</head> <body>Innate Immune Response Map The network map of innate immune response in cancer covers major signaling mechanisms occurring within and between different players of the innate immune component in TME. It represents both direct and indirect molecular interactions in innate immune cells, between immune cells and tumor cells. The structure of the map reflects the conceptual understanding of diversity and integrity of innate immunity system. The signaling within each innate immunity cell type is depicted in the form of separate maps covering signaling maps of macrophages, dendritic cells, myeloid-derived suppressor cells, natural killers, neutrophils and mast cells. These cell type-specific maps, integrated together and completed by interactions and crosstalk between them and the map of tumor cell, gave rise to a seamless comprehensive map of innate immune response in cancer. The innate immune response map demonstrates signaling responsible for anti- and pro-tumour activities of innate immunity system as a whole. The map contains 1476 objects (proteins, genes, small molecules, reactions etc.) and based on the information manually retrieved from 821 cell type specific and cancer-relates articles. </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_9" value="#66ff66ff"/> <colorDefinition id="color_2" value="#cccc00ff"/> <colorDefinition id="color_5" value="#ccffccff"/> <colorDefinition id="color_8" value="#ccff66ff"/> <colorDefinition id="color_14" value="#808080ff"/> <colorDefinition id="color_6" value="#f7f7f7ff"/> <colorDefinition id="color_10" value="#ffccccff"/> <colorDefinition id="color_7" value="#ffffccff"/> <colorDefinition id="color_12" value="#ffff66ff"/> <colorDefinition id="color_16" value="#00ff00ff"/> <colorDefinition id="color_13" value="#cc99ffff"/> <colorDefinition 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y="8670.0"/> </glyph> <glyph class="nucleic acid feature" id="s962_sa373" compartmentRef="c38_ca38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR93 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:25277195 Inhibition of MIR20A or MIR93 upregulates translation of their predicted targets (MICA, MICB, ULBP2 or ULBP3) in tumor cells and upregulates NK cytotoxicity against these cells. References_end </body> </html> </notes> <label text="MIR93"/> <bbox w="90.0" h="25.0" x="12465.0" y="457.5"/> <glyph class="unit of information" id="_e02c072b-cf30-4983-9c65-65ebb7cafac9"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12495.0" y="452.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s963_sa372" compartmentRef="c38_ca38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR20A Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:25277195, PMID:24813230 Inhibition of MIR20A or MIR93 upregulates translation of their predicted targets (MICA, MICB, ULBP2 or ULBP3) in tumor cells and upregulates NK cytotoxicity against these cells. PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. References_end </body> </html> </notes> <label text="MIR20A"/> <bbox w="90.0" h="25.0" x="12735.0" y="347.5"/> <glyph class="unit of information" id="_d7e27d73-dd4d-4e25-ad6d-567fde129073"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12765.0" y="342.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1024_sa986" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR17 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. References_end </body> </html> </notes> <label text="MIR17"/> <bbox w="90.0" h="25.0" x="2495.0" y="4414.375"/> <glyph class="unit of information" id="_a9ceeae9-971e-4990-bcfc-70e65a1fa9eb"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2525.0" y="4409.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1025_sa966" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR20A Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:25277195, PMID:24813230 Inhibition of MIR20A or MIR93 upregulates translation of their predicted targets (MICA, MICB, ULBP2 or ULBP3) in tumor cells and upregulates NK cytotoxicity against these cells. PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. References_end </body> </html> </notes> <label text="MIR20A"/> <bbox w="90.0" h="25.0" x="2495.0" y="4334.375"/> <glyph class="unit of information" id="_fbfe99a2-9d97-43ed-a35e-f29c0350a457"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2525.0" y="4329.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1341_sa201" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR183 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="2991.875" y="4520.625"/> <glyph class="unit of information" id="_afb05936-ce4e-436f-add8-ca78eee5923c"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3021.875" y="4515.625"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1528_sa1932" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR212 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="12280.0" y="4531.25"/> <glyph class="unit of information" id="_b4016d23-bb93-4bdf-b19b-ba7428cc2fdf"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12310.0" y="4526.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1529_sa1936" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR132 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: CASCADE:IL12 MAP:NATURAL_KILLER 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="12390.0" y="4531.25"/> <glyph class="unit of information" id="_85403cad-14c2-4a46-979c-6baaa41bf540"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12420.0" y="4526.