PMID:23572582 NOXA , a proapoptotic Bcl-2 homology domain (BH3)-only protein, is an important regulator of survival in NK cells ans SOCS1 are mir155 targets in NK cells References_end</body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="1925.0" y="1767.5"/> <glyph class="unit of information" id="_57acd660-465f-4492-8d36-d86cf0f955b3"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1955.0" y="1762.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1526_sa798" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="70.0" h="25.0" x="5135.0" y="1227.5"/> </glyph> <glyph class="nucleic acid feature" id="s1527_sa799" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="90.0" h="25.0" x="5125.0" y="1287.5"/> <glyph class="unit of information" id="_6f3018db-b213-429b-a989-19e4e0af50f1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5160.0" y="1282.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1528_sa800" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR212 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR212"/> <bbox w="90.0" h="25.0" x="5255.0" y="1297.5"/> <glyph class="unit of information" id="_f8b5a210-c03c-4726-8a4e-1367a69860b1"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5285.0" y="1292.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1529_sa801" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR132 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR132"/> <bbox w="90.0" h="25.0" x="5365.0" y="1297.5"/> <glyph class="unit of information" id="_ffbf4965-2d20-43a6-853b-a7c2e18d661e"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5395.0" y="1292.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1530_sa802" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR200A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR200A"/> <bbox w="90.0" h="25.0" x="5465.0" y="1297.5"/> <glyph class="unit of information" id="_157e48ec-3bf7-4bf4-8333-d916fa4845b8"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5495.0" y="1292.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1531_sa803" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR212 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR212"/> <bbox w="70.0" h="25.0" x="5265.0" y="1227.5"/> </glyph> <glyph class="nucleic acid feature" id="s1532_sa804" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR132 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR132"/> <bbox w="70.0" h="25.0" x="5375.0" y="1237.5"/> </glyph> <glyph class="nucleic acid feature" id="s1533_sa805" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR200A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR200A"/> <bbox w="70.0" h="25.0" x="5465.0" y="1237.5"/> </glyph> <glyph class="complex" id="s1534_csa102" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MIR212:STAT4 Identifiers_end</body> </html> </notes> <label text="s1534"/> <bbox w="100.0" h="120.0" x="5200.0" y="1410.0"/> <glyph class="nucleic acid feature" id="s1537_sa806"> <notes> <html xmlns="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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. 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References_end</body> </html> </notes> <label text="MIR132"/> <bbox w="90.0" h="25.0" x="5315.0" y="1437.5"/> <glyph class="unit of information" id="_71f1b0b4-7dd6-46c7-b489-3fc2999200ce"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5345.0" y="1432.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1536_csa104" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MIR200A:STAT4 Identifiers_end</body> </html> </notes> <label text="s1536"/> <bbox w="100.0" h="120.0" x="5430.0" y="1410.0"/> <glyph class="nucleic acid feature" id="s1539_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: HUGO:STAT4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="STAT4"/> <bbox w="90.0" h="25.0" x="5435.0" y="1467.5"/> <glyph class="unit of information" id="_664025eb-696b-4d87-99b1-354aeb731575"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5470.0" y="1462.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1542_sa811"> <notes> <html xmlns="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: HUGO:MIR200A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:22077060 The miRs-132, 212, and 200a were shown to be induced in human NK cells by IL-12 stimulation, which in turn target STAT4 mRNA, thereby providing a negative regulatory pathway for IL-12 signaling. References_end</body> </html> </notes> <label text="MIR200A"/> <bbox w="90.0" h="25.0" x="5435.0" y="1437.5"/> <glyph class="unit of information" id="_d4a3d8f2-799f-4e70-a9df-f05810aa0a64"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5465.0" y="1432.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1543_sa812" compartmentRef="c7_ca7"> <label text="csa102_degraded"/> <bbox w="30.0" h="30.0" x="5235.0" y="1555.0"/> </glyph> <glyph class="source and sink" id="s1544_sa813" compartmentRef="c7_ca7"> <label text="csa103_degraded"/> <bbox w="30.0" h="30.0" x="5345.0" y="1555.0"/> </glyph> <glyph class="source and sink" id="s1545_sa814" compartmentRef="c7_ca7"> <label text="csa104_degraded"/> <bbox w="30.0" h="30.0" x="5475.0" y="1555.0"/> </glyph> <glyph class="nucleic acid feature" id="s1546_sa815" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22378844, PMID:24227772 miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. IL15 and KLRB1 (NK1.1) ligation also induce MIR155 expression. MIR155 expression is upregulated by IL18 via IL18 receptor. PMID:23572582 IL12 induces MIR155 expression via STAT4. PMID: PMID:22701882 IL2,IL15,IL21 upregulate MIR155, MIR15a, mir1246 in NK cells.MiR-155 increased human NK cell-mediated killing activity. References_end</body> </html> </notes> <label text="MIR155"/> <bbox w="70.0" h="25.0" x="1935.0" y="1677.5"/> </glyph> <glyph class="macromolecule" id="s1554_sa820"> <label text="IgG*"/> <bbox w="80.0" h="40.0" x="5550.0" y="4220.0"/> </glyph> <glyph class="complex" id="s1559_csa106" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD247:Fc_gamma_RIII*:IgG* Identifiers_end References_begin: PMID:18768831 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. PMID:7523143, PMID:10358164 Triggering of human natural killer cells through CD16 induces tyrosine phosphorylation of the p72syk kinase. PMID:8344348 CD16: zeta: gamma complex may use a ZAP-70-related non-receptor tyrosine kinase, in the CD16 signaling cascade leading to NK cell activation. PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. PMID:8551221, PMID:10358164 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. References_end</body> </html> </notes> <label text="s1081"/> <bbox w="100.0" h="180.0" x="5620.0" y="3380.0"/> <glyph class="macromolecule" id="s1561_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10562324, PMID:23414611 To initiate signal transduction, NKp30 associates with immunoreceptor tyrosine based activation motif (ITAM)-containing adaptor proteins, such as disulfide-linked homodimers of CD247 (CD3zeta). PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells. PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK References_end</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="5630.0" y="3445.0"/> <glyph class="state variable" id="_df4e4acc-0dde-4fb9-9b15-55f4b1c31ed9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5622.5" y="3465.0"/> </glyph> <glyph class="unit of information" id="_df9691ab-707b-44d5-983d-7a4178cd510b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5647.5" y="3440.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1560_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:FCGR3A HUGO:FCGR3B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:11449354, PMID:12393695 Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3 References_end</body> </html> </notes> <label text="FcγRIII*"/> <bbox w="80.0" h="50.0" x="5630.0" y="3495.0"/> <glyph class="unit of information" id="_dd2ff985-6481-4a62-ab3f-e4596d34f715"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5647.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1558_sa823"> <label text="IgG*"/> <bbox w="80.0" h="40.0" x="5630.0" y="3390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1562_sa824" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 were the only two cytokines among those tested that were able to induce Shc phosphorylation in NK cells. PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHC1"/> <clone/> <bbox w="80.0" h="40.0" x="5390.0" y="2600.0"/> <glyph class="state variable" id="_a35da380-0424-4819-a274-885b21a3ebfe"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5385.0" y="2615.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1562_sa919" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 were the only two cytokines among those tested that were able to induce Shc phosphorylation in NK cells. PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHC1"/> <clone/> <bbox w="80.0" h="40.0" x="6180.0" y="1950.0"/> <glyph class="state variable" id="_18cf27bc-dece-4b6f-8a37-45684913f818"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6175.0" y="1965.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1569_sa827" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:19359473, PMID:22378844 Inositol phosphatase SHIP1 is a primary and direct target of miR-155. miR-155 upregulates IFNG production in natural killer cells via SHIP1 downregulation. References_end</body> </html> </notes> <label text="SHIP1*"/> <bbox w="90.0" h="25.0" x="1355.0" y="2137.5"/> <glyph class="unit of information" id="_81d755ea-6515-47a3-9807-deb52d8342ca"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1390.0" y="2132.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1570_sa828" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:19359473, PMID:22378844 Inositol phosphatase SHIP1 is a primary and direct target of miR-155. miR-155 upregulates IFNG production in natural killer cells via SHIP1 downregulation. References_end</body> </html> </notes> <label text="SHIP1*"/> <bbox w="70.0" h="25.0" x="1365.0" y="2077.5"/> </glyph> <glyph class="complex" id="s1571_csa107" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MIR155:SHIP1* Identifiers_end</body> </html> </notes> <label text="s1571"/> <bbox w="100.0" h="100.0" x="1550.0" y="2110.0"/> <glyph class="nucleic acid feature" id="s1572_sa829"> <notes> <html xmlns="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: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:19359473, PMID:22378844 Inositol phosphatase SHIP1 is a primary and direct target of miR-155. miR-155 upregulates IFNG production in natural killer cells via SHIP1 downregulation. References_end</body> </html> </notes> <label text="SHIP1*"/> <bbox w="90.0" h="25.0" x="1555.0" y="2127.5"/> <glyph class="unit of information" id="_8dd0c6f0-e713-41c2-b49f-a06fd5eac149"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1590.0" y="2122.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1573_sa830"> <notes> <html xmlns="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: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:23422749 The enhanced NK-cell survival, expansion, activation, and tumor control result from overexpression of miR-155 in NK cells. PMID:19359473, PMID:22378844, PMID:24227772 Inositol phosphatase SHIP1 is a primary and direct target of miR-155. miR-155 upregulates IFNG production in natural killer cells via SHIP1 downregulation. Inhibition of either calcineurin or PI3Kled to a dose-responsive decrease in the differential between 155−/− and WT NK cell PMID:24227772 But an the same time mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. PMID:23572582 NOXA , a proapoptotic Bcl-2 homology domain (BH3)-only protein, is an important regulator of survival in NK cells ans SOCS1 are mir155 targets in NK cells References_end</body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="1555.0" y="2157.5"/> <glyph class="unit of information" id="_206e8d20-e353-41ac-b146-33179c019805"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1585.0" y="2152.5"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1574_sa831" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LCP2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:24227772 mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. References_end</body> </html> </notes> <label text="LCP2"/> <bbox w="90.0" h="25.0" x="4705.0" y="3077.5"/> <glyph class="unit of information" id="_9099a7cc-a327-41af-a130-276b6e58f8a4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4740.0" y="3072.5"/> </glyph> </glyph> <glyph class="complex" id="s1576_csa108" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:LCP2:MIR155 Identifiers_end</body> </html> </notes> <label text="s1576"/> <bbox w="100.0" h="120.0" x="4730.0" y="3140.0"/> <glyph class="nucleic acid feature" id="s1577_sa833"> <notes> <html xmlns="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: HUGO:LCP2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:24227772 mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. References_end</body> </html> </notes> <label text="LCP2"/> <bbox w="90.0" h="25.0" x="4735.0" y="3207.5"/> <glyph class="unit of information" id="_4a18333a-abff-44d7-97a1-935170049ace"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4770.0" y="3202.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1578_sa834"> <notes> <html xmlns="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: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:23422749 The enhanced NK-cell survival, expansion, activation, and tumor control result from overexpression of miR-155 in NK cells. PMID:19359473, PMID:22378844, PMID:24227772 Inositol phosphatase SHIP1 is a primary and direct target of miR-155. miR-155 upregulates IFNG production in natural killer cells via SHIP1 downregulation. Inhibition of either calcineurin or PI3Kled to a dose-responsive decrease in the differential between 155−/− and WT NK cell PMID:24227772 But an the same time mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. PMID:23572582 NOXA , a proapoptotic Bcl-2 homology domain (BH3)-only protein, is an important regulator of survival in NK cells ans SOCS1 are mir155 targets in NK cells References_end</body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="4735.0" y="3177.5"/> <glyph class="unit of information" id="_930f744c-17e1-47d9-86df-f6ab067440b8"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4765.0" y="3172.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1579_sa835" compartmentRef="c7_ca7"> <label text="csa108_degraded"/> <bbox w="30.0" h="30.0" x="4775.0" y="3295.0"/> </glyph> <glyph class="source and sink" id="s1580_sa836" compartmentRef="c7_ca7"> <label text="csa107_degraded"/> <bbox w="30.0" h="30.0" x="1675.0" y="2145.0"/> </glyph> <glyph class="nucleic acid feature" id="s1586_sa842" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR29A HUGO:MIR29B1 HUGO:MIR29B2 HUGO:MIR29C Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:21785411 miR-29 suppressed IFN-γ production by directly targeting IFNG mRNA in NK cells. Activation of NK cells inhinit mir29 expression probably via NFkB binding to the promoter of the gene encoding miR-29 (ref. 33) or activating the transcription suppressor YY1. References_end</body> </html> </notes> <label text="MIR29*"/> <bbox w="90.0" h="25.0" x="3765.0" y="1117.5"/> <glyph class="unit of information" id="_0b7b706e-2eb9-43b7-afc4-02ba31293101"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3795.0" y="1112.5"/> </glyph> </glyph> <glyph class="complex" id="s1587_csa109" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:IFNG:MIR29* Identifiers_end</body> </html> </notes> <label text="s1587"/> <bbox w="100.0" h="110.0" x="3730.0" y="935.0"/> <glyph class="nucleic acid feature" id="s1588_sa843"> <notes> <html xmlns="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: HUGO:MIR29A HUGO:MIR29B1 HUGO:MIR29B2 HUGO:MIR29C Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:21785411 miR-29 suppressed IFN-γ production by directly targeting IFNG mRNA in NK cells. Activation of NK cells inhinit mir29 expression probably via NFkB binding to the promoter of the gene encoding miR-29 (ref. 33) or activating the transcription suppressor YY1. References_end</body> </html> </notes> <label text="MIR29*"/> <bbox w="90.0" h="25.0" x="3735.0" y="952.5"/> <glyph class="unit of information" id="_6d2af678-d367-4015-8694-7561859c77c8"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3765.0" y="947.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1589_sa844"> <notes> <html xmlns="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: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:8700208, PMID:9715265, PMID:11449378 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. PMID:12759422 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:18768831, PMID:16713975 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end</body> </html> </notes> <label text="IFNG"/> <bbox w="90.0" h="25.0" x="3735.0" y="982.5"/> <glyph class="unit of information" id="_bc19e5a2-4f03-4022-909a-05c17d6683a3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3770.0" y="977.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1590_sa845" compartmentRef="c7_ca7"> <label text="csa109_degraded"/> <bbox w="30.0" h="30.0" x="3735.0" y="1075.0"/> </glyph> <glyph class="nucleic acid feature" id="s1591_sa846" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR27A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21960590 IL15 induces mir27A* expression in activated NK cells. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. Tumor growth was inhibited by mNK cells, the inhibitory effect of mNK cells was significantly decreased by miR-27a* overexpression. In contrast, transfection of mNK cells with miR-27a* inhibitor resulted in enhanced antitumor activity References_end</body> </html> </notes> <label text="MIR27A*"/> <bbox w="90.0" h="25.0" x="2155.0" y="1757.5"/> <glyph class="unit of information" id="_88bbfaee-be4e-4c7c-84cb-73b4e5d4df36"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2185.0" y="1752.5"/> </glyph> </glyph> <glyph class="complex" id="s1592_csa110" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MIR27A*:PRF1 Identifiers_end</body> </html> </notes> <label text="s1592"/> <bbox w="100.0" h="120.0" x="2920.0" y="2720.0"/> <glyph class="nucleic acid feature" id="s1596_sa848"> <notes> <html xmlns="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: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="2925.0" y="2767.5"/> <glyph class="unit of information" id="_092a24a8-6e20-4f19-8df1-2d7fdc2dba1d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2960.0" y="2762.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1597_sa849"> <notes> <html xmlns="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: HUGO:MIR27A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21960590 IL15 induces mir27A* expression in activated NK cells. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. Tumor growth was inhibited by mNK cells, the inhibitory effect of mNK cells was significantly decreased by miR-27a* overexpression. In contrast, transfection of mNK cells with miR-27a* inhibitor resulted in enhanced antitumor activity References_end</body> </html> </notes> <label text="MIR27A*"/> <bbox w="90.0" h="25.0" x="2925.0" y="2727.5"/> <glyph class="unit of information" id="_22657ef8-1cc8-456a-a9a4-6b71795354a0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2955.0" y="2722.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1593_csa111" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GZMB:MIR27A* Identifiers_end</body> </html> </notes> <label text="s1593"/> <bbox w="100.0" h="120.0" x="2790.0" y="2720.0"/> <glyph class="nucleic acid feature" id="s1594_sa847"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="2795.0" y="2767.5"/> <glyph class="unit of information" id="_4135d515-de7e-42a0-8ab6-17139c5daa84"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2830.0" y="2762.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1595_sa850"> <notes> <html xmlns="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: HUGO:MIR27A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21960590 IL15 induces mir27A* expression in activated NK cells. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. Tumor growth was inhibited by mNK cells, the inhibitory effect of mNK cells was significantly decreased by miR-27a* overexpression. In contrast, transfection of mNK cells with miR-27a* inhibitor resulted in enhanced antitumor activity References_end</body> </html> </notes> <label text="MIR27A*"/> <bbox w="90.0" h="25.0" x="2795.0" y="2737.5"/> <glyph class="unit of information" id="_ba85316b-e890-4737-ba0e-925aa88ea731"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2825.0" y="2732.5"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1600_sa853" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR27A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21960590 IL15 induces mir27A* expression in activated NK cells. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. References_end</body> </html> </notes> <label text="MIR27A*"/> <bbox w="70.0" h="25.0" x="2165.0" y="1677.5"/> </glyph> <glyph class="nucleic acid feature" id="s1601_sa854" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR150 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively. Immunodeficient mice were injected with miR-150(-/-) NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma. 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Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively. Immunodeficient mice were injected with miR-150(-/-) NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma. 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PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="3055.0" y="2767.5"/> <glyph class="unit of information" id="_930e3308-64ca-43a3-af2b-f71d05def06f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3090.0" y="2762.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1604_sa858"> <notes> <html xmlns="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: HUGO:MIR150 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively. Immunodeficient mice were injected with miR-150(-/-) NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma. 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References_end</body> </html> </notes> <label text="MIR378"/> <bbox w="90.0" h="25.0" x="2375.0" y="1757.5"/> <glyph class="unit of information" id="_ffba6a8f-f0f1-43a3-9647-5e9140a2ab6d"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2405.0" y="1752.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1608_sa861" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR30E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22649192 miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="90.0" h="25.0" x="2465.0" y="1747.5"/> <glyph class="unit of information" id="_7bb04584-322f-42d4-a684-5769ee923730"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2495.0" y="1742.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1609_sa862" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR378 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22649192 miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. 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References_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="70.0" h="25.0" x="2465.0" y="1677.5"/> </glyph> <glyph class="complex" id="s1611_csa113" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GZMB:MIR378 Identifiers_end</body> </html> </notes> <label text="s1611"/> <bbox w="100.0" h="120.0" x="3240.0" y="2720.0"/> <glyph class="nucleic acid feature" id="s1612_sa864"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="3245.0" y="2757.5"/> <glyph class="unit of information" id="_b2ebb4e0-bf78-4388-9703-d3e1fccbd556"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3280.0" y="2752.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1613_sa865"> <notes> <html xmlns="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: HUGO:MIR378 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22649192 miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="MIR378"/> <bbox w="90.0" h="25.0" x="3245.0" y="2727.5"/> <glyph class="unit of information" id="_e736b23e-d612-4668-9635-3e3e304ae626"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3275.0" y="2722.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1614_csa114" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MIR30E:PRF1 Identifiers_end</body> </html> </notes> <label text="s1614"/> <bbox w="100.0" h="80.0" x="3240.0" y="2950.0"/> <glyph class="nucleic acid feature" id="s1952_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:MIR30E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22649192 miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="MIR30E"/> <bbox w="90.0" h="25.0" x="3245.0" y="2957.5"/> <glyph class="unit of information" id="_55d5a86f-4894-4c3b-80e3-d999ff17d963"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3275.0" y="2952.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1616_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. References_end</body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="3245.0" y="2987.5"/> <glyph class="unit of information" id="_99bc472a-6762-48ab-a6f5-432eb8be5eef"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3280.0" y="2982.5"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1617_sa868" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR223 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20935160 miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following IL15 activation. miR-223 specifically targets the 3' untranslated region of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. References_end</body> </html> </notes> <label text="MIR223"/> <bbox w="90.0" h="25.0" x="2045.0" y="1757.5"/> <glyph class="unit of information" id="_0987be64-b4f5-4f24-af99-c1127d9a7fbc"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2075.0" y="1752.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1618_sa869" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR223 HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20935160 miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following IL15 activation. miR-223 specifically targets the 3' untranslated region of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. References_end</body> </html> </notes> <label text="MIR223"/> <bbox w="70.0" h="25.0" x="2045.0" y="1677.5"/> </glyph> <glyph class="complex" id="s1619_csa115" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GZMB:MIR223 Identifiers_end</body> </html> </notes> <label text="s1619"/> <bbox w="100.0" h="120.0" x="2660.0" y="2720.0"/> <glyph class="nucleic acid feature" id="s1620_sa870"> <notes> <html xmlns="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: HUGO:MIR223 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20935160 miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following IL15 activation. miR-223 specifically targets the 3' untranslated region of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. References_end</body> </html> </notes> <label text="MIR223"/> <bbox w="90.0" h="25.0" x="2665.0" y="2727.5"/> <glyph class="unit of information" id="_50d30074-5ac1-450c-b6c2-f40ac5a82b7c"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2695.0" y="2722.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1621_sa871"> <notes> <html xmlns="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: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end</body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="2665.0" y="2757.5"/> <glyph class="unit of information" id="_c64cbf88-032d-4e71-8f39-c1a207139f0f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2700.0" y="2752.5"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1623_sa873" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR15A HUGO:MIR15B HUGO:MIR16-1 HUGO::MIR16-2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22379033 IL-15 plus IL-12, or plate-bound anti-NK1.1, resulted in a significant reduction of miR-15b in both conditions, and a significant reduction in miR-15a and miR-16 in the 12+15 condition miRs-15a/15b/16 were identified as abundant miRNAs in NK cells that directly target the murine IFN-γ 3'UTR. References_end</body> </html> </notes> <label text="MIR15/16*"/> <bbox w="90.0" h="25.0" x="2295.0" y="1547.5"/> <glyph class="unit of information" id="_126ff4b2-a85f-4c89-bd56-176638710a7d"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2325.0" y="1542.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1624_sa874" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MIR15A HUGO:MIR15B HUGO:MIR16-1 HUGO::MIR16-2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22379033 IL-15 plus IL-12, or plate-bound anti-NK1.1, resulted in a significant reduction of miR-15b in both conditions, and a significant reduction in miR-15a and miR-16 in the 12+15 condition miRs-15a/15b/16 were identified as abundant miRNAs in NK cells that directly target the murine IFNG 3'UTR. PMID: PMID:22701882 IL2,IL15,IL21 upregulate MIR155, MIR15a, mir1246 in NK cells. References_end</body> </html> </notes> <label text="MIR15/16*"/> <bbox w="70.0" h="25.0" x="2305.0" y="1477.5"/> </glyph> <glyph class="complex" id="s1625_csa116" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:IFNG:MIR15/16* Identifiers_end</body> </html> </notes> <label text="s1625"/> <bbox w="100.0" h="120.0" x="3570.0" y="930.0"/> <glyph class="nucleic acid feature" id="s1626_sa875"> <notes> <html xmlns="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: HUGO:MIR15A HUGO:MIR15B HUGO:MIR16-1 HUGO::MIR16-2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22379033 IL-15 plus IL-12, or plate-bound anti-NK1.1, resulted in a significant reduction of miR-15b in both conditions, and a significant reduction in miR-15a and miR-16 in the 12+15 condition miRs-15a/15b/16 were identified as abundant miRNAs in NK cells that directly target the murine IFN-γ 3'UTR. References_end</body> </html> </notes> <label text="MIR15/16*"/> <bbox w="90.0" h="25.0" x="3575.0" y="977.5"/> <glyph class="unit of information" id="_6046bd03-8711-4b8f-8a8e-309c7ed25e20"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3605.0" y="972.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1628_sa876"> <notes> <html xmlns="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: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:8700208, PMID:9715265, PMID:11449378 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. PMID:12759422 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:18768831, PMID:16713975 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end</body> </html> </notes> <label text="IFNG"/> <bbox w="90.0" h="25.0" x="3575.0" y="947.5"/> <glyph class="unit of information" id="_2212f27d-9c87-4c34-b32d-ab219a731d50"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3610.0" y="942.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1627_sa877" compartmentRef="c7_ca7"> <label text="csa116_degraded"/> <bbox w="30.0" h="30.0" x="3575.0" y="1075.0"/> </glyph> <glyph class="complex" id="s1637_csa118" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL21R:IL2RG Identifiers_end</body> </html> </notes> <label text="s1637"/> <bbox w="165.0" h="120.0" x="6247.5" y="920.0"/> <glyph class="macromolecule" id="s1641_sa885"> <notes> <html xmlns="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: HUGO:IL21R Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:24751819 Interleukin-21 (IL-21) is produced by CD4+ T cell populations, with the highest production by T follicular helper (TFH) cells and TH17 cells, and slightly lower levels produced by natural killer T (NKT) cells. IL-21 signals via heterodimers of the IL-21 receptor (IL-21R) and the common cytokine receptor γ-chain, (encoded by IL2RG) References_end</body> </html> </notes> <label text="IL21R"/> <bbox w="80.0" h="50.0" x="6327.5" y="955.0"/> <glyph class="unit of information" id="_335358ba-46a5-4741-8f3c-57c0cc74328d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6345.0" y="950.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1642_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="6247.5" y="955.0"/> <glyph class="unit of information" id="_a4bcbfe5-e599-4b56-91c5-bcdbccbff837"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6265.0" y="950.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1644_csa119" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL21:IL21R:IL2RG Identifiers_end References_begin: PMID:24751819 Interleukin-21 (IL-21) is produced by CD4+ T cell populations, with the highest production by T follicular helper (TFH) cells and TH17 cells, and slightly lower levels produced by natural killer T (NKT) cells. IL-21 signals via heterodimers of the IL-21 receptor (IL-21R) and the common cytokine receptor γ-chain, (encoded by IL2RG) References_end</body> </html> </notes> <label text="s1637"/> <bbox w="172.5" h="140.0" x="6273.75" y="1100.0"/> <glyph class="macromolecule" id="s1645_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL21R Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:24751819 Interleukin-21 (IL-21) is produced by CD4+ T cell populations, with the highest production by T follicular helper (TFH) cells and TH17 cells, and slightly lower levels produced by natural killer T (NKT) cells. IL-21 signals via heterodimers of the IL-21 receptor (IL-21R) and the common cytokine receptor γ-chain, (encoded by IL2RG) References_end</body> </html> </notes> <label text="IL21R"/> <bbox w="80.0" h="50.0" x="6353.75" y="1155.0"/> <glyph class="unit of information" id="_ae6b1afc-0c6f-4514-b5ca-067d1301b41c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6371.25" y="1150.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1646_sa888"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="6273.75" y="1155.0"/> <glyph class="unit of information" id="_95e35e0b-5fa2-4747-b21e-2a81f33b7c98"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6291.25" y="1150.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1643_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL21 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:24751819 Interleukin-21 (IL-21) is produced by CD4+ T cell populations, with the highest production by T follicular helper (TFH) cells and TH17 cells, and slightly lower levels produced by natural killer T (NKT) cells. IL-21 signals via heterodimers of the IL-21 receptor (IL-21R) and the common cytokine receptor γ-chain, (encoded by IL2RG) Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). IL-21 binding to IL-21R can also activate the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways. PMID:12244150 IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. PMID:16081783 IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. PMID:16785506 Interleukin-21 enhances NK cell activation in response to antibody-coated targets (CD16 dependent). References_end</body> </html> </notes> <label text="IL21"/> <bbox w="80.0" h="40.0" x="6356.25" y="1110.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1647_sa890" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 IL-15 and IL-21 up-regulated MyD88 gene expression in NK cells. both IL-15 and IL-21 induced STAT binding to MyD88 GAS. Anti-STAT5 and anti-STAT1 Abs supershifted both of the IL-15-induced MyD88 GAS complexes, whereas anti-STAT3 Ab supershifted IL-21-induced MyD88 GAS binding complexes References_end</body> </html> </notes> <label text="MYD88"/> <bbox w="70.0" h="25.0" x="4302.5" y="1007.5"/> </glyph> <glyph class="nucleic acid feature" id="s1648_sa891" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 IL-15 and IL-21 up-regulated MyD88 gene expression in NK cells References_end</body> </html> </notes> <label text="MYD88"/> <bbox w="90.0" h="25.0" x="4285.0" y="917.5"/> <glyph class="unit of information" id="_b1d53f44-728e-4c5e-a708-431596818b43"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4320.0" y="912.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1649_sa894" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2RA IL-12Rb2 IL-18Rα and IL-18Rβ in NK cells. PMID: PMID:9834059 NK cells stimulated by IL12 accumulate much higher levels of the IL-12Rbeta2-chain mRNA and are significantly more responsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor. References_end</body> </html> </notes> <label text="IL12RB2"/> <bbox w="70.0" h="25.0" x="5655.0" y="1367.5"/> </glyph> <glyph class="nucleic acid feature" id="s1650_sa895" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL18RAP"/> <bbox w="70.0" h="25.0" x="5655.0" y="1327.5"/> </glyph> <glyph class="nucleic acid feature" id="s1651_sa896" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL18R1"/> <bbox w="70.0" h="25.0" x="5655.0" y="1277.5"/> </glyph> <glyph class="nucleic acid feature" id="s1652_sa897" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL18R1"/> <bbox w="90.0" h="25.0" x="5765.0" y="1277.5"/> <glyph class="unit of information" id="_03ce46d8-1f92-4849-9435-137d9c37aaad"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5800.0" y="1272.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1653_sa898" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL18RAP"/> <bbox w="90.0" h="25.0" x="5765.0" y="1327.5"/> <glyph class="unit of information" id="_a7cc0e8c-5e79-4528-ab9d-b86ab7934f8a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5800.0" y="1322.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1654_sa899" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end</body> </html> </notes> <label text="IL12RB2"/> <bbox w="90.0" h="25.0" x="5775.0" y="1367.5"/> <glyph class="unit of information" id="_2d2e5ea0-751a-4fb5-b5a8-3f4b7c320b7d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5810.0" y="1362.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1655_sa900" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL18R1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18R1"/> <bbox w="80.0" h="50.0" x="5870.0" y="1265.0"/> <glyph class="unit of information" id="_4e01d7cf-a180-4c62-badd-6663690e30fa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5887.5" y="1260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1656_sa901" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL18RAP Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18RAP"/> <bbox w="80.0" h="50.0" x="5870.0" y="1325.0"/> <glyph class="unit of information" id="_be83cf09-54f7-45bc-84c4-456557eb30c4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5887.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1657_sa902" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB2"/> <bbox w="80.0" h="50.0" x="5870.0" y="1375.0"/> <glyph class="unit of information" id="_764f75d9-18d0-45f3-9795-0792daf0164a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5887.5" y="1370.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1659_sa904" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ETS1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end</body> </html> </notes> <label text="ETS1"/> <bbox w="90.0" h="25.0" x="3545.0" y="1477.5"/> <glyph class="unit of information" id="_1f2312e6-4866-415a-8646-73812f5aae6c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3580.0" y="1472.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1662_sa907" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MNK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end</body> </html> </notes> <label text="MNK1"/> <bbox w="80.0" h="40.0" x="3760.0" y="2100.0"/> <glyph class="state variable" id="_150d9331-abf5-4b3e-8152-e1649ac8eabc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3755.0" y="2115.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1663_sa908" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MNK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end</body> </html> </notes> <label text="MNK1"/> <bbox w="80.0" h="40.0" x="3760.0" y="2020.0"/> <glyph class="state variable" id="_aae889cf-e3e3-426a-a928-aecb7c90fe82"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3752.5" y="2035.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1664_sa910" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:EIF4E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end</body> </html> </notes> <label text="EIF4E"/> <bbox w="80.0" h="40.0" x="3620.0" y="2000.0"/> <glyph class="state variable" id="_968edec0-96a5-4069-a711-088201074256"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3615.0" y="2015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1665_sa911" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:EIF4E Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end</body> </html> </notes> <label text="EIF4E"/> <bbox w="80.0" h="40.0" x="3620.0" y="1930.0"/> <glyph class="state variable" id="_8040d8cc-0480-4919-bbe9-78647c7b6e33"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3612.5" y="1945.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1315_sa615" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ETS1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end</body> </html> </notes> <label text="ETS1"/> <bbox w="80.0" h="40.0" x="3550.0" y="1540.0"/> </glyph> <glyph class="nucleic acid feature" id="s1666_sa912" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR1 Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: ACTIVATING_RECEPTORS PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end</body> </html> </notes> <label text="NKp46*"/> <bbox w="70.0" h="25.0" x="4895.0" y="3177.5"/> </glyph> <glyph class="nucleic acid feature" id="s1667_sa913" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR1 Identifiers_end Maps_Modules_begin: MODULE:NK Maps_Modules_end References_begin: ACTIVATING_RECEPTORS PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end</body> </html> </notes> <label text="NKp46*"/> <bbox w="90.0" h="25.0" x="4895.0" y="3237.5"/> <glyph class="unit of information" id="_c5a9eb8e-eb36-4a5b-8215-648a2acde6b7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4930.0" y="3232.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1668_sa915" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:WASF2 Identifiers_end Maps_Modules_begin: MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:NK Maps_Modules_end References_begin: PMID:21383498 IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function. References_end</body> </html> </notes> <label text="WASF2"/> <bbox w="80.0" h="40.0" x="3230.0" y="2160.0"/> <glyph class="state variable" id="_1041bcad-b265-4f04-b6b7-a885374aa85e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3222.5" y="2175.0"/> </glyph> </glyph> <glyph class="complex" id="s1669_csa120" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GRB2:LAT Identifiers_end</body> </html> </notes> <label text="s1669"/> <bbox w="100.0" h="120.0" x="5820.0" y="2920.0"/> <glyph class="macromolecule" id="s1670_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:LAT Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10072481,PMID:16329184, PMID:11169415 LAT participate in NK-cell cytotoxicity against tumor cells downstream of CD16 and 2B4 signaling. LAT is phosphorylated downstream of 2B4 and CD16 PMID:9489702, PMID:10072481, PMID:7523143 LAT is a substrate for ZAP-70, Syk protein tyrosine kinases in T cells and probably in NK cells. PMID:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway. PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1. References_end</body> </html> </notes> <label text="LAT"/> <bbox w="80.0" h="50.0" x="5830.0" y="2975.0"/> <glyph class="state variable" id="_a7f4b237-2e0c-40dd-8a90-bee48def74f1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5822.5" y="2995.0"/> </glyph> <glyph class="unit of information" id="_520ee6b5-3e76-4ec2-b7e9-759be4d16356"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5847.5" y="2970.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1671_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:GRB2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16887996, PMID:16582911 Vav1 interacts with DAP10 YxNM motifs through the adaptor protein Grb2 and is required for activation of PI3K-dependent Akt signaling. binding of DAP10‭ ‬to either p85‭ ‬or Grb2‭ ‬alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 References_end</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="5830.0" y="2930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1678_sa920" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 were the only two cytokines among those tested that were able to induce Shc phosphorylation in NK cells. PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHC1"/> <bbox w="80.0" h="40.0" x="6180.0" y="2070.0"/> <glyph class="state variable" id="_7cbb6041-97c2-4b2a-8169-4064268f8cc1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6172.5" y="2085.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1681_sa703" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS The phosphorylation of Ser329 by PKC was later found to be critical for the association between DNAM-1 and CD18(LFA-1) in NK cells.17 This association is required for DNAM-1 signalling. PMID:19965656 Coengagement of DNAM-1 and CD18 (LFA-)1 by a Drosophila cell line transfected to express CD155 and intercellular adhesion molecule 1 triggered the IFN-g production by NK cells, while these ligands alone had no effects, reinforcing the functional link between DNAM-1 and LFA-1 in driving NK cell activation. PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. LFA-1 is required for NKG2D-mediated conjugate formation and cytotoxicity. References_end</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="6980.0" y="2225.0"/> <glyph class="unit of information" id="_4ea46584-5781-4867-8af7-b082edb109ff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6997.5" y="2220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1683_sa924" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:FYN Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:10591186, PMID:24440149 Cross-Linking of LFA-1 induces tyrosine Phosphorylation of DNAM-,FYN probably phosphorylates DNAM1 Y322 in NK cells PMID: PMID:22683124 Fyn-deficient NK cells exhibited defective killing. References_end</body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="4510.0" y="3010.0"/> <glyph class="state variable" id="_e8ade0e2-ef73-4a46-9b41-8cd2e1469d17"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4505.0" y="3025.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1686_sa710" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="6580.0" y="2645.0"/> <glyph class="unit of information" id="_125f1bb4-c573-4c62-a63c-bd59d6f142a8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6597.5" y="2640.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1696_sa931" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:GZMA Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end</body> </html> </notes> <label text="GZMA "/> <bbox w="70.0" h="25.0" x="3075.0" y="3077.5"/> </glyph> <glyph class="macromolecule" id="s1697_sa932"> <notes> <html xmlns="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: HUGO:FASLG Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. PMID:9858524 Mature CD56(+) NK cells mediate TRAIL-dependent and FasL-dependent cytotoxicity of tumor cells. PMID:8892629 IFN-gamma-inducing factor (IL18) up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones References_end</body> </html> </notes> <label text="FASL*"/> <bbox w="80.0" h="40.0" x="1740.0" y="3840.0"/> </glyph> <glyph class="macromolecule" id="s1699_sa933"> <notes> <html xmlns="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: HUGO:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:9858524 Mature CD56(+) NK cells mediate TRAIL-dependent and FasL-dependent cytotoxicity of tumor cells. PMID:11257133 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. References_end</body> </html> </notes> <label text="TRAIL*"/> <bbox w="80.0" h="40.0" x="1620.0" y="3840.0"/> </glyph> <glyph class="complex" id="s1700_csa121" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CDC42:GTP Identifiers_end</body> </html> </notes> <label text="s1700"/> <bbox w="100.0" h="120.0" x="3930.0" y="2260.0"/> <glyph class="macromolecule" id="s1694_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CDC42 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17785506 TRIP10 (CIP4) functions downstream of Cdc42 to induce MTOC polarization to the IS and cytotoxicity. PMID:16329184 VAV1 and VAV2 proteins can activate cdc42 PMID: PMID:15001467 CD16 signaling activates cdc24 in NK cells probably via vav proteins. PMID:22126964 Cdc42 activation is downstream of PI3K pathway (probably via VAVs) References_end</body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="3940.0" y="2280.0"/> </glyph> <glyph class="simple chemical" id="s1701_sa937"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="3945.0" y="2327.5"/> </glyph> </glyph> <glyph class="complex" id="s1703_csa122" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CDC42:GDP Identifiers_end</body> </html> </notes> <label text="s1703"/> <bbox w="100.0" h="120.0" x="4120.0" y="2260.0"/> <glyph class="simple chemical" id="s1704_sa936"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="4138.75" y="2316.875"/> </glyph> <glyph class="macromolecule" id="s1702_sa938"> <notes> <html xmlns="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: HUGO:CDC42 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17785506 TRIP10 (CIP4) functions downstream of Cdc42 to induce MTOC polarization to the IS and cytotoxicity. PMID:16329184 VAV1 and VAV2 proteins can activate cdc42 PMID: PMID:15001467 CD16 signaling activates cdc24 in NK cells probably via vav proteins. PMID:22126964 Cdc42 activation is downstream of PI3K pathway (probably via VAVs) References_end</body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="4130.0" y="2270.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1705_sa223" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:WAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15001467, PMID:14707117 CD16 or ITGB2 (CD18) stimulation resulted in the induction of WASp tyrosine phosphorylation in NK cells, probubly by Fyn. Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation in T cells. PMID:12177428 NK cell cytotoxicity was deficient in WAS patients and WASp catalyzes actin polymerization. It binds actin monomers as well as the actin-related protein (ARP) 2/3 complex to catalyze branching of filamentous actin (F-actin) PMID:16606694 WIPF1 forms complex with WASP. References_end</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="2790.0" y="1860.0"/> <glyph class="state variable" id="_867d26e1-5a4d-4be6-88d9-bc4921b0e870"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2782.5" y="1875.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1324_sa625" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. PMID:18768831 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end</body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="6620.0" y="1630.0"/> </glyph> <glyph class="macromolecule" id="s1067_sa206" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CCL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway. References_end</body> </html> </notes> <label text="CCL4"/> <bbox w="80.0" h="40.0" x="6690.0" y="1700.0"/> </glyph> <glyph class="macromolecule" id="s1712_sa940" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:GZMH Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15607806,PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end</body> </html> </notes> <label text="GZMH"/> <bbox w="80.0" h="40.0" x="2170.0" y="2930.0"/> </glyph> <glyph class="macromolecule" id="s1713_sa941" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:GZMM Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end</body> </html> </notes> <label text="GZMM"/> <bbox w="80.0" h="40.0" x="2260.0" y="2960.0"/> </glyph> <glyph class="macromolecule" id="s1714_sa942" compartmentRef="c4_ca4"> <notes> <html xmlns="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: HUGO:GNLY Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:14499265 Granulysin is a member of the saposin-like protein family that includes amoebapores and NK lysin. It is a cytolytic protein present in the granules of human CTLs and NK cells and is lytic against both microbes and tumors. http://dx.doi.org/10.5402/2012/876203 References_end</body> </html> </notes> <label text="GNLY"/> <bbox w="80.0" h="40.0" x="2360.0" y="2980.0"/> </glyph> <glyph class="source and sink" id="s1715_sa943" compartmentRef="c7_ca7"> <label text="csa114_degraded"/> <bbox w="30.0" h="30.0" x="3275.0" y="2895.0"/> </glyph> <glyph class="complex" id="s1717_csa123" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:BCAR1:CBL:CRK:CRKL:RAPGEF1 Identifiers_end</body> </html> </notes> <label text="s1717"/> <bbox w="210.0" h="191.25" x="3845.0" y="2804.375"/> <glyph class="macromolecule" id="s1723_sa688"> <notes> <html xmlns="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: HUGO:RAPGEF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. RAPGEF1(C3G) activates the GTPase Rap1 References_end</body> </html> </notes> <label text="RAPGEF1"/> <bbox w="80.0" h="40.0" x="3905.0" y="2814.375"/> </glyph> <glyph class="macromolecule" id="s1718_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:BCAR1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18835194 Several YxxP motifs for binding of (CrkII) are also present in the scaffold protein BCAR1 (p130CAS). Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. References_end</body> </html> </notes> <label text="BCAR1"/> <bbox w="80.0" h="40.0" x="3865.0" y="2864.375"/> <glyph class="state variable" id="_7d683937-5b23-48a9-b894-428af1027009"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3857.5" y="2879.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1719_sa945"> <notes> <html xmlns="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: HUGO:CRK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity. PMID:22464172 The intensity of p-Vav1 in Crk-silenced NK cells was decreased References_end</body> </html> </notes> <label text="CRK"/> <bbox w="80.0" h="40.0" x="3955.0" y="2914.375"/> <glyph class="state variable" id="_f2944f81-12ff-4c2a-b19d-6ebc018ff782"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3950.0" y="2929.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1720_sa946"> <notes> <html xmlns="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: HUGO:CRLK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:18835194 CrkL suppression resulted in a significant decrease in cytotoxicity against P815 tumor targets coated with either anti-NKG2D or anti-FcR, and against MICA-expressing BaF3 cells. But at the same time,CrkL was shown to be phosphorylated in an Abl-dependent manner upon ligation of inhibitory killer Ig-related receptors (KIRs) to terminate signaling from activating receptors. References_end</body> </html> </notes> <label text="CRKL"/> <bbox w="80.0" h="40.0" x="3865.0" y="2914.375"/> <glyph class="state variable" id="_ce5e2957-3438-4805-b93b-d6862a1096f4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3860.0" y="2929.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1722_sa948"> <notes> <html xmlns="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: HUGO:CBL Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20189481, PMID: PMID:18835194 CBL inhibited Vav1-dependent activation signals in NK via VAV1 ubiquitination. Tyrosine phosphorylation of c-Cbl was detected after stimulation NKL cells by either NKG2D, 2B4, or the synergistic NKG2D and 2B4 combination. Cbl Limits NK Cell Activation. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. References_end</body> </html> </notes> <label text="CBL"/> <bbox w="80.0" h="40.0" x="3955.0" y="2864.375"/> <glyph class="state variable" id="_6c1c3305-276c-47c5-8dfe-8009d3f92389"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3947.5" y="2879.375"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1721_sa947" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTK2B Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, probaby via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="PTK2B"/> <bbox w="80.0" h="40.0" x="6460.0" y="2520.0"/> <glyph class="state variable" id="_ccb9422c-8437-4e21-ad52-2f5b53f63587"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6455.0" y="2535.0"/> </glyph> </glyph> <glyph class="complex" id="s1724_csa124" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:BCAR1:CBL:CRK:CRKL:RAPGEF1 Identifiers_end</body> </html> </notes> <label text="s1717"/> <bbox w="210.0" h="191.25" x="3475.0" y="2804.375"/> <glyph class="macromolecule" id="s1725_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: HUGO:RAPGEF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. RAPGEF1(C3G) activates the GTPase Rap1 References_end</body> </html> </notes> <label text="RAPGEF1"/> <bbox w="80.0" h="40.0" x="3535.0" y="2814.375"/> </glyph> <glyph class="macromolecule" id="s1726_sa950"> <notes> <html xmlns="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: HUGO:BCAR1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:18835194 Several YxxP motifs for binding of (CrkII) are also present in the scaffold protein BCAR1 (p130CAS). Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. References_end</body> </html> </notes> <label text="BCAR1"/> <bbox w="80.0" h="40.0" x="3495.0" y="2864.375"/> <glyph class="state variable" id="_66f99960-3a7c-433f-b951-68978212e7f5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3487.5" y="2879.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1729_sa951"> <notes> <html xmlns="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: HUGO:CRK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18835194 Through its SH3 domain, CRK (CrkII) recruits the GEF C3G, which activates the GTPase Rap in NK cells. Association of CrkII with c-Cbl, p130CAS, and C3G was induced by activation of NK cells. Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity. PMID:22464172 The intensity of p-Vav1 in Crk-silenced NK cells was decreased References_end</body> </html> </notes> <label text="CRK"/> <bbox w="80.0" h="40.0" x="3585.0" y="2914.375"/> <glyph class="state variable" id="_9999ffb4-141e-43c9-bd19-30b0caf36eba"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3577.5" y="2929.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1730_sa952"> <notes> <html xmlns="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: HUGO:CRLK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:18835194 CrkL suppression resulted in a significant decrease in cytotoxicity against P815 tumor targets coated with either anti-NKG2D or anti-FcR, and against MICA-expressing BaF3 cells. But at the same time,CrkL was shown to be phosphorylated in an Abl-dependent manner upon ligation of inhibitory killer Ig-related receptors (KIRs) to terminate signaling from activating receptors. References_end</body> </html> </notes> <label text="CRKL"/> <bbox w="80.0" h="40.0" x="3495.0" y="2914.375"/> <glyph class="state variable" id="_8c44c6a2-73a8-46a9-a704-e08010656a6a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3487.5" y="2929.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1728_sa953"> <notes> <html xmlns="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: HUGO:CBL Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20189481, PMID: PMID:18835194 CBL inhibited Vav1-dependent activation signals in NK via VAV1 ubiquitination. Tyrosine phosphorylation of c-Cbl was detected after stimulation NKL cells by either NKG2D, 2B4, or the synergistic NKG2D and 2B4 combination. Cbl Limits NK Cell Activation. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. References_end</body> </html> </notes> <label text="CBL"/> <bbox w="80.0" h="40.0" x="3585.0" y="2864.375"/> <glyph class="state variable" id="_8ed97358-0fd8-42af-812d-e9545cd5a0b5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3577.5" y="2879.375"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1731_sa954"> <notes> <html xmlns="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: HUGO:GNLY Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:14499265 Granulysin is a member of the saposin-like protein family that includes amoebapores and NK lysin. It is a cytolytic protein present in the granules of human CTLs and NK cells and is lytic against both microbes and tumors. http://dx.doi.org/10.5402/2012/876203 References_end</body> </html> </notes> <label text="GNLY"/> <bbox w="80.0" h="40.0" x="2110.0" y="4040.0"/> </glyph> <glyph class="macromolecule" id="s1732_sa955"> <notes> <html xmlns="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: HUGO:GZMM Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end</body> </html> </notes> <label text="GZMM"/> <bbox w="80.0" h="40.0" x="2060.0" y="3980.0"/> </glyph> <glyph class="macromolecule" id="s1733_sa956"> <notes> <html xmlns="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: HUGO:GZMH Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:15607806,PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end</body> </html> </notes> <label text="GZMH"/> <bbox w="80.0" h="40.0" x="1970.0" y="3950.0"/> </glyph> <glyph class="macromolecule" id="s1734_sa957"> <notes> <html xmlns="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: HUGO:GZMK Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:LYTIC_GRANULES_EXOCYTOSIS Maps_Modules_end References_begin: PMID:16106370, PMID:15607806,PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end</body> </html> </notes> <label text="GZMK"/> <bbox w="80.0" h="40.0" x="1860.0" y="3880.0"/> </glyph> <glyph class="macromolecule" id="s1419_sa718" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RASSF5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:16892067 Ligation of either FcR or NKG2D increased phosphorylation of MST1 in NK cells. Probably via RASSF5 (RAPL). References_end</body> </html> </notes> <label text="RASSF5"/> <bbox w="80.0" h="40.0" x="3390.0" y="2570.0"/> </glyph> <glyph class="complex" id="s1736_csa125" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MST1:RASSF5 Identifiers_end</body> </html> </notes> <label text="s1736"/> <bbox w="100.0" h="120.0" x="3450.0" y="2370.0"/> <glyph class="macromolecule" id="s1739_sa959"> <notes> <html xmlns="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: HUGO:MTS1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:16892067 Ligation of either FcR or NKG2D increased phosphorylation of MST1 in NK cells. Probably via RAPL. NKG2D signaling increases integrin-dependent NK cell adgesion, promably via MST1 which can upregulate LFA-1/ICAM1 adhesion References_end</body> </html> </notes> <label text="MST1"/> <bbox w="80.0" h="40.0" x="3460.0" y="2380.0"/> <glyph class="state variable" id="_b94ca38b-ec05-4da9-bf44-6b88d67f2cd1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3455.0" y="2395.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1738_sa960"> <notes> <html xmlns="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: HUGO:RASSF5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:16892067 Ligation of either FcR or NKG2D increased phosphorylation of MST1 in NK cells. Probably via RASSF5 (RAPL). References_end</body> </html> </notes> <label text="RASSF5"/> <bbox w="80.0" h="40.0" x="3460.0" y="2430.0"/> </glyph> </glyph> <glyph class="complex" id="s1737_csa126" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:MST1:RASSF5 Identifiers_end</body> </html> </notes> <label text="s1737"/> <bbox w="100.0" h="120.0" x="3600.0" y="2370.0"/> <glyph class="macromolecule" id="s1735_sa958"> <notes> <html xmlns="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: HUGO:MTS1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:16892067 Ligation of either FcR or NKG2D increased phosphorylation of MST1 in NK cells. Probably via RAPL. NKG2D signaling increases integrin-dependent NK cell adgesion, promably via MST1 which can upregulate LFA-1/ICAM1 adhesion References_end</body> </html> </notes> <label text="MST1"/> <bbox w="80.0" h="40.0" x="3610.0" y="2380.0"/> <glyph class="state variable" id="_3236d8ea-afe1-4198-8c59-4da01a7fd7e1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3602.5" y="2395.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1741_sa962"> <notes> <html xmlns="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: HUGO:RASSF5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19454690, PMID:16892067 Ligation of either FcR or NKG2D increased phosphorylation of MST1 in NK cells. Probably via RASSF5 (RAPL). References_end</body> </html> </notes> <label text="RASSF5"/> <bbox w="80.0" h="40.0" x="3610.0" y="2430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1742_sa963" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTK2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:8892616 PTK2 (FAK) Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. References_end</body> </html> </notes> <label text="PTK2"/> <clone/> <bbox w="80.0" h="40.0" x="6590.0" y="2350.0"/> </glyph> <glyph class="macromolecule" id="s1742_sa1081" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTK2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:8892616 PTK2 (FAK) Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. References_end</body> </html> </notes> <label text="PTK2"/> <clone/> <bbox w="80.0" h="40.0" x="6590.0" y="2440.0"/> </glyph> <glyph class="macromolecule" id="s1743_sa964" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:25312647 SLAMF7 is a self-ligand; i.e., it recognizes as ligand another SLAMF7 molecule on another cell. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <clone/> <bbox w="80.0" h="50.0" x="690.0" y="1785.0"/> <glyph class="state variable" id="_f9786f4a-7de7-4328-8e57-c20b7a9243b8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="685.0" y="1805.0"/> </glyph> <glyph class="unit of information" id="_d0b5c0df-4762-4413-b6db-f35fbf5e96d6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="707.5" y="1780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1743_sa968" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:25312647 SLAMF7 is a self-ligand; i.e., it recognizes as ligand another SLAMF7 molecule on another cell. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="3385.0"/> <glyph class="state variable" id="_db3f1235-b42a-4c3d-ae6b-ac2c749d21a2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6415.0" y="3405.0"/> </glyph> <glyph class="unit of information" id="_e768e286-6e91-4b60-ae16-5290af888fd2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6437.5" y="3380.0"/> </glyph> </glyph> <glyph class="complex" id="s1747_csa128" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:SLAMF7 Identifiers_end</body> </html> </notes> <label text="s1747"/> <bbox w="100.0" h="120.0" x="6350.0" y="3060.0"/> <glyph class="macromolecule multimer" id="s1745_sa970"> <notes> <html xmlns="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: HUGO:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:25312647 SLAMF7 is a self-ligand; i.e., it recognizes as ligand another SLAMF7 molecule on another cell. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <bbox w="86.0" h="56.0" x="6357.0" y="3102.0"/> <glyph class="unit of information" id="_83d62522-3955-455e-a167-0c1d551ceb36"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6390.0" y="3097.0"/> </glyph> <glyph class="state variable" id="_a5df279a-c053-42a8-9029-10e26f0ae41f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6352.0" y="3125.0"/> </glyph> <glyph class="unit of information" id="_42198b62-0bf7-46d2-ba52-0aa13589bcab"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6377.5" y="3097.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1751_sa971" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:SH2D1B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:25312647, PMID:19151721 SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor SH2D1B (EAT-2). SLAMF7 binds SH2D1B (EAT-2) via phosphorylated tyrosine 281 (Y281) in its cytoplasmic segment, thereby triggering activating signals. PMID:16339536, PMID:24687958, PMID:PMID:19151721 SH2D1B (EAT-2) also associates with 2B4 predominantly in resting NK cells, whereas SAP preferentially binds 2B4 upon activation. Tyrosine phosphorylation of cytoplasmic ITSMs of 2B4 augments their affinity for SAP, while reducing the affinity for EAT-2. Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl probably via EAT2.Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2. EAT-2 stimulates granule polarization by way of Y127 and Ca2+ fluxes. References_end</body> </html> </notes> <label text="SH2D1B"/> <bbox w="90.0" h="50.0" x="6255.0" y="3005.0"/> <glyph class="state variable" id="_05f5cce5-65e3-45a5-a057-30c6641742ec"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6250.0" y="3025.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1754_sa972" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15998796, PMID:15169881,PMID:15713798 SAP and FYN are required for the ability of NK cells to eliminate tumor cells in vitro and in vivo downstream of 2B4. Probably SAP couples Fyn to 2B4. PMID:22683124 Fyn-Binding Site of SH2D1A (SAP) is necessary for 2B4-Mediated NK Cell activation. NK cells, those lacking SAP displayed markedly reduced conjugate formation via inhibition of LFA1-ICAM1 association. PMID:17171759 SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(I:C))and to a lesser extent by IFN-α. References_end</body> </html> </notes> <label text="SH2D1A "/> <bbox w="70.0" h="25.0" x="6085.0" y="2807.5"/> </glyph> <glyph class="nucleic acid feature" id="s1755_sa973" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15998796, PMID:15169881,PMID:15713798 SAP and FYN are required for the ability of NK cells to eliminate tumor cells in vitro and in vivo downstream of 2B4. Probably SAP couples Fyn to 2B4. PMID:17171759 SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(I:C))and to a lesser extent by IFN-α. The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4. References_end</body> </html> </notes> <label text="SH2D1A "/> <bbox w="90.0" h="25.0" x="6075.0" y="2877.5"/> <glyph class="unit of information" id="_0f9a2a29-a0ae-460d-8547-947d02a4ed54"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6110.0" y="2872.5"/> </glyph> </glyph> <glyph class="complex" id="s1758_csa129" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:2B4*:SH2D1B Identifiers_end</body> </html> </notes> <label text="s1758"/> <bbox w="110.0" h="140.0" x="6105.0" y="3490.0"/> <glyph class="macromolecule" id="s1756_sa974"> <notes> <html xmlns="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: HUGO:SH2D1B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:25312647, PMID:19151721 SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor SH2D1B (EAT-2). SLAMF7 binds SH2D1B (EAT-2) via phosphorylated tyrosine 281 (Y281) in its cytoplasmic segment, thereby triggering activating signals. PMID:16339536, PMID:24687958, PMID:PMID:19151721 SH2D1B (EAT-2) also associates with 2B4 predominantly in resting NK cells, whereas SAP preferentially binds 2B4 upon activation. Tyrosine phosphorylation of cytoplasmic ITSMs of 2B4 augments their affinity for SAP, while reducing the affinity for EAT-2. Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl probably via EAT2.Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2. EAT-2 stimulates granule polarization by way of Y127 and Ca2+ fluxes. References_end</body> </html> </notes> <label text="SH2D1B"/> <bbox w="80.0" h="40.0" x="6115.0" y="3560.0"/> <glyph class="state variable" id="_7f961e71-d69f-4c4b-aaae-a69939185740"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6110.0" y="3575.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1759_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: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:16081768, PMID:15905190, PMID:15905190 2B4 works as activator in human model and as inhibitor of NK activity in mouse model. NK cells costimulate each other through 2B4-CD48 interactions PMID: The cytoplasmic domains of murine 2B4L and human 2B4 contain three and four immunoreceptor tyrosine-based switch motifs (ITSM) Upon engagement, the receptor is recruited to lipid rafts at the target cell interface in an actin-dependent manner, and tyrosine residues in the ITSM sequences are phosphorylated . Phosphorylation of the ITSM sequences creates specific binding sites for SAP (SH2D1A). SAP is an SH2 domain-containing adaptor that links 2B4 to the Src family PTK Fyn. PMID:17171759 The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 PMID:20189481, PMID: PMID:22786724 2B4 signaling acts synergistically with NG2D and DNAM1 signalings in NK activation and tumor cells lysis. It activates LCP2/VAV1/PCLG pathway. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. DNAM1 induces VAV1 pathway probably via LCP2 (SLP76). It demonstrate synergy with 2B4 in activation of vav1 pathway. PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. 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SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <bbox w="86.0" h="56.0" x="6492.0" y="2952.0"/> <glyph class="unit of information" id="_9f05267f-7878-47d3-92ad-8bf1956e3ab7"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6525.0" y="2947.0"/> </glyph> <glyph class="state variable" id="_12a98636-ff9f-4382-9376-395000960392"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6484.5" y="2975.0"/> </glyph> <glyph class="unit of information" id="_8c27afad-5a23-41f9-9004-a264d2257041"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6512.5" y="2947.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1766_sa977"> <notes> <html xmlns="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: HUGO:SH2D1B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:25312647, PMID:19151721 SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor SH2D1B (EAT-2). SLAMF7 binds SH2D1B (EAT-2) via phosphorylated tyrosine 281 (Y281) in its cytoplasmic segment, thereby triggering activating signals. PMID:16339536, PMID:24687958, PMID:PMID:19151721 SH2D1B (EAT-2) also associates with 2B4 predominantly in resting NK cells, whereas SAP preferentially binds 2B4 upon activation. Tyrosine phosphorylation of cytoplasmic ITSMs of 2B4 augments their affinity for SAP, while reducing the affinity for EAT-2. Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl probably via EAT2.Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2. EAT-2 stimulates granule polarization by way of Y127 and Ca2+ fluxes. References_end</body> </html> </notes> <label text="SH2D1B"/> <bbox w="80.0" h="40.0" x="6485.0" y="2890.0"/> <glyph class="state variable" id="_b5a25556-2485-41cb-ad4e-6cf2557be7f6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6477.5" y="2905.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1774_csa127" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:SLAMF7 Identifiers_end</body> </html> </notes> <label text="s1747"/> <bbox w="100.0" h="120.0" x="1040.0" y="1660.0"/> <glyph class="macromolecule multimer" id="s1775_sa966"> <notes> <html xmlns="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: HUGO:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:25312647 SLAMF7 is a self-ligand; i.e., it recognizes as ligand another SLAMF7 molecule on another cell. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <bbox w="86.0" h="56.0" x="1047.0" y="1702.0"/> <glyph class="unit of information" id="_3fce8fbb-ffe3-4786-bf63-5dc39c8083eb"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1080.0" y="1697.0"/> </glyph> <glyph class="state variable" id="_db38c660-e4de-4cfa-9a3e-34fc94dbf431"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1039.5" y="1725.0"/> </glyph> <glyph class="unit of information" id="_a7e2d306-72a1-4078-9979-df849f26b7c4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1067.5" y="1697.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1777_sa981" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTPRC Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:25312647 CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. References_end</body> </html> </notes> <label text="PTPRC"/> <bbox w="80.0" h="40.0" x="6290.0" y="2870.0"/> </glyph> <glyph class="macromolecule" id="s1778_sa982" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:ITGAM Identifiers_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:2060581 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity References_end</body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="6900.0" y="2475.0"/> <glyph class="unit of information" id="_e8bde193-1af3-40cc-9e50-2812ceba80dc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6917.5" y="2470.0"/> </glyph> </glyph> <glyph class="complex" id="s1779_csa131" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD11b*:CD18* Identifiers_end References_begin: PMID:2060581, PMID:9218574 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity References_end</body> </html> </notes> <label text="s1779"/> <bbox w="100.0" h="130.0" x="6990.0" y="2405.0"/> <glyph class="macromolecule" id="s1780_sa983"> <notes> <html xmlns="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>HUGO:ITGAM ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:2060581 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity References_end</body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="7000.0" y="2420.0"/> <glyph class="unit of information" id="_b8b415b2-92e4-4c16-af24-ae6418b10133"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7017.5" y="2415.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1782_sa985"> <notes> <html xmlns="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: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS The phosphorylation of Ser329 by PKC was later found to be critical for the association between DNAM-1 and CD18(LFA-1) in NK cells.17 This association is required for DNAM-1 signalling. PMID:19965656 Coengagement of DNAM-1 and CD18 (LFA-)1 by a Drosophila cell line transfected to express CD155 and intercellular adhesion molecule 1 triggered the IFN-g production by NK cells, while these ligands alone had no effects, reinforcing the functional link between DNAM-1 and LFA-1 in driving NK cell activation. PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. LFA-1 is required for NKG2D-mediated conjugate formation and cytotoxicity. References_end</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="7000.0" y="2460.0"/> <glyph class="unit of information" id="_3b442c21-35da-4af3-9ed3-0b6258594218"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7017.5" y="2455.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1789_sa991" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PTK2B Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, probaby via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="PTK2B"/> <bbox w="80.0" h="40.0" x="6460.0" y="2440.0"/> <glyph class="state variable" id="_66a5d74c-121d-4372-a1e5-963e0ee705dc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6452.5" y="2455.0"/> </glyph> </glyph> <glyph class="complex" id="s1796_csa133" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:2B4*:CD48:SH2D1A Identifiers_end References_begin: PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15169881, PMID:22683124 2B4 signaling induces phosphorylation of SHIP1,VAV1( (probably via LCP2),CBL. This phosphorylation is dependent on SAP and FYN. 2B4-evoked tyrosine phosphorylation of Vav-1 was nearly abolished in SAP-deficient and SAP R78A NK cells References_end</body> </html> </notes> <label text="s1022"/> <bbox w="180.0" h="150.0" x="6090.0" y="3105.0"/> <glyph class="macromolecule" id="s1797_sa998"> <notes> <html xmlns="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: HUGO:CD48 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10359122, PMID:16081768 CD48 is a counter-receptor for 2B4 receptor, which is widely expressed on hemopoietic cells. NK cells costimulate each other through 2B4-CD48 interactions. PMID:15998796 Expression of CD48 was detected on the membrane of some tumor cells,all of which were found to be lysed by a SAP-dependent NK cell cytotoxicity. References_end</body> </html> </notes> <label text="CD48"/> <bbox w="80.0" h="40.0" x="6180.0" y="3120.0"/> </glyph> <glyph class="macromolecule" id="s1798_sa999"> <notes> <html xmlns="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: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15998796, PMID:15169881,PMID:15713798 SAP and FYN are required for the ability of NK cells to eliminate tumor cells in vitro and in vivo downstream of 2B4. Probably SAP couples Fyn to 2B4. PMID:22683124 Fyn-Binding Site of SH2D1A (SAP) is necessary for 2B4-Mediated NK Cell activation. NK cells, those lacking SAP displayed markedly reduced conjugate formation via inhibition of LFA1-ICAM1 association. References_end</body> </html> </notes> <label text="SH2D1A"/> <bbox w="80.0" h="40.0" x="6100.0" y="3180.0"/> </glyph> <glyph class="macromolecule" id="s1953_sa1000"> <notes> <html xmlns="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: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:16081768, PMID:15905190, PMID:15905190 2B4 works as activator in human model and as inhibitor of NK activity in mouse model. NK cells costimulate each other through 2B4-CD48 interactions PMID: The cytoplasmic domains of murine 2B4L and human 2B4 contain three and four immunoreceptor tyrosine-based switch motifs (ITSM) Upon engagement, the receptor is recruited to lipid rafts at the target cell interface in an actin-dependent manner, and tyrosine residues in the ITSM sequences are phosphorylated . Phosphorylation of the ITSM sequences creates specific binding sites for SAP (SH2D1A). SAP is an SH2 domain-containing adaptor that links 2B4 to the Src family PTK Fyn. PMID:17171759 The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 PMID:20189481, PMID: PMID:22786724 2B4 signaling acts synergistically with NG2D and DNAM1 signalings in NK activation and tumor cells lysis. It activates LCP2/VAV1/PCLG pathway. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. DNAM1 induces VAV1 pathway probably via LCP2 (SLP76). It demonstrate synergy with 2B4 in activation of vav1 pathway. PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="2B4*"/> <bbox w="80.0" h="50.0" x="6180.0" y="3175.0"/> <glyph class="state variable" id="_87487db7-0e2b-4f95-b2ad-8e82d7474fda"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6172.5" y="3195.0"/> </glyph> <glyph class="unit of information" id="_f6e605a2-e82b-4cd4-8bb1-9acdd6f9cb43"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6197.5" y="3170.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1800_csa37" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:2B4*:3BP2*:CD48:SH2D1A Identifiers_end References_begin: PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15169881, PMID:22683124 2B4 signaling induces phosphorylation of SHIP1,VAV1( (probably via LCP2),CBL. This phosphorylation is dependent on SAP and FYN. 2B4-evoked tyrosine phosphorylation of Vav-1 was nearly abolished in SAP-deficient and SAP R78A NK cells References_end</body> </html> </notes> <label text="s1022"/> <bbox w="180.0" h="150.0" x="5870.0" y="3155.0"/> <glyph class="macromolecule" id="s1802_sa367"> <notes> <html xmlns="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: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10358138 Phosphorylated h2B4 recruits SH2D1A (SAP). Association of SAP with h2B4 prevents recruitment of PTPN11 (SHP-2). PMID:15998796, PMID:15169881,PMID:15713798 SAP and FYN are required for the ability of NK cells to eliminate tumor cells in vitro and in vivo downstream of 2B4. Probably SAP couples Fyn to 2B4. PMID:22683124 Fyn-Binding Site of SH2D1A (SAP) is necessary for 2B4-Mediated NK Cell activation. NK cells, those lacking SAP displayed markedly reduced conjugate formation via inhibition of LFA1-ICAM1 association. References_end</body> </html> </notes> <label text="SH2D1A"/> <bbox w="80.0" h="40.0" x="5880.0" y="3230.0"/> </glyph> <glyph class="macromolecule" id="s1954_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:16081768, PMID:15905190, PMID:15905190 2B4 works as activator in human model and as inhibitor of NK activity in mouse model. NK cells costimulate each other through 2B4-CD48 interactions PMID: The cytoplasmic domains of murine 2B4L and human 2B4 contain three and four immunoreceptor tyrosine-based switch motifs (ITSM) Upon engagement, the receptor is recruited to lipid rafts at the target cell interface in an actin-dependent manner, and tyrosine residues in the ITSM sequences are phosphorylated . Phosphorylation of the ITSM sequences creates specific binding sites for SAP (SH2D1A). SAP is an SH2 domain-containing adaptor that links 2B4 to the Src family PTK Fyn. PMID:17171759 The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4 PMID:20189481, PMID: PMID:22786724 2B4 signaling acts synergistically with NG2D and DNAM1 signalings in NK activation and tumor cells lysis. It activates LCP2/VAV1/PCLG pathway. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. DNAM1 induces VAV1 pathway probably via LCP2 (SLP76). It demonstrate synergy with 2B4 in activation of vav1 pathway. PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end</body> </html> </notes> <label text="2B4*"/> <bbox w="80.0" h="50.0" x="5960.0" y="3225.0"/> <glyph class="state variable" id="_e2281548-50e5-4e04-b38b-83661cd73a09"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5952.5" y="3245.0"/> </glyph> <glyph class="unit of information" id="_e55bae82-0355-4db8-b0da-d7c94fa41bd6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5977.5" y="3220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1801_sa925"> <notes> <html xmlns="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: HUGO:CD48 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10359122, PMID:16081768 CD48 is a counter-receptor for 2B4 receptor, which is widely expressed on hemopoietic cells. NK cells costimulate each other through 2B4-CD48 interactions. PMID:15998796 Expression of CD48 was detected on the membrane of some tumor cells,all of which were found to be lysed by a SAP-dependent NK cell cytotoxicity. References_end</body> </html> </notes> <label text="CD48"/> <bbox w="80.0" h="40.0" x="5960.0" y="3180.0"/> </glyph> <glyph class="macromolecule" id="s1804_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:SH3BP2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID: PMID:11390470, PMID:16177062 SH3BP2 (3BP2) is involevd in NK-activation. 3BP2 is coupled to activating receptors on NK cells.It is phosphorylated after NK stimulation. CD244 ligation induces 3BP2 phosphorylation and Vav recruitment. The adaptor protein 3BP2 binds human 2B4 (CD244) and links this receptor to Vav signaling, PLCG, ERK activation, and NK cell killing. SH2 domain of 3BP2 is required for optimal tyrosine phosphorylation of 3BP2 following FcR cross-linking and for its ability to associate with the transmembrane adaptor protein LAT. Phosphorylated tyrosine-183 of 3BP2 binds PLCG1 and PLCG2 and Vav1 during activation of NK cells through natural cytotoxicity receptors. References_end</body> </html> </notes> <label text="3BP2*"/> <bbox w="80.0" h="40.0" x="5880.0" y="3180.0"/> <glyph class="state variable" id="_87bb81cd-314f-40f5-b131-d30cf3befc45"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5872.5" y="3195.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1016_sa358" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:LAT Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:10072481,PMID:16329184, PMID:11169415 LAT participate in NK-cell cytotoxicity against tumor cells downstream of CD16 and 2B4 signaling. LAT is phosphorylated downstream of 2B4 and CD16 PMID:9489702, PMID:10072481, PMID:7523143 LAT is a substrate for ZAP-70, Syk protein tyrosine kinases in T cells and probably in NK cells. PMID:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway. PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1. References_end</body> </html> </notes> <label text="LAT"/> <bbox w="80.0" h="50.0" x="5750.0" y="3305.0"/> <glyph class="state variable" id="_7c86535d-ed88-4ac6-b9d8-597804bbb011"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5745.0" y="3325.0"/> </glyph> <glyph class="unit of information" id="_c41d5f29-608e-4c7f-a64b-b382e744d0d6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5767.5" y="3300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1710_sa202" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway via NKG2D. PMID:11015446 Cross-linking of the KIR2DS2/DAP12 receptor on NKL cells resulted in the dose-dependent secretion of IFNG and GM-CSF References_end</body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="6750.0" y="1760.0"/> </glyph> <glyph class="macromolecule" id="s1805_sa1001" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="1730.0" y="2855.0"/> <glyph class="state variable" id="_c7ff049a-e2f1-4246-a548-b500802d02be"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1725.0" y="2875.0"/> </glyph> <glyph class="unit of information" id="_1d2e02bd-39c8-4187-b6a8-7650950a06a3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1747.5" y="2850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1806_sa1002" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NCR1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:23414611 NKp30 (NCR3), NKp44 (NCR2), NKp46 (NCR1) are major activating receptors in NK cells (NCRs). The efficiency of tumour cell killing by NK cells has been shown to correlate with the expression level of the NCRs PMID:10562324, PMID:11385609,PMID:12731048 NKp30 cooperates with NKp46 and NKp44 in the induction of NK-mediated cytotoxicity probably via the same pathways. The engagement of one NCR appears to be able to activate the signaling cascades associated with the other NCR, possibly resulting in the amplification of the activating signals PMID:23414611, PMID:23414611, PMID:9625766 Nkp46 (NCR1) is the most specific marker of NK cells reported so far. For signalling, NKp46 associates with CD247 (CD3ζ) and also with the γ-chain of FcɛRI. Nkp46 signaling is activated by unknown ligands expressed on tumor cells . Ncr1 knockout mice exhibit an increase in tumour metastasis. PMID:22267813 NK cells with defective cell-surface expression of NKp46 are hyperreactive in responses to the prototypic NK cell tumor target cell line. But Ncr1 knockout mice have been reported to be highly susceptible to the infections. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. PMID:9603467 NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 References_end</body> </html> </notes> <label text="NKp46*"/> <bbox w="80.0" h="50.0" x="4910.0" y="3295.0"/> <glyph class="unit of information" id="_76fc51b3-24df-4608-a3df-09db8745fc50"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4927.5" y="3290.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1807_sa1004" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL18RAP Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18RAP"/> <bbox w="80.0" h="50.0" x="4390.0" y="615.0"/> <glyph class="unit of information" id="_d9bdd696-d13e-469a-b52f-964efb6bcf20"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4407.5" y="610.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1808_sa1003" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL18R1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end</body> </html> </notes> <label text="IL18R1"/> <bbox w="80.0" h="50.0" x="4280.0" y="615.0"/> <glyph class="unit of information" id="_dc5898fa-6ddf-44cb-a64a-1b22cb01f54d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4297.5" y="610.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1809_sa1005" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL2RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. References_end</body> </html> </notes> <label text="IL2RA"/> <bbox w="80.0" h="50.0" x="5570.0" y="915.0"/> <glyph class="unit of information" id="_c825d129-eef0-43fa-bbf1-4a453b4582f9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5587.5" y="910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1810_sa1006" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL2RB Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. References_end</body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="5690.0" y="915.0"/> <glyph class="state variable" id="_3859a2fb-8f86-4d56-a671-a739311043cb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5685.0" y="935.0"/> </glyph> <glyph class="unit of information" id="_7ce46fae-7d1b-4da1-b374-4a9f66f2c684"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5707.5" y="910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1811_sa1007" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <clone/> <bbox w="80.0" h="50.0" x="5570.0" y="825.0"/> <glyph class="unit of information" id="_f1169a2f-8423-4835-90d8-8f172d329086"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5587.5" y="820.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1811_sa1010" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="1285.0"/> <glyph class="unit of information" id="_d0f719e9-597c-4c68-a329-c14a1bde151a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6437.5" y="1280.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1812_sa1008" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL12RB1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB1"/> <bbox w="80.0" h="50.0" x="4890.0" y="685.0"/> <glyph class="unit of information" id="_8990fc06-f9c7-4572-b78c-23f7a01ad5c0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4907.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1813_sa1009" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12RB2"/> <bbox w="80.0" h="50.0" x="4990.0" y="685.0"/> <glyph class="unit of information" id="_730eed6b-a87f-476d-8a66-9ab06ff58719"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5007.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1815_sa1011" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL15RA Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. http://cancerres.aacrjournals.org/content/72/8_Supplement/3506.short IL-15/IL-15Rα complexes activates natural killer cells and enhances anti-GD2 monoclonal antibody-mediated antibody-dependent cellular cytotoxicity in vitro and in vivo. References_end</body> </html> </notes> <label text="IL15RA"/> <bbox w="80.0" h="50.0" x="6420.0" y="1355.0"/> <glyph class="unit of information" id="_6a827c6b-5b79-40fb-bf1d-c24bf2f9ddbf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6437.5" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s117_sa1012"> <notes> <html xmlns="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: HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12p40*"/> <bbox w="80.0" h="40.0" x="5006.5" y="140.0"/> </glyph> <glyph class="macromolecule" id="s221_sa1013"> <notes> <html xmlns="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: HUGO:IL12A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:15546391 Interleukin (IL)-12 is a heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40. This cytokine is produced by a variety cells including monocytes, neutrophils, and B cells, but the major producers of IL-12 are macrophages and dendritic cells (DCs). The IL-12 receptor (IL-12R) is composed of two subunits termed β1 and β2, which are structurally related to the type I cytokine receptor superfamily (44–47). The affinity of IL-12 for either subunit alone is low, but coexpression of both β1 and β2 subunits generates human IL-12 high-affinity binding sites. IL-12p40 interacts predominantly with the β1 subunit, whereas p35 interacts largely with the β2 subunit. References_end</body> </html> </notes> <label text="IL12p35*"/> <bbox w="80.0" h="40.0" x="5100.0" y="140.0"/> </glyph> <glyph class="macromolecule" id="s1816_sa1014" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 GENECARDS:CALM2 HUGO:CALM3 HGNC:1449 ENTREZ:808 GENECARDS:CALM3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: calmodulin 1 (phosphorylase kinase, delta) CALML2 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:805 WIKI:CALM2 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 2 (phosphorylase kinase, delta) REACTOME:51306 KEGG:805 WIKI:CALM2 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 3 (phosphorylase kinase, delta) REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:805 WIKI:CALM2 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells. References_end</body> </html> </notes> <label text="Calmodulin*"/> <bbox w="80.0" h="40.0" x="5210.0" y="1850.0"/> </glyph> <glyph class="complex" id="s1817_csa134" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:Ca2+:Calmodulin* Identifiers_end References_begin: PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells References_end</body> </html> </notes> <label text="s1817"/> <bbox w="100.0" h="120.0" x="5180.0" y="1690.0"/> <glyph class="macromolecule" id="s1818_sa1015"> <notes> <html xmlns="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: HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 GENECARDS:CALM2 HUGO:CALM3 HGNC:1449 ENTREZ:808 GENECARDS:CALM3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: calmodulin 1 (phosphorylase kinase, delta) CALML2 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:805 WIKI:CALM2 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 2 (phosphorylase kinase, delta) REACTOME:51306 KEGG:805 WIKI:CALM2 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 3 (phosphorylase kinase, delta) REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:805 WIKI:CALM2 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells. References_end</body> </html> </notes> <label text="Calmodulin*"/> <bbox w="80.0" h="40.0" x="5190.0" y="1700.0"/> </glyph> <glyph class="simple chemical" id="s1819_sa1016"> <notes> <html xmlns="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>PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PMID:12740575, PMID:15972651 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release. The calcium signal generated by PLCG is required for NKG2D-initiated killing. PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells</body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="5217.5" y="1757.5"/> </glyph> </glyph> <glyph class="complex" id="s1822_csa135" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CNA*:CNB* Identifiers_end References_begin: PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells References_end</body> </html> </notes> <label text="s1822"/> <bbox w="100.0" h="120.0" x="5300.0" y="1640.0"/> <glyph class="macromolecule" id="s1820_sa1017"> <notes> <html xmlns="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: HUGO:PPP3CA HGNC:9314 ENTREZ:5530 UNIPROT:Q08209 GENECARDS:PPP3CA HUGO:PPP3CB HGNC:9315 ENTREZ:5532 UNIPROT:P16298 GENECARDS:PPP3CB HUGO:PPP3CC HGNC:9316 ENTREZ:5533 UNIPROT:P48454 GENECARDS:PPP3CC Identifiers_end References_begin: protein phosphatase 3, catalytic subunit, alpha isozyme CALN, CALNA, "protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform", "protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform (calcineurin A alpha)" REACTOME:61110 KEGG:5530 ATLASONC:GC_PPP3CA WIKI:PPP3CA protein phosphatase 3, catalytic subunit, beta isozyme CALNB, "protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform", "protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform (calcineurin A beta)" REACTOME:403037 KEGG:5532 ATLASONC:GC_PPP3CB WIKI:PPP3CB protein phosphatase 3, catalytic subunit, gamma isozyme "protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform", "protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform (calcineurin A gamma)" REACTOME:61114 KEGG:5533 ATLASONC:GC_PPP3CC WIKI:PPP3CC PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells References_end</body> </html> </notes> <label text="CNA*"/> <bbox w="80.0" h="40.0" x="5310.0" y="1650.0"/> </glyph> <glyph class="macromolecule" id="s1821_sa1018"> <notes> <html xmlns="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: HUGO:PPP3R1 HGNC:9317 ENTREZ:5534 UNIPROT:P63098 GENECARDS:PPP3R1 HUGO:PPP3PR2 GENECARDS:PPP3PR2 HUGO:PPP3R2 HGNC:9318 ENTREZ:5535 UNIPROT:Q96LZ3 GENECARDS:PPP3R2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: protein phosphatase 3, regulatory subunit B, alpha "protein phosphatase 3 (formerly 2B), regulatory subunit B (19kD), alpha isoform (calcineurin B, type I)", "protein phosphatase 3 (formerly 2B), regulatory subunit B, 19kDa, alpha isoform (calcineurin B, type I)", "protein phosphatase 3 (formerly 2B), regulatory subunit B, alpha isoform" REACTOME:51292 KEGG:5534 ATLASONC:GC_PPP3R1 WIKI:PPP3R1 protein phosphatase 3, regulatory subunit B, beta WIKI:PPP3PR2 KEGG:5535 ATLASONC:GC_PPP3R2 WIKI:PPP3R2 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells References_end</body> </html> </notes> <label text="CNB*"/> <bbox w="80.0" h="40.0" x="5310.0" y="1700.0"/> </glyph> </glyph> <glyph class="complex" id="s1823_csa136" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:CNA*:CNB*:Ca2+:Calmodulin* Identifiers_end References_begin: PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells. Additionally CD16 signaling induces NF-AT mRNA expression and protein synthesis via Calmodulin/ Calcineurin. References_end</body> </html> </notes> <label text="s1823"/> <bbox w="180.0" h="140.0" x="4930.0" y="1710.0"/> <glyph class="simple chemical" id="s1824_sa1019"> <notes> <html xmlns="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>PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PMID:12740575, PMID:15972651 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release. The calcium signal generated by PLCG is required for NKG2D-initiated killing. PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). (PMID:10089876). This signaling is activated downstream of CD16</body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="5057.5" y="1787.5"/> </glyph> <glyph class="macromolecule" id="s1825_sa1020"> <notes> <html xmlns="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: HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 GENECARDS:CALM2 HUGO:CALM3 HGNC:1449 ENTREZ:808 GENECARDS:CALM3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: calmodulin 1 (phosphorylase kinase, delta) CALML2 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:805 WIKI:CALM2 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 2 (phosphorylase kinase, delta) REACTOME:51306 KEGG:805 WIKI:CALM2 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 3 (phosphorylase kinase, delta) REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 REACTOME:51306 KEGG:805 WIKI:CALM2 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells. References_end</body> </html> </notes> <label text="Calmodulin*"/> <bbox w="80.0" h="40.0" x="5020.0" y="1730.0"/> </glyph> <glyph class="macromolecule" id="s1827_sa1022"> <notes> <html xmlns="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: HUGO:PPP3CA HGNC:9314 ENTREZ:5530 UNIPROT:Q08209 GENECARDS:PPP3CA HUGO:PPP3CB HGNC:9315 ENTREZ:5532 UNIPROT:P16298 GENECARDS:PPP3CB HUGO:PPP3CC HGNC:9316 ENTREZ:5533 UNIPROT:P48454 GENECARDS:PPP3CC Identifiers_end References_begin: protein phosphatase 3, catalytic subunit, alpha isozyme CALN, CALNA, "protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform", "protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform (calcineurin A alpha)" REACTOME:61110 KEGG:5530 ATLASONC:GC_PPP3CA WIKI:PPP3CA protein phosphatase 3, catalytic subunit, beta isozyme CALNB, "protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform", "protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform (calcineurin A beta)" REACTOME:403037 KEGG:5532 ATLASONC:GC_PPP3CB WIKI:PPP3CB protein phosphatase 3, catalytic subunit, gamma isozyme "protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform", "protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform (calcineurin A gamma)" REACTOME:61114 KEGG:5533 ATLASONC:GC_PPP3CC WIKI:PPP3CC PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells References_end</body> </html> </notes> <label text="CNA*"/> <bbox w="80.0" h="40.0" x="4940.0" y="1730.0"/> </glyph> <glyph class="macromolecule" id="s1828_sa1023"> <notes> <html xmlns="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: HUGO:PPP3R1 HGNC:9317 ENTREZ:5534 UNIPROT:P63098 GENECARDS:PPP3R1 HUGO:PPP3PR2 GENECARDS:PPP3PR2 HUGO:PPP3R2 HGNC:9318 ENTREZ:5535 UNIPROT:Q96LZ3 GENECARDS:PPP3R2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: protein phosphatase 3, regulatory subunit B, alpha "protein phosphatase 3 (formerly 2B), regulatory subunit B (19kD), alpha isoform (calcineurin B, type I)", "protein phosphatase 3 (formerly 2B), regulatory subunit B, 19kDa, alpha isoform (calcineurin B, type I)", "protein phosphatase 3 (formerly 2B), regulatory subunit B, alpha isoform" REACTOME:51292 KEGG:5534 ATLASONC:GC_PPP3R1 WIKI:PPP3R1 protein phosphatase 3, regulatory subunit B, beta WIKI:PPP3PR2 KEGG:5535 ATLASONC:GC_PPP3R2 WIKI:PPP3R2 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells References_end</body> </html> </notes> <label text="CNB*"/> <bbox w="80.0" h="40.0" x="4940.0" y="1780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1829_sa1025" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="NFAT*"/> <bbox w="80.0" h="40.0" x="4670.0" y="1770.0"/> <glyph class="state variable" id="_bf7ddcc7-3a78-48a5-810a-1a961c920da0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4665.0" y="1785.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1831_sa1024" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="NFAT*"/> <bbox w="80.0" h="40.0" x="4800.0" y="1870.0"/> <glyph class="state variable" id="_ada8e3b8-c4ce-4854-96eb-2bbc4a0b892e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4792.5" y="1885.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1833_sa1027" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="NFAT*"/> <bbox w="70.0" h="25.0" x="4665.0" y="1667.5"/> </glyph> <glyph class="nucleic acid feature" id="s1834_sa1028" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 PMID:10089876, PMID:7650486, PMID:9973469 Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 (Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). This signaling is activated downstream of CD16 in NK cells PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="NFAT*"/> <bbox w="90.0" h="25.0" x="4655.0" y="1727.5"/> <glyph class="unit of information" id="_970870b4-11a1-443a-ac3d-404c513d7597"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4690.0" y="1722.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1835_sa1029" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="TNF"/> <bbox w="90.0" h="25.0" x="6505.0" y="1687.5"/> <glyph class="unit of information" id="_76ef677d-bf52-45ca-b9d6-d2c242c88583"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6540.0" y="1682.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1836_sa1030" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="TNF"/> <bbox w="70.0" h="25.0" x="6395.0" y="1747.5"/> </glyph> <glyph class="nucleic acid feature" id="s1837_sa1031" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="CSF2"/> <bbox w="90.0" h="25.0" x="6635.0" y="1817.5"/> <glyph class="unit of information" id="_9cf03e65-8044-4359-86b8-2fe4dd85e155"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6670.0" y="1812.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1838_sa1032" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="CSF2"/> <bbox w="70.0" h="25.0" x="6495.0" y="1857.5"/> </glyph> <glyph class="nucleic acid feature" id="s1839_sa1033" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="IL2"/> <bbox w="70.0" h="25.0" x="5395.0" y="1187.5"/> </glyph> <glyph class="nucleic acid feature" id="s1840_sa1034" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="IL2"/> <bbox w="90.0" h="25.0" x="5385.0" y="1137.5"/> <glyph class="unit of information" id="_83d75e7b-c9ac-424a-a333-d1e9c62e24d1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5420.0" y="1132.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1841_sa1035" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="IL4"/> <bbox w="70.0" h="25.0" x="1695.0" y="1797.5"/> </glyph> <glyph class="nucleic acid feature" id="s1842_sa1036" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end</body> </html> </notes> <label text="IL4"/> <bbox w="90.0" h="25.0" x="1685.0" y="1707.5"/> <glyph class="unit of information" id="_58913a8e-1807-4fcc-b8be-ab28eaea9672"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1720.0" y="1702.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1843_sa1037" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end</body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="1690.0" y="1630.0"/> </glyph> <glyph class="complex" id="s1844_csa137" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:SHC1:SHIP1* Identifiers_end References_begin: PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="s1844"/> <bbox w="100.0" h="120.0" x="5480.0" y="2670.0"/> <glyph class="macromolecule" id="s1845_sa1038"> <notes> <html xmlns="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: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 were the only two cytokines among those tested that were able to induce Shc phosphorylation in NK cells. PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHC1"/> <bbox w="80.0" h="40.0" x="5490.0" y="2730.0"/> <glyph class="state variable" id="_3b01ce67-c981-4c19-86dc-61a487a27cbe"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5485.0" y="2745.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1846_sa1039"> <notes> <html xmlns="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: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:22483603 SH2-domain containing inositol-5-phosphatase (SHIP) de-phosphorylates PI(3,4,5)P3 at the D5 position of the inositol ring to create PI(3,4)P2. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1,CBL. This phosphorylation is dependent on SAP and FYN. PMID:22683124 2B4-mediated inhibition was restored when SHIP-1 was reintroduced in SHIP-1-deficient cells. In the NK cells lacking SHIP-1, there was a prominent diminution of the inhibitory influence of 2B4 (to ∼25% of control). PMID:12393695 CD16 stimulation on human primary natural killer (NK) cells induces the rapid and transient translocation of SHIP-1 in the lipid-enriched plasma membrane microdomains, termed rafts, where it associates with tyrosine-phosphorylated zeta chain and shc adaptor protein. SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="5490.0" y="2680.0"/> <glyph class="state variable" id="_0296b8ff-cb51-41d0-ac8e-ddd98b4dfca5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5482.5" y="2695.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1847_sa1040" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SOS1 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 GENECARDS:SOS1 HUGO:SOS2 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 GENECARDS:SOS2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:64848 KEGG:6654 ATLASONC:GC_SOS1 WIKI:SOS1 son of sevenless homolog 2 (Drosophila) REACTOME:64850 ATLASONC:GC_SOS2 WIKI:SOS2 GINGF "gingival fibromatosis hereditary 1" "son of sevenless (Drosophilia) homolog 2" PMID:8551221 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. References_end</body> </html> </notes> <label text="SOS*"/> <clone/> <bbox w="80.0" h="40.0" x="5280.0" y="2570.0"/> </glyph> <glyph class="macromolecule" id="s1847_sa1049" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:SOS1 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 GENECARDS:SOS1 HUGO:SOS2 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 GENECARDS:SOS2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:64848 KEGG:6654 ATLASONC:GC_SOS1 WIKI:SOS1 son of sevenless homolog 2 (Drosophila) REACTOME:64850 ATLASONC:GC_SOS2 WIKI:SOS2 GINGF "gingival fibromatosis hereditary 1" "son of sevenless (Drosophilia) homolog 2" PMID:8551221 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. References_end</body> </html> </notes> <label text="SOS*"/> <clone/> <bbox w="90.0" h="50.0" x="5095.0" y="2565.0"/> </glyph> <glyph class="complex" id="s1849_csa138" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GTP:HRAS Identifiers_end References_begin: PMID:8551221 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. References_end</body> </html> </notes> <label text="s1849"/> <bbox w="100.0" h="120.0" x="5190.0" y="2440.0"/> <glyph class="simple chemical" id="s1850_sa1043"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="5205.0" y="2497.5"/> </glyph> <glyph class="macromolecule" id="s1851_sa1044"> <notes> <html xmlns="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: HUGO:HRAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:8551221 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. References_end</body> </html> </notes> <label text="HRAS"/> <bbox w="80.0" h="40.0" x="5200.0" y="2450.0"/> </glyph> </glyph> <glyph class="complex" id="s1852_csa139" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GDP:HRAS Identifiers_end References_begin: PMID:8551221, PMID:10358164 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="s1852"/> <bbox w="100.0" h="120.0" x="5360.0" y="2440.0"/> <glyph class="macromolecule" id="s1848_sa1041"> <notes> <html xmlns="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: HUGO:HRAS Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:8551221 CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. References_end</body> </html> </notes> <label text="HRAS"/> <bbox w="80.0" h="40.0" x="5370.0" y="2450.0"/> </glyph> <glyph class="simple chemical" id="s1853_sa1042"> <label text="GDP"/> <bbox w="70.0" h="25.0" x="5375.0" y="2497.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1855_sa1050" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RAF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15516985, PMID:12566895 HRAS activates MEK/ERK pathway via RAF phosphorylation in NK cells. Ras functions asan adapter that binds to Raf kinases. Raf can activate both MEK1 and MEK2 (also called MKK1 and MKK2) References_end</body> </html> </notes> <label text="RAF1"/> <bbox w="80.0" h="40.0" x="5090.0" y="2370.0"/> <glyph class="state variable" id="_21e5fcbb-eabe-4851-a554-ae083f7a8b04"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5085.0" y="2385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1856_sa1051" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:RAF1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15516985, PMID:12566895 HRAS activates MEK/ERK pathway via RAF phosphorylation in NK cells. Ras functions asan adapter that binds to Raf kinases. Raf can activate both MEK1 and MEK2 (also called MKK1 and MKK2) References_end</body> </html> </notes> <label text="RAF1"/> <bbox w="80.0" h="40.0" x="5090.0" y="2280.0"/> <glyph class="state variable" id="_ee23f810-801e-415d-aebc-d47e6641012c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5082.5" y="2295.0"/> </glyph> </glyph> <glyph class="complex" id="s1133_csa44" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:GRB2:SHC1 Identifiers_end References_begin: PMID:16212621,PMID:10849428 IL-2- and IL-15-induced phosphorylation of the adapter protein Shc and Shc/Grb2 coupling in NK cells and T cells. PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells. PMID:8551221, PMID:10358164 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2. CD16 and IL-2R Triggering Activate p21RAS in Human NK Cells via LAT/SHC/GRB2/sos pathway. Phosphorylated Shc interacts with Grb2, which, in turn, interacts with Sos. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="s1133"/> <bbox w="100.0" h="120.0" x="5180.0" y="2690.0"/> <glyph class="macromolecule" id="s1679_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10849428 IL-2 and IL-15 were the only two cytokines among those tested that were able to induce Shc phosphorylation in NK cells. PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells. PMID:11449354, PMID:12393695 CD16 cross-linking on human NK cells induces the association of SHIP-1 with receptor zeta-chain through the adaptor protein shc. Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3. References_end</body> </html> </notes> <label text="SHC1"/> <bbox w="80.0" h="40.0" x="5192.5" y="2700.0"/> <glyph class="state variable" id="_51822247-272f-4f39-986f-30ee36ce11e0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5185.0" y="2715.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1134_sa427"> <notes> <html xmlns="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: HUGO:GRB2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:16887996, PMID:16582911 Vav1 interacts with DAP10 YxNM motifs through the adaptor protein Grb2 and is required for activation of PI3K-dependent Akt signaling. binding of DAP10‭ ‬to either p85‭ ‬or Grb2‭ ‬alone is not sufficient to trigger DAP10-mediated cytotoxicity and that both binding sites are necessary for NKG2D-initiated killing. PMID:10982827 Shc and GRB2 mediate Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation in B cells PMID:8551221 SHC1 protein is phosphorylated upon CD16 and IL-2R Stimulation in Human NK Cells and interacts with GRB2 References_end</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="5190.0" y="2750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1858_sa1055" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CYTH1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11050434 The cytohesin and centaurin protein families are potential targets for PtdIns(3,4,5)P3 that also regulate and interact with Arf GTPases. PMID:1511013, PMID:10652308 Cytohesin-1 (B2-1) found at high levels in natural killer and cytotoxic T-cells and at very low levels in monocytes and several cultured cell lines. The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Cytohesin-1 can activate ARF6 References_end</body> </html> </notes> <label text="CYTH1"/> <clone/> <bbox w="80.0" h="40.0" x="5590.0" y="2390.0"/> </glyph> <glyph class="macromolecule" id="s1858_sa1058" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CYTH1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11050434 The cytohesin and centaurin protein families are potential targets for PtdIns(3,4,5)P3 that also regulate and interact with Arf GTPases. PMID:1511013, PMID:10652308 Cytohesin-1 (B2-1) found at high levels in natural killer and cytotoxic T-cells and at very low levels in monocytes and several cultured cell lines. The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Cytohesin-1 can activate ARF6 References_end</body> </html> </notes> <label text="CYTH1"/> <clone/> <bbox w="80.0" h="40.0" x="5590.0" y="2310.0"/> </glyph> <glyph class="macromolecule" id="s1859_sa1056" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PDL1 HUGO:PDL2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PLD-dependent pathway is involved in CD16-mediated NK cell granule exocytosis. References_end</body> </html> </notes> <label text="PLD*"/> <clone/> <bbox w="80.0" h="40.0" x="5110.0" y="2150.0"/> </glyph> <glyph class="macromolecule" id="s1859_sa1064" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PDL1 HUGO:PDL2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PLD-dependent pathway is involved in CD16-mediated NK cell granule exocytosis. References_end</body> </html> </notes> <label text="PLD*"/> <clone/> <bbox w="80.0" h="40.0" x="5110.0" y="2050.0"/> </glyph> <glyph class="macromolecule" id="s1860_sa1057" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PIP5K1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion PIP2 is mainly synthesized by the phosphorylation of phosphatidylinositol4-phosphate (PI4P) at the D-5 position of the inositol ring by phosphatidylinositol4phosphate 5-kinase type I (PI5KI) References_end</body> </html> </notes> <label text="PIP5K1A"/> <clone/> <bbox w="80.0" h="40.0" x="5300.0" y="2210.0"/> </glyph> <glyph class="macromolecule" id="s1860_sa1065" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PIP5K1A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion PIP2 is mainly synthesized by the phosphorylation of phosphatidylinositol4-phosphate (PI4P) at the D-5 position of the inositol ring by phosphatidylinositol4phosphate 5-kinase type I (PI5KI) References_end</body> </html> </notes> <label text="PIP5K1A"/> <clone/> <bbox w="80.0" h="40.0" x="5300.0" y="2300.0"/> </glyph> <glyph class="complex" id="s1861_csa141" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:ARF6:GDP Identifiers_end</body> </html> </notes> <label text="s1861"/> <bbox w="100.0" h="120.0" x="5390.0" y="2060.0"/> <glyph class="macromolecule" id="s1863_sa1054"> <notes> <html xmlns="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: HUGO:ARF6 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15817676 CD16 on primary human natural killer (NK) cells induces a phosphatidylinositol 3-kinase (PI3K)–dependent activation of the small G protein Arf6. Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion References_end</body> </html> </notes> <label text="ARF6"/> <bbox w="80.0" h="40.0" x="5400.0" y="2070.0"/> </glyph> <glyph class="simple chemical" id="s1862_sa1063"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="5408.75" y="2116.875"/> </glyph> </glyph> <glyph class="complex" id="s1864_csa142" compartmentRef="c7_ca7"> <notes> <html xmlns="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: NAME:ARF6:GTP Identifiers_end</body> </html> </notes> <label text="s1864"/> <bbox w="100.0" h="120.0" x="5250.0" y="2060.0"/> <glyph class="macromolecule" id="s1857_sa1059"> <notes> <html xmlns="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: HUGO:ARF6 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15817676 CD16 on primary human natural killer (NK) cells induces a phosphatidylinositol 3-kinase (PI3K)–dependent activation of the small G protein Arf6. Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion References_end</body> </html> </notes> <label text="ARF6"/> <bbox w="80.0" h="40.0" x="5260.0" y="2070.0"/> </glyph> <glyph class="simple chemical" id="s1865_sa1062"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="5265.0" y="2117.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s1866_sa1066" compartmentRef="c7_ca7"> <notes> <html xmlns="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>References_begin: PMID:15817676 PIP2 is mainly synthesized by the phosphorylation of phosphatidylinositol4-phosphate (PI4P) at the D-5 position of the inositol ring by phosphatidylinositol4phosphate 5-kinase type I (PI5KI) References_end</body> </html> </notes> <label text="PtdIns(4)-P"/> <bbox w="70.0" h="25.0" x="5545.0" y="2597.5"/> </glyph> <glyph class="macromolecule" id="s1867_sa1067" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLA2G4A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end</body> </html> </notes> <label text="PLA2G4A"/> <bbox w="80.0" h="40.0" x="4470.0" y="2050.0"/> <glyph class="state variable" id="_964fab98-4ea4-4840-802d-a18af28ddd62"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4465.0" y="2065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1868_sa1069" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLA2G2A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9973479 BETA1 integrin cross-linking inhibits CD16-induced sPLA2, but not cPLA2 nor PI-PLC, activity in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PMID:9120268 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end</body> </html> </notes> <label text="PLA2G2A"/> <bbox w="80.0" h="40.0" x="4470.0" y="2130.0"/> <glyph class="state variable" id="_d71581fc-1b1b-46dd-9b7d-b741fe45fa2c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4465.0" y="2145.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1869_sa1068" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLA2G4A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end</body> </html> </notes> <label text="PLA2G4A"/> <bbox w="80.0" h="40.0" x="4600.0" y="2050.0"/> <glyph class="state variable" id="_5f78df1a-7539-45ec-b205-9f8e17c5ac9b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4592.5" y="2065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1870_sa1070" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:PLA2G2A Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9973479 BETA1 integrin cross-linking inhibits CD16-induced sPLA2, but not cPLA2 nor PI-PLC, activity in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PMID:9120268 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end</body> </html> </notes> <label text="PLA2G2A"/> <bbox w="80.0" h="40.0" x="4599.0" y="2130.0"/> <glyph class="state variable" id="_19c56a17-c63a-4585-a0ef-155b248cfbe0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4591.5" y="2145.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1871_sa1071"> <notes> <html xmlns="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: HUGO:FN1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="80.0" h="40.0" x="6710.0" y="4110.0"/> </glyph> <glyph class="macromolecule" id="s1872_sa1072"> <notes> <html xmlns="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: HUGO:ICAM2 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:20955708 ICAM2 is Associated With a Potential Anti-Tumor Immune Response in Early Intraepithelial Stages of Human Pancreatic Carcinogenesis. The anti-tumor immune reaction changed from an immune response to immune tolerance between the stages of intraductal papillary mucinous adenoma (IPMA) and intraductal papillary mucinous carcinoma (IPMC). Expression levels oF ICAM2 is up-regulated exclusively in IPMA and disappeared from IPMC. References_end</body> </html> </notes> <label text="ICAM2"/> <bbox w="80.0" h="40.0" x="6970.0" y="4110.0"/> </glyph> <glyph class="macromolecule" id="s1873_sa1073"> <notes> <html xmlns="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: HUGO:ICAM3 Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:8579109, PMID:8568591 ICAM-3 is absent on endothelial cells in normal tissues but ICAM-3 expression on endothelial cells was high on both benign and malignant tumors. The increased expression of adhesion molecules ICAM-3 presents on breast cancer endothelium. References_end</body> </html> </notes> <label text="ICAM3"/> <bbox w="80.0" h="40.0" x="7070.0" y="4110.0"/> </glyph> <glyph class="complex" id="s1878_csa143" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:Fibronectin*:ITGA4:ITGB1 Identifiers_end References_begin: PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. the level of activity of Fyn, Lyn, and Zap- 70, as well as FAK. but not Src, was significantly increased in FN-stimulated cells PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end</body> </html> </notes> <label text="s1407"/> <bbox w="112.5" h="205.0" x="6773.75" y="2657.5"/> <glyph class="macromolecule" id="s1877_sa1080"> <notes> <html xmlns="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: HUGO:FN1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="80.0" h="40.0" x="6790.0" y="2780.0"/> </glyph> <glyph class="macromolecule" id="s1880_sa1078"> <notes> <html xmlns="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: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end</body> </html> </notes> <label text="ITGA4"/> <bbox w="80.0" h="50.0" x="6793.75" y="2717.5"/> <glyph class="unit of information" id="_f65755ee-eec8-49e3-93c5-26ee2a9c5895"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6811.25" y="2712.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1879_sa1077"> <notes> <html xmlns="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: HUGO:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="6793.75" y="2667.5"/> <glyph class="unit of information" id="_9e18e558-20f6-4510-a0ef-bb7dfb28fb6c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6811.25" y="2662.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1884_csa144" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:ITGA5:ITGB1 Identifiers_end References_begin: PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. References_end</body> </html> </notes> <label text="s1884"/> <bbox w="100.0" h="130.0" x="6870.0" y="2885.0"/> <glyph class="macromolecule" id="s1882_sa1082"> <notes> <html xmlns="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: HUGO:ITGA5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. the level of activity of Fyn, Lyn, and Zap- 70, as well as FAK. but not Src, was significantly increased in FN-stimulated cells PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="50.0" x="6880.0" y="2890.0"/> <glyph class="unit of information" id="_2a086ae6-ee70-44de-bca4-12d6ce5da871"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6897.5" y="2885.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1883_sa1083"> <notes> <html xmlns="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: HUGO:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="6880.0" y="2940.0"/> <glyph class="unit of information" id="_0fdab47d-668e-472a-926c-f6d578540097"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6897.5" y="2935.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1886_csa145" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:Fibronectin*:ITGA5:ITGB1 Identifiers_end References_begin: PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. the level of activity of Fyn, Lyn, and Zap- 70, as well as FAK. but not Src, was significantly increased in FN-stimulated cells PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end</body> </html> </notes> <label text="s1884"/> <bbox w="110.0" h="205.0" x="6930.0" y="2615.0"/> <glyph class="macromolecule" id="s1887_sa1084"> <notes> <html xmlns="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: HUGO:ITGA5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. the level of activity of Fyn, Lyn, and Zap- 70, as well as FAK. but not Src, was significantly increased in FN-stimulated cells PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end</body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="50.0" x="6940.0" y="2620.0"/> <glyph class="unit of information" id="_636d6151-0248-4031-9379-9efc582656c0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6957.5" y="2615.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1888_sa1085"> <notes> <html xmlns="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: HUGO:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end</body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="6940.0" y="2670.0"/> <glyph class="unit of information" id="_38632bcd-52dc-40b5-a4e6-4185eab29824"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6957.5" y="2665.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1885_sa1086"> <notes> <html xmlns="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: HUGO:FN1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end</body> </html> </notes> <label text="Fibronectin*"/> <bbox w="80.0" h="40.0" x="6940.0" y="2740.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1890_sa1087" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LYN Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. FN adhesion-induced activity of the PTKs pl2SFAK, Fyn, Lyn, and Zap-70. Lyn activity was induced by cross-linking of a4pI integrins, but not by cross-linking of asp, either with a-specific mAbs. References_end</body> </html> </notes> <label text="LYN"/> <bbox w="80.0" h="40.0" x="6700.0" y="2240.0"/> <glyph class="state variable" id="_d62499f9-c71e-41f4-ad10-a4df618244ce"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6692.5" y="2255.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1788_sa990" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:LYN Identifiers_end Maps_Modules_begin: MODULE:NK_ACTIVATING_RECEPTORS MODULE:NK Maps_Modules_end References_begin: PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. FN adhesion-induced activity of the PTKs pl2SFAK, Fyn, Lyn, and Zap-70. Lyn activity was induced by cross-linking of a4pI integrins, but not by cross-linking of asp, either with a-specific mAbs. References_end</body> </html> </notes> <label text="LYN"/> <bbox w="80.0" h="40.0" x="6700.0" y="2320.0"/> <glyph class="state variable" id="_bf80556c-e890-479f-ace4-43bcf2951043"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6695.0" y="2335.0"/> </glyph> </glyph> <glyph class="complex" id="s1891_csa132" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:CD11b*:CD18*:ICAM1 Identifiers_end References_begin: PMID:2060581 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity References_end</body> </html> </notes> <label text="MAC1"/> <bbox w="100.0" h="195.0" x="7220.0" y="2312.5"/> <glyph class="macromolecule" id="s1785_sa986"> <notes> <html xmlns="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: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS The phosphorylation of Ser329 by PKC was later found to be critical for the association between DNAM-1 and CD18(LFA-1) in NK cells.17 This association is required for DNAM-1 signalling. PMID:19965656 Coengagement of DNAM-1 and CD18 (LFA-)1 by a Drosophila cell line transfected to express CD155 and intercellular adhesion molecule 1 triggered the IFN-g production by NK cells, while these ligands alone had no effects, reinforcing the functional link between DNAM-1 and LFA-1 in driving NK cell activation. PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. LFA-1 is required for NKG2D-mediated conjugate formation and cytotoxicity. References_end</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="7230.0" y="2367.5"/> <glyph class="unit of information" id="_655c36f1-03ae-418a-b9bb-b61a051f97e1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7247.5" y="2362.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1786_sa987"> <notes> <html xmlns="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>HUGO:ITGAM ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:2060581 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity References_end</body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="7230.0" y="2327.5"/> <glyph class="unit of information" id="_d2aef6a2-11a8-4ae1-92f6-56da74eb27fa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7247.5" y="2322.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1783_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). References_end</body> </html> </notes> <label text="ICAM1"/> <bbox w="80.0" h="40.0" x="7230.0" y="2427.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1894_sa1091" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAP2K3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="MAP2K3"/> <bbox w="80.0" h="40.0" x="4700.0" y="1540.0"/> <glyph class="state variable" id="_d38232ed-fc18-4938-a01b-d51768e523bb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4695.0" y="1555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1895_sa1093" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CXCL8 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 mRNA expression and protein production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="IL8*"/> <bbox w="80.0" h="40.0" x="6570.0" y="1570.0"/> </glyph> <glyph class="nucleic acid feature" id="s1896_sa1094" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CXCL8 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 mRNA expression and protein production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="IL8*"/> <bbox w="70.0" h="25.0" x="6345.0" y="1687.5"/> </glyph> <glyph class="nucleic acid feature" id="s1897_sa1095" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:CXCL8 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:NK Maps_Modules_end References_begin: PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 mRNA expression and protein production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="IL8*"/> <bbox w="90.0" h="25.0" x="6435.0" y="1647.5"/> <glyph class="unit of information" id="_9eb097a1-9169-44f7-ba2e-c393145c1350"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6470.0" y="1642.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1898_sa1092" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:MAP2K3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. References_end</body> </html> </notes> <label text="MAP2K3"/> <bbox w="80.0" h="40.0" x="4700.0" y="1440.0"/> <glyph class="state variable" id="_0f8f679a-1548-4900-8ec0-2da7a776eed9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4692.5" y="1455.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s122_sa1102" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 References_end</body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="1110.0" y="1325.0"/> <glyph class="state variable" id="_5650c771-1a88-4274-9f3c-255305cf060d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1185.0" y="1359.3893"/> </glyph> <glyph class="unit of information" id="_aceddf06-3668-4a4d-bc23-cc0427046955"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1127.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s238_sa1103" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1. 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NK cells stimuletad by IL4 have NK2 subtype PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end</body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="1395.5" y="1306.0"/> </glyph> <glyph class="macromolecule" id="s333_sa1111"> <notes> <html xmlns="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: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 References_end</body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="1476.3572" y="1307.6428"/> <glyph class="state variable" id="_a3a6f834-e082-4924-ba4e-9c0f68980919"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1551.3572" y="1342.0321"/> </glyph> <glyph class="unit of information" id="_713e928e-284b-4252-96dd-aea0bfe67579"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1493.8572" y="1302.6428"/> </glyph> </glyph> <glyph class="macromolecule" id="s332_sa1112"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="1476.3572" y="1268.6428"/> <glyph class="unit of information" id="_afc387ec-7a58-48c0-a026-ebf76d051aaa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1493.8572" y="1263.6428"/> </glyph> </glyph> <glyph class="macromolecule" id="s1918_sa1129"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). 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References_end</body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="1560.0" y="1300.0"/> <glyph class="state variable" id="_e550a8e3-6381-4ce5-8d32-a6bfe02d1231"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1555.0" y="1315.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1919_sa1131"> <notes> <html xmlns="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: HUGO:JAK3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2Rβ are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:10849428 JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="1560.0" y="1340.0"/> </glyph> </glyph> <glyph class="complex" id="s1906_csa148" compartmentRef="c6_ca6"> <notes> <html xmlns="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: NAME:IL13RA1:IL4:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 Type II IL-4 receptors associates with Jak1,JAK2 and TYK2 References_end</body> </html> </notes> <label text="IL4/Receptor-TYPE_2"/> <bbox w="284.0" h="173.0" x="1048.0" y="1443.5"/> <glyph class="macromolecule" id="s431_sa1118"> <notes> <html xmlns="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: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end</body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="1048.5" y="1496.0"/> </glyph> <glyph class="macromolecule" id="s434_sa1119"> <notes> <html xmlns="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: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1. References_end</body> </html> </notes> <label text="IL13RA1"/> <bbox w="80.0" h="50.0" x="1128.8572" y="1495.6428"/> <glyph class="state variable" id="_4a1ced5b-17d6-4b04-a790-4c1a18e0e599"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1203.8572" y="1529.3995"/> </glyph> <glyph class="unit of information" id="_7edfcaa8-e59e-4091-b8bc-60702b7c50c8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1146.3572" y="1490.6428"/> </glyph> </glyph> <glyph class="macromolecule" id="s433_sa1120"> <notes> <html xmlns="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: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 References_end</body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="1128.8572" y="1456.6428"/> <glyph class="state variable" id="_65953f3f-b33d-4907-8a6d-eb0861799ba4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1203.8572" y="1491.0321"/> </glyph> <glyph class="unit of information" id="_d9206176-cf0e-4717-85db-0a5a99ea4cf9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1146.3572" y="1451.6428"/> </glyph> </glyph> <glyph class="macromolecule" id="s1915_sa1125"> <notes> <html xmlns="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: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="1231.1471" y="1562.6471"/> <glyph class="state variable" id="_5c7a1576-4820-4a32-81bf-dd66d55dd8e9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1226.1471" y="1577.6471"/> </glyph> </glyph> <glyph class="macromolecule" id="s1916_sa1127"> <notes> <html xmlns="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: HUGO:JAK1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2RB are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). PMID:12759422 IL15 and IL21 induces STAT4 and STAT1 phosphorylation and binding to IFNG promotor, probably via JAK1 References_end</body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="1231.1471" y="1462.6471"/> </glyph> <glyph class="macromolecule" id="s1914_sa1128"> <notes> <html xmlns="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: HUGO:TYK2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:15864272 I IFN receptor has a multichain structures, which are composed of at least two distinct subunits: IFNAR1 and IFNAR2. IFNAR1 subunit is constitutively associated with tyrosine kinase 2 (TYK2), whereas IFNAR2 is associated with JAK1. The initial step in both type-I- and type-II-IFN-mediated signalling is the activation of these receptor-associated JAKs , which occurs in response to a ligand-dependent rearrangement and dimerization of the receptor subunits, followed by autophosphorylation and activation of the associated JAKs which in turn regulate the phosphorylation and activation of STATs. PMID:8683106 IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. References_end</body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="1231.1471" y="1512.6471"/> <glyph class="state variable" id="_6a8c8be8-1dcd-41d1-8c2b-13dfaa7490f5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1226.1471" y="1527.6471"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s311_sa1097"> <notes> <html xmlns="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: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end</body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="1030.0" y="970.0"/> </glyph> <glyph class="nucleic acid feature" id="s1921_sa1132" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL5"/> <bbox w="70.0" h="25.0" x="1735.0" y="1547.5"/> </glyph> <glyph class="nucleic acid feature" id="s1922_sa1133" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL5"/> <bbox w="90.0" h="25.0" x="1725.0" y="1477.5"/> <glyph class="unit of information" id="_a918127e-5350-4ef3-b02e-408c5ed214a1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1760.0" y="1472.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1923_sa1134" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL5"/> <bbox w="80.0" h="40.0" x="1730.0" y="1400.0"/> </glyph> <glyph class="nucleic acid feature" id="s1924_sa1135" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL13"/> <bbox w="70.0" h="25.0" x="1825.0" y="1507.5"/> </glyph> <glyph class="nucleic acid feature" id="s1925_sa1136" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL13"/> <bbox w="90.0" h="25.0" x="1815.0" y="1447.5"/> <glyph class="unit of information" id="_47bacf7f-87d3-4502-831c-07978b78b376"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1850.0" y="1442.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1926_sa1137" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="1820.0" y="1360.0"/> </glyph> <glyph class="macromolecule" id="s1930_sa1141" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:9834059 NK cells stimulated by IL12 induces IL10 production. PMID:9780204, PMID:10508240 IL-10 did not induce the production of IFN-γ by NK cells, it did enhance the ability of IL-18 to stimulate NK cell production of IFN-γ. In addition, IL-10 augmented NK cell proliferation and cytotoxic activity when combined with IL-18. References_end</body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="1900.0" y="1320.0"/> </glyph> <glyph class="macromolecule" id="s1932_sa1142"> <notes> <html xmlns="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: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:9834059 NK cells stimulated by IL12 induces IL10 production. PMID:9780204, PMID:10508240 IL-10 did not induce the production of IFN-γ by NK cells, it did enhance the ability of IL-18 to stimulate NK cell production of IFN-γ. In addition, IL-10 augmented NK cell proliferation and cytotoxic activity when combined with IL-18. References_end</body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="1520.0" y="800.0"/> </glyph> <glyph class="macromolecule" id="s1933_sa1121" compartmentRef="c7_ca7"> <notes> <html xmlns="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: HUGO:JAK3 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:20732639, PMID:8683106 IL-2 is a 4-bundle alpha-helical protein of 15 kDa predominately produced by antigen-activated T cells that binds to a high-affinity receptor consisting of three subunits, IL2RA (CD25), IL2RB (CD122), and IL2G (CD132), The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2RB and IL2RG, respectively. Three tyrosine residues within the cytoplasmic tail of IL-2Rβ are phosphorylated to promote recruitment of the adaptor Shc (Y338 human; Y341 mouse), leading to activation of the MAPK and PI-3K kinase pathways, and predominately the Stat5 transcription factor (Y392 and Y510 human; Y398 and Y505 mouse), resulting in Stat5-dependent gene regulation PMID:8683106 IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 in NK cells. PMID:16815076, PMID:11345192, PMID:12244150 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. IL-15-mediated signaling results in the activation of Janus kinase (JAK), The IL-2RB chain recruits JAK1, whereas IL-2RG activates JAK3, , which in turn results in the phosphorylation and activation of STAT3 and STAT5, respectively. PMID:10849428 JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. PMID:24751819, PMID:12244150 Interleukin-21 (IL-21) binding stabilizes the complex between the IL-21 receptor (IL-21R) and the common cytokine-γ chain, γc, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which allows the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (predominantly STAT3, but also STAT1 and STAT5). References_end</body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="1570.0" y="1500.0"/> </glyph> <glyph class="macromolecule" id="s1934_sa1101" compartmentRef="c6_ca6"> <notes> <html xmlns="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: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:NK MODULE:IMMUNOSTIMULATORY_CYTOKINES_PATHWAYS Maps_Modules_end References_begin: PMID:10358772, PMID:10856136 IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end References_end</body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="1160.0" y="1215.0"/> <glyph class="unit of information" id="_e7478abc-daa2-4d70-9405-0187ab3e3290"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1177.5" y="1210.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1935_sa1144"> <notes> <html xmlns="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: HUGO:IL5 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL5"/> <bbox w="80.0" h="40.0" x="1350.0" y="900.0"/> </glyph> <glyph class="macromolecule" id="s1936_sa1143"> <notes> <html xmlns="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: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end</body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="1440.0" y="860.0"/> </glyph> <glyph class="source and sink" id="s1598_sa851" compartmentRef="c7_ca7"> <label text="csa110_degraded"/> <bbox w="30.0" h="30.0" x="2955.0" y="2645.0"/> </glyph> <glyph class="source and sink" id="s1599_sa852" compartmentRef="c7_ca7"> <label text="csa111_degraded"/> <bbox w="30.0" h="30.0" x="2825.0" y="2645.0"/> </glyph> <glyph class="source and sink" id="s1622_sa944" compartmentRef="c7_ca7"> <label text="csa115_degraded"/> <bbox w="30.0" h="30.0" x="2695.0" y="2645.0"/> </glyph> <glyph class="source and sink" id="s1685_sa926" compartmentRef="c7_ca7"> <label text="csa113_degraded"/> <bbox w="30.0" h="30.0" x="3275.0" y="2645.0"/> </glyph> <glyph class="macromolecule" id="s1947_sa1154"> <notes> <html xmlns="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: HUGO:ADAM10 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _ACTIVATING_RECEPTORS PMID:18676862 Tumor-Associated MICA Is shed by ADAM10 and ADAM17 proteases. References_end</body> </html> </notes> <label text="ADAM10"/> <bbox w="80.0" h="40.0" x="3530.0" y="4310.0"/> </glyph> <glyph class="macromolecule" id="s1948_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CDH1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH1"/> <clone/> <bbox w="80.0" h="40.0" x="350.0" y="2940.0"/> </glyph> <glyph class="macromolecule" id="s1948_sa787"> <notes> <html xmlns="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: HUGO:CDH1 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH1"/> <clone/> <bbox w="80.0" h="40.0" x="280.0" y="4270.0"/> </glyph> <glyph class="macromolecule" id="s1949_sa776"> <notes> <html xmlns="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: HUGO:CDH2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:17307799 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH2"/> <clone/> <bbox w="80.0" h="40.0" x="460.0" y="2940.0"/> </glyph> <glyph class="macromolecule" id="s1949_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CDH2 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340, PMID:17307799 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH2"/> <clone/> <bbox w="80.0" h="40.0" x="390.0" y="4270.0"/> </glyph> <glyph class="macromolecule" id="s1950_sa777"> <notes> <html xmlns="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: HUGO:CDH4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH4"/> <clone/> <bbox w="80.0" h="40.0" x="580.0" y="2940.0"/> </glyph> <glyph class="macromolecule" id="s1950_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"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CDH4 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS PMID:16461340 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. References_end</body> </html> </notes> <label text="CDH4"/> <clone/> <bbox w="80.0" h="40.0" x="510.0" y="4270.0"/> </glyph> <glyph class="macromolecule" id="s1951_sa967"> <notes> <html xmlns="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: HUGO:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:25312647 SLAMF7 is a self-ligand; i.e., it recognizes as ligand another SLAMF7 molecule on another cell. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <clone/> <bbox w="80.0" h="50.0" x="130.0" y="4255.0"/> <glyph class="state variable" id="_12e71284-f239-47e8-9efd-fdb604dc5f0d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="125.0" y="4275.0"/> </glyph> <glyph class="unit of information" id="_188ac38b-5994-4872-9734-e4781985db0f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="147.5" y="4250.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1951_sa969"> <notes> <html xmlns="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: HUGO:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:NK MODULE:NK_INHIBITING_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: _INHIBITING_RECEPTORS _ACTIVATING_RECEPTORS PMID:25312647 SLAMF7 is a self-ligand; i.e., it recognizes as ligand another SLAMF7 molecule on another cell. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express (activating) or do not express (inhibiting) the adaptor EAT-2. SLAMF7-mediated inhibition in NK cells is accompanied by tyrosine phosphorylation of SHIP-1. Src family kinases (fyn, probably) are responsible for SLAMF7-dependent tyrosine phosphorylation of SHIP-1. CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. PMID:16339536, PMID:17599905, PMID:25312647 SLAMF7 (CRACC) binds EAT-2, EAT-2 mediates phosphorylation of CRACC probably via recruitment of src kynasees, probably FYN. PMID:16339536 Ligation of CRACC induces the activation of PLCγ1 and PLCγ2 and PI3K signaling pathways Ligation of CRACC induced modest tyrosine phosphorylation of the guanine nucleotide exchange factors Vav1 and the 5′ inositol phosphatase SHIP-1 and E3 ubiquitin ligase c-Cbl. PMID:24687958 Conserved C-terminal tyrosine (Y127) is critical for activating function of human EAT-2 References_end</body> </html> </notes> <label text="SLAMF7"/> <clone/> <bbox w="80.0" h="50.0" x="6370.0" y="4105.0"/> <glyph class="state variable" id="_653f0e84-bdf5-45e0-abac-233547741bba"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6365.0" y="4125.0"/> </glyph> <glyph class="unit of information" id="_f9f37c5b-e700-484a-972d-a4a82fed8812"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6387.5" y="4100.0"/> </glyph> </glyph> <glyph class="process" orientation="vertical" id="pr_f8c223e1-9fe7-4fd9-a4a1-9d80fcc82d54"> <bbox w="10.0" h="10.0" x="2040.0" y="3585.0"/> <port id="pr_f8c223e1-9fe7-4fd9-a4a1-9d80fcc82d54_p1" x="2045.0" y="3575.0"/> <port id="pr_f8c223e1-9fe7-4fd9-a4a1-9d80fcc82d54_p2" x="2045.0" y="3605.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4dd33b3a-b5a6-4910-9b77-1d45ca6c4bef"> <notes> <html xmlns="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>References_begin: PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:18287025 Inhibition of JNK activity blocked polarization of granzyme B, a component of cytolytic granules. 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References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4690.0" y="3591.6323"/> <port id="pr_8649aabf-2dae-47e8-ba8a-13b1f9c8e400_p1" x="4695.0" y="3611.6323"/> <port id="pr_8649aabf-2dae-47e8-ba8a-13b1f9c8e400_p2" x="4695.0" y="3581.6323"/> </glyph> <glyph class="or" orientation="vertical" id="logicglyph_f6df0207-4e51-465c-8238-2afb340bf2cd"> <bbox w="20.0" h="20.0" x="4922.0312" y="4043.125"/> <port id="logicglyph_f6df0207-4e51-465c-8238-2afb340bf2cd_p1" x="4932.0312" y="4073.125"/> <port id="logicglyph_f6df0207-4e51-465c-8238-2afb340bf2cd_p2" x="4932.0312" y="4033.125"/> </glyph> <glyph class="process" orientation="vertical" id="pr_dae581f8-20e0-464b-a29a-1a7e179ee77e"> <notes> <html xmlns="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:NK Maps_Modules_end References_begin: PMID:20814939, PMID:12731048 Phosphorylation of the ITAM sequence in the associated partner chains induces binding and phosphorylation of tyrosine kinases Syk and ZAP70 to the ITAM downstream of NKp30 or NKp46 or NKp44 References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5365.0" y="3080.0"/> <port id="pr_dae581f8-20e0-464b-a29a-1a7e179ee77e_p1" x="5370.0" y="3100.0"/> <port id="pr_dae581f8-20e0-464b-a29a-1a7e179ee77e_p2" x="5370.0" y="3070.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a1ea1918-3e35-4a85-a912-976b3379e45f"> <notes> <html xmlns="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:NK Maps_Modules_end References_begin: PMID:20814939, PMID:12731048 Phosphorylation of the ITAM sequence in the associated partner chains induces binding and phosphorylation of tyrosine kinases Syk and ZAP70 to the ITAM downstream of NKp30 or NKp46 or NKp44 References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4975.0" y="3025.0"/> <port id="pr_a1ea1918-3e35-4a85-a912-976b3379e45f_p1" x="4980.0" y="3045.0"/> <port id="pr_a1ea1918-3e35-4a85-a912-976b3379e45f_p2" x="4980.0" y="3015.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c7860c94-7f95-4b2a-ab67-debad8ac1ad3"> <bbox w="10.0" h="10.0" x="5685.0" y="2560.0"/> <port id="pr_c7860c94-7f95-4b2a-ab67-debad8ac1ad3_p1" x="5690.0" y="2580.0"/> <port id="pr_c7860c94-7f95-4b2a-ab67-debad8ac1ad3_p2" x="5690.0" y="2550.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2502bc69-5df8-4b16-8ad9-008f0c1b15c2"> <notes> <html xmlns="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>References_begin: PMID:16713974 TLR signaling activates and IFNG inhibits PI3K pathway PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:10426994 Phosphorylated DAP10 directly interacts with regulatory subunit (p85) of PI3K and activates downstream pathway. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="5917.5" y="2655.0"/> <port id="pr_2502bc69-5df8-4b16-8ad9-008f0c1b15c2_p1" x="5922.5" y="2675.0"/> <port id="pr_2502bc69-5df8-4b16-8ad9-008f0c1b15c2_p2" x="5922.5" y="2645.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bb6971ed-4c23-4f8b-a011-fd3e921276f9"> <bbox w="10.0" h="10.0" x="3995.0" y="2120.0"/> <port id="pr_bb6971ed-4c23-4f8b-a011-fd3e921276f9_p1" x="4000.0" y="2140.0"/> <port id="pr_bb6971ed-4c23-4f8b-a011-fd3e921276f9_p2" x="4000.0" y="2110.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_22b658eb-4df4-4873-99d7-f2045bbcfa8d"> <bbox w="10.0" h="10.0" x="4145.0" y="2150.0"/> <port id="pr_22b658eb-4df4-4873-99d7-f2045bbcfa8d_p1" x="4150.0" y="2170.0"/> <port id="pr_22b658eb-4df4-4873-99d7-f2045bbcfa8d_p2" x="4150.0" y="2140.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_73cabf39-46a0-40f0-822d-7c951800aaaf"> <bbox w="10.0" h="10.0" x="4285.0" y="2205.0"/> <port id="pr_73cabf39-46a0-40f0-822d-7c951800aaaf_p1" x="4290.0" y="2225.0"/> <port id="pr_73cabf39-46a0-40f0-822d-7c951800aaaf_p2" x="4290.0" y="2195.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_10fd933e-461b-4150-addf-947c126c87f9"> <notes> <html xmlns="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>References_begin: PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4497.5" y="2295.0"/> <port id="pr_10fd933e-461b-4150-addf-947c126c87f9_p1" x="4517.5" y="2300.0"/> <port id="pr_10fd933e-461b-4150-addf-947c126c87f9_p2" x="4487.5" y="2300.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c60e2c02-e97a-41d3-86fd-45331b308a98"> <bbox w="10.0" h="10.0" x="4875.0" y="2555.0"/> <port id="pr_c60e2c02-e97a-41d3-86fd-45331b308a98_p1" x="4880.0" y="2575.0"/> <port id="pr_c60e2c02-e97a-41d3-86fd-45331b308a98_p2" x="4880.0" y="2545.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_60197397-beea-41de-9477-37ca0f8f9007"> <bbox w="10.0" h="10.0" x="4695.0" y="2565.0"/> <port id="pr_60197397-beea-41de-9477-37ca0f8f9007_p1" x="4700.0" y="2585.0"/> <port id="pr_60197397-beea-41de-9477-37ca0f8f9007_p2" x="4700.0" y="2555.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1fc58fd2-92cc-4489-920e-158ca0745cff"> <bbox w="10.0" h="10.0" x="5805.0" y="2610.0"/> <port id="pr_1fc58fd2-92cc-4489-920e-158ca0745cff_p1" x="5810.0" y="2630.0"/> <port id="pr_1fc58fd2-92cc-4489-920e-158ca0745cff_p2" x="5810.0" y="2600.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_59778e3c-b4c8-4e2d-8f5d-63cd5f109eb9"> <bbox w="10.0" h="10.0" x="5115.0" y="3525.0"/> <port id="pr_59778e3c-b4c8-4e2d-8f5d-63cd5f109eb9_p1" x="5105.0" y="3530.0"/> <port id="pr_59778e3c-b4c8-4e2d-8f5d-63cd5f109eb9_p2" x="5135.0" y="3530.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2c56b16a-9bf4-42f4-8c4f-c3ba33dbae4a"> <bbox w="10.0" h="10.0" x="2975.0" y="3495.0"/> <port id="pr_2c56b16a-9bf4-42f4-8c4f-c3ba33dbae4a_p1" x="2965.0" y="3500.0"/> <port id="pr_2c56b16a-9bf4-42f4-8c4f-c3ba33dbae4a_p2" x="2995.0" y="3500.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9522a3fa-dcf2-4882-9ab9-771b86eb9b7e"> <bbox w="10.0" h="10.0" x="4526.25" y="2557.5"/> <port id="pr_9522a3fa-dcf2-4882-9ab9-771b86eb9b7e_p1" x="4531.25" y="2577.5"/> <port id="pr_9522a3fa-dcf2-4882-9ab9-771b86eb9b7e_p2" x="4531.25" y="2547.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dcabc64e-52c8-421e-b530-bcd0a60dd5ce"> <bbox w="10.0" h="10.0" x="3890.75" y="3534.8225"/> <port id="pr_dcabc64e-52c8-421e-b530-bcd0a60dd5ce_p1" x="3880.75" y="3539.8225"/> <port id="pr_dcabc64e-52c8-421e-b530-bcd0a60dd5ce_p2" x="3910.75" y="3539.8225"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ea9a0c7e-17f4-4cd5-9608-615390aec4ca"> <bbox w="10.0" h="10.0" x="5135.0" y="3020.0"/> <port id="pr_ea9a0c7e-17f4-4cd5-9608-615390aec4ca_p1" x="5140.0" y="3040.0"/> <port id="pr_ea9a0c7e-17f4-4cd5-9608-615390aec4ca_p2" x="5140.0" y="3010.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6132429c-75ff-4a0e-a1f9-1e3e8b47af2d"> <notes> <html xmlns="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>References_begin: PMID:12740575, PMID:15972651 In NK cells NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release. The calcium signal generated by PLCG is required for NKG2D-initiated killing. 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predominantly acting through IKKb in an IKKg-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. PMID:17485448 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1.. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4305.0" y="1840.0"/> <port id="pr_c20e3a88-82d8-46d1-9b7a-d9a063cf783e_p1" x="4325.0" y="1845.0"/> <port id="pr_c20e3a88-82d8-46d1-9b7a-d9a063cf783e_p2" x="4295.0" y="1845.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_78956e9e-ffba-47f7-9bef-baad72e8da28"> <notes> <html xmlns="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>References_begin: PMID:15145317 The activated IKK complex catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4150.65" y="1923.2632"/> <port id="pr_78956e9e-ffba-47f7-9bef-baad72e8da28_p1" x="4155.65" y="1913.2632"/> <port id="pr_78956e9e-ffba-47f7-9bef-baad72e8da28_p2" x="4155.65" y="1943.2632"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2daac2ca-298d-4add-a59e-6bd20016b9f9"> <bbox w="10.0" h="10.0" x="4376.0234" y="1929.25"/> <port id="pr_2daac2ca-298d-4add-a59e-6bd20016b9f9_p1" x="4381.0234" y="1949.25"/> <port id="pr_2daac2ca-298d-4add-a59e-6bd20016b9f9_p2" x="4381.0234" y="1919.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_75776934-7f75-46e5-9a79-3781ef3282a9"> <notes> <html xmlns="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>References_begin: PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via prevention of degradation of IkBa PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4332.5" y="1983.6842"/> <port id="pr_75776934-7f75-46e5-9a79-3781ef3282a9_p1" x="4322.5" y="1988.6842"/> <port id="pr_75776934-7f75-46e5-9a79-3781ef3282a9_p2" x="4352.5" y="1988.6842"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_e18daa83-29a4-4e20-ac91-02a05cc25eec"> <notes> <html xmlns="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>References_begin: PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1. PMID:21232017, PMID:21133840, PMID:17301840 PMID:24958845, PMID:24699077 The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex downstream of TNF and upregulates IkBa degradetion. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4300.0" y="1655.0"/> <port id="pr_e18daa83-29a4-4e20-ac91-02a05cc25eec_p1" x="4290.0" y="1660.0"/> <port id="pr_e18daa83-29a4-4e20-ac91-02a05cc25eec_p2" x="4320.0" y="1660.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_583b1b43-b321-4d3a-8e74-496f9908f3e1"> <notes> <html xmlns="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>References_begin: PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages PMID:14660645, PMID:15644117 p38 MAPK participates in HMGB1-induced NF-κB Activation PMID:14660645 HMGB1 induces nuclear NF-κB translocation and activation of NFkB signaling via TLR4 and TLR2. PMID:17404308 CSF2 induces RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="3969.5" y="1910.4117"/> <port id="pr_583b1b43-b321-4d3a-8e74-496f9908f3e1_p1" x="3959.5" y="1915.4117"/> <port id="pr_583b1b43-b321-4d3a-8e74-496f9908f3e1_p2" x="3989.5" y="1915.4117"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1978e6ff-dd10-440a-86d2-78495c3dd36f"> <bbox w="10.0" h="10.0" x="3745.0376" y="675.1875"/> <port id="pr_1978e6ff-dd10-440a-86d2-78495c3dd36f_p1" x="3750.0376" y="665.1875"/> <port id="pr_1978e6ff-dd10-440a-86d2-78495c3dd36f_p2" x="3750.0376" y="695.1875"/> </glyph> <glyph class="process" orientation="vertical" id="pr_985b8b5b-961d-4920-ab30-7ce3ff21bd03"> <bbox w="10.0" h="10.0" x="3305.0" y="1190.0"/> <port id="pr_985b8b5b-961d-4920-ab30-7ce3ff21bd03_p1" x="3310.0" y="1180.0"/> <port id="pr_985b8b5b-961d-4920-ab30-7ce3ff21bd03_p2" x="3310.0" y="1210.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_27897c3b-78a5-49a4-9092-3710b87b2579"> <bbox w="10.0" h="10.0" x="5035.0" y="1315.0"/> <port id="pr_27897c3b-78a5-49a4-9092-3710b87b2579_p1" x="5040.0" y="1305.0"/> <port id="pr_27897c3b-78a5-49a4-9092-3710b87b2579_p2" x="5040.0" y="1335.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6ed5cb1d-0b05-4d28-8108-50b86a8e689c"> <bbox w="10.0" h="10.0" x="5740.0" y="1455.0"/> <port id="pr_6ed5cb1d-0b05-4d28-8108-50b86a8e689c_p1" x="5730.0" y="1460.0"/> <port id="pr_6ed5cb1d-0b05-4d28-8108-50b86a8e689c_p2" x="5760.0" y="1460.0"/> </glyph> <glyph class="and" orientation="vertical" id="logicglyph_1f06bac5-4a66-426f-a9f3-a4bdd93c8de9"> <bbox w="20.0" h="20.0" x="5853.3335" y="1675.8334"/> <port id="logicglyph_1f06bac5-4a66-426f-a9f3-a4bdd93c8de9_p1" x="5863.3335" y="1705.8334"/> <port id="logicglyph_1f06bac5-4a66-426f-a9f3-a4bdd93c8de9_p2" x="5863.3335" y="1665.8334"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_8de5b62f-18bd-4c4c-a883-e018a3a91b98"> <bbox w="10.0" h="10.0" x="5867.5" y="1455.0"/> <port id="pr_8de5b62f-18bd-4c4c-a883-e018a3a91b98_p1" x="5857.5" y="1460.0"/> <port id="pr_8de5b62f-18bd-4c4c-a883-e018a3a91b98_p2" x="5887.5" y="1460.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d5e47830-aadf-49b4-8294-bb87568c62de"> <notes> <html xmlns="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>References_begin: PMID:11875494 IL10-induced p38 phosphorylation. PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. PMID:10925299 IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation downstream of IL13. PMID:23508573 HMGB1 induces activation (phosphorylation) of p38 via TLR4. PMID:12811837, PMID:16713974 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. References_end</body> </html> </notes> <bbox w="10.0" h="10.0" x="4605.0" y="1405.0"/> <port id="pr_d5e47830-aadf-49b4-8294-bb87568c62de_p1" x="4610.0" y="1395.0"/> <port id="pr_d5e47830-aadf-49b4-8294-bb87568c62de_p2" x="4610.0" y="1425.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_53f57e32-a3a1-4594-abd2-338a7cee6ffc"> <bbox w="10.0" h="10.0" x="5044.0674" y="748.25"/> <port id="pr_53f57e32-a3a1-4594-abd2-338a7cee6ffc_p1" x="5049.0674" y="738.25"/> <port id="pr_53f57e32-a3a1-4594-abd2-338a7cee6ffc_p2" x="5049.0674" y="768.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a3c9df53-ff5c-4ac8-9326-2f9b23963b79"> <bbox w="10.0" h="10.0" x="5155.0" y="1060.0"/> <port id="pr_a3c9df53-ff5c-4ac8-9326-2f9b23963b79_p1" x="5160.0" y="1050.0"/> <port id="pr_a3c9df53-ff5c-4ac8-9326-2f9b23963b79_p2" x="5160.0" y="1080.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_10aa6749-92bf-49a5-81f3-f74e788c2993"> <bbox w="10.0" h="10.0" x="5025.0" 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</glyph> <glyph class="process" orientation="vertical" id="pr_60ab2dfa-e416-4fd9-9e5b-e1c694ec9353"> <bbox w="10.0" h="10.0" x="4975.0" y="1545.0"/> <port id="pr_60ab2dfa-e416-4fd9-9e5b-e1c694ec9353_p1" x="4980.0" y="1535.0"/> <port id="pr_60ab2dfa-e416-4fd9-9e5b-e1c694ec9353_p2" x="4980.0" y="1565.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5215211e-3329-41ee-beb3-daddb6f1caf9"> <bbox w="10.0" h="10.0" x="4975.0" y="1616.25"/> <port id="pr_5215211e-3329-41ee-beb3-daddb6f1caf9_p1" x="4980.0" y="1606.25"/> <port id="pr_5215211e-3329-41ee-beb3-daddb6f1caf9_p2" x="4980.0" y="1636.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_40e17cf9-a21e-4c95-b63b-eeb16520a2c9"> <bbox w="10.0" h="10.0" x="4631.779" y="661.6875"/> <port id="pr_40e17cf9-a21e-4c95-b63b-eeb16520a2c9_p1" x="4636.779" y="651.6875"/> <port id="pr_40e17cf9-a21e-4c95-b63b-eeb16520a2c9_p2" x="4636.779" y="681.6875"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2e990244-f8be-4734-ad48-420a9039bd8c"> <notes> <html xmlns="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>References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. 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