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1530_sa1940" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR200A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="12490.0" y="4531.25"/> <glyph class="unit of information" id="_0f7e6170-032c-45b3-a46b-43a823d2ee85"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12520.0" y="4526.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1578_sa1001" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:KLRB1 PMID:24227772 KLRB1 (NK1.1) ligation also induce MIR155 expression 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 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 PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES PMID:21385848 miR155 induction is required for efficient DC maturation and is critical for the ability of DCs to promote antigen-specific T-cell activation. miR155 expression was increased strongly in mature Mo-DCs relative to monocytes and immature Mo-DCs. References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="12170.0" y="4531.25"/> <glyph class="unit of information" id="_dcc5b240-7940-47aa-8b19-5b9c7c185ea3"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12200.0" y="4526.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1591_sa211" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR27A Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 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="4709.375" y="4396.875"/> <glyph class="unit of information" id="_24cc4323-505b-4a8d-91e7-62b2b0f3c11f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4739.375" y="4391.875"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1601_sa209" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR150 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 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. References_end </body> </html> </notes> <label text="MIR150"/> <bbox w="90.0" h="25.0" x="4839.375" y="4396.875"/> <glyph class="unit of information" id="_5dc50ff8-d9b7-472e-bbc7-c424065852ef"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4869.375" y="4391.875"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1607_sa207" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR378 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB 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="4975.0" y="4405.375"/> <glyph class="unit of information" id="_11000cef-fbcb-4ff7-8ed4-4ff9024c58ff"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5005.0" y="4400.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1608_sa206" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR30E Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB 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="5055.0" y="4404.375"/> <glyph class="unit of information" id="_d10e4673-acfe-4b38-a95c-8d12b6f08e27"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5085.0" y="4399.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1617_sa313" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR223 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 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. PMID:21939504 The shuttling of fluorescently-labeled exogenous miRNAs from IL-4-activated macrophages to co-cultivated breast cancer cells without direct cell-cell contact was observed. miR-223, a miRNA specific for IL-4-activated macrophages, was detected within the exosomes released by macrophages and was significantly elevated in the co-cultivated SKBR3 and MDA-MB-231 cells. The invasiveness of the co-cultivated breast cancer cells decreased when the IL-4-activated macrophages were treated with a miR-223 antisense oligonucleotide (ASO) that would inhibit miR-223 expression. Furthermore, results from a functional assay revealed that miR-223 promoted the invasion of breast cancer cells via the Mef2c-β-catenin References_end </body> </html> </notes> <label text="MIR223"/> <bbox w="90.0" h="25.0" x="4629.375" y="4396.875"/> <glyph class="unit of information" id="_03205eb6-e318-4d56-b15d-fee4ee94cf96"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4659.375" y="4391.875"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1623_sa192" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR15A HUGO:MIR15B HUGO:MIR16-1 HUGO:MIR16-2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 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="3225.0" y="4538.125"/> <glyph class="unit of information" id="_6d9cdbda-738d-47e4-a1e6-3212202aa5c0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3255.0" y="4533.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1629_sa355" compartmentRef="c38_ca38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR10 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22915757 MiR-10b downregulates the stress-induced cell surface molecule MICB, a critical ligand for cancer cell recognition by natural killer cells. The downregulation of MICB by miR-10b results in reduced NKG2D-mediated killing. References_end </body> </html> </notes> <label text="MIR10B"/> <bbox w="90.0" h="25.0" x="12095.0" y="507.5"/> <glyph class="unit of information" id="_7e46d2d5-dc5f-48b8-9326-b89b70a34a9c"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12125.0" y="502.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1630_sa354" compartmentRef="c38_ca38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR34A Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22102694 Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D. Activation of p53 by Nutlin3a resulted in upregulation of Mir34a/c expression. References_end </body> </html> </notes> <label text="MIR34A"/> <bbox w="90.0" h="25.0" x="12727.5" y="460.0"/> <glyph class="unit of information" id="_0d980dc3-e34c-4003-8695-4b0c0d6b5485"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12757.5" y="455.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1631_sa353" compartmentRef="c38_ca38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR34C Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22102694 Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D. Activation of p53 by Nutlin3a resulted in upregulation of Mir34a/c expression. References_end </body> </html> </notes> <label text="MIR34C"/> <bbox w="90.0" h="25.0" x="12825.0" y="457.5"/> <glyph class="unit of information" id="_b3d3b16b-5cd6-4830-8e07-757531b9f836"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12855.0" y="452.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3812_sa2269" compartmentRef="c43_ca43"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 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. PMID:21939504 The shuttling of fluorescently-labeled exogenous miRNAs from IL-4-activated macrophages to co-cultivated breast cancer cells without direct cell-cell contact was observed. miR-223, a miRNA specific for IL-4-activated macrophages, was detected within the exosomes released by macrophages and was significantly elevated in the co-cultivated SKBR3 and MDA-MB-231 cells. The invasiveness of the co-cultivated breast cancer cells decreased when the IL-4-activated macrophages were treated with a miR-223 antisense oligonucleotide (ASO) that would inhibit miR-223 expression. Furthermore, results from a functional assay revealed that miR-223 promoted the invasion of breast cancer cells via the Mef2c-β-catenin References_end </body> </html> </notes> <label text="MIR223"/> <bbox w="90.0" h="25.0" x="4675.0" y="8829.0"/> <glyph class="unit of information" id="_3b4f5619-6b46-4704-9f02-a27fdad0ae83"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4705.0" y="8824.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4028_sa2516" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR125B1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: PMID:16243976 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 ion resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR References_end </body> </html> </notes> <label text="MIR125B1"/> <bbox w="90.0" h="25.0" x="12040.0" y="4531.25"/> <glyph class="unit of information" id="_a983db02-a56f-4e33-bc2d-d154b9aa31a7"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12070.0" y="4526.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4280_sa200" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR1245A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="3125.0" y="4528.125"/> <glyph class="unit of information" id="_c4456ce1-6701-4719-a523-d17ae7a4028d"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3155.0" y="4523.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4281_sa928" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR185 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="2895.0" y="4508.125"/> <glyph class="unit of information" id="_a2e3250d-3664-4210-9af4-8a63cab8bc69"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2925.0" y="4503.125"/> </glyph> </glyph> <glyph class="complex" id="s29_csa268" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IkB*:NFKB1_p50*:RELB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s29"/> <bbox w="105.0" h="155.0" x="12930.0" y="3742.5"/> <glyph class="macromolecule" id="s2292_sa2032"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RELB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:9881974 RelB is essential for the development of myeloid-related CD8alpha- dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. PMID:2308644 RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. After stimulation with the TLR9 ligand CpG or the TLR2 ligand Pam3CSK4 for 24 h, we indeed observed reduced surface expression of DC activation markers MHCII, CD86, CD80 and CD40 in Relb−/− DCs (Fig. 5a and Supplementary Fig. 5a,b). Expression of proinflammatory genes, Tnf and Il23a, correlated with the kinetics of CpG or Pam3CSK4-induced RelB activation and were reduced in Relb−/− DCs (Fig. 5b). In EMSAs, activated RelB-p50 bound to DNA probes containing the κB sites found in the Tnf and Il23a promoters Relb transcripts were reduced by ~40% in Rel−/− relative to wild-type BMDC PMID:23086447 Alternative NFkB pathway induces via phosphorylation of IκB-specific kinase α (IKK-α) the cleavage of p100-RelB to p52-RelB, which then translocates as heterodimer into the nucleus. Both complete p100 degradation and p100 processing to p52 may occur in Dcs and expression of IKKa, the kinase determining the activity of noncanonical NF-κB pathway, gradually increased during DC differentiation with concomitant p100 processing to p52  PMID:2649237 In macrophages RELB /p52 pathway is associated with M1 polarization () References_end </body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="40.0" x="12940.0" y="3797.5"/> </glyph> <glyph class="macromolecule" id="s3507_sa2033"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:NFKB1 MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF 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. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="12945.0" y="3837.5"/> <glyph class="unit of information" id="_2e229fb1-c84e-4d6f-8feb-6772a010144c"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12960.0" y="3832.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3490_sa2034"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL13 CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε PMID:10607713 Maturation of dendritic cells correlates with an increase in IκBα, IκBε, and Bcl-3 PMID:17550372, PMID:9743347 IL13 inhibits NFBB activation via inhibition of p65 nuclear migration in inflammatory macrophages and via prevention of degradation of IkBa ( References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="12945.0" y="3757.5"/> <glyph class="state variable" id="_65045b52-289c-4ade-9094-cd5eb52edf36"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12940.0" y="3772.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s32_csa273" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL10RA:IkB*:NFKB1_p50* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s32"/> <bbox w="107.5" h="160.0" x="12931.25" y="3962.5"/> <glyph class="macromolecule" id="s34_sa2046"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:NFKB1 MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF 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. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="12946.25" y="4062.5"/> <glyph class="unit of information" id="_8b387092-d522-49c6-9d78-cfc813468644"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12961.25" y="4057.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s41_sa2047"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RELB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:9881974 RelB is essential for the development of myeloid-related CD8alpha- dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. PMID:2308644 RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. After stimulation with the TLR9 ligand CpG or the TLR2 ligand Pam3CSK4 for 24 h, we indeed observed reduced surface expression of DC activation markers MHCII, CD86, CD80 and CD40 in Relb−/− DCs (Fig. 5a and Supplementary Fig. 5a,b). Expression of proinflammatory genes, Tnf and Il23a, correlated with the kinetics of CpG or Pam3CSK4-induced RelB activation and were reduced in Relb−/− DCs (Fig. 5b). In EMSAs, activated RelB-p50 bound to DNA probes containing the κB sites found in the Tnf and Il23a promoters Relb transcripts were reduced by ~40% in Rel−/− relative to wild-type BMDC PMID:23086447 Alternative NFkB pathway induces via phosphorylation of IκB-specific kinase α (IKK-α) the cleavage of p100-RelB to p52-RelB, which then translocates as heterodimer into the nucleus. Both complete p100 degradation and p100 processing to p52 may occur in Dcs and expression of IKKa, the kinase determining the activity of noncanonical NF-κB pathway, gradually increased during DC differentiation with concomitant p100 processing to p52  PMID:2649237 In macrophages RELB /p52 pathway is associated with M1 polarization () References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="90.0" h="40.0" x="12941.25" y="4022.5"/> </glyph> <glyph class="macromolecule" id="s3495_sa2048"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 HUGO:NFKBIB HUGO:NFKBIE Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL13 CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε PMID:10607713 Maturation of dendritic cells correlates with an increase in IκBα, IκBε, and Bcl-3 PMID:17550372, PMID:9743347 IL13 inhibits NFBB activation via inhibition of p65 nuclear migration in inflammatory macrophages and via prevention of degradation of IkBa ( References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="12946.25" y="3972.5"/> <glyph class="state variable" id="_bc0c92c3-2620-40a0-be63-0f2853667976"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12938.75" y="3987.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s38_csa272" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IkB*:NFKB1_p50*:cREL* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s38"/> <bbox w="115.0" h="155.0" x="12697.5" y="3962.5"/> <glyph class="macromolecule" id="s40_sa2043"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:NFKB1 MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF 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. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="12712.5" y="4057.5"/> <glyph class="unit of information" id="_d0ec5cd4-8779-40cc-a53c-608fb36ec917"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12727.5" y="4052.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s43_sa2044"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:REL Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:2308644 Relb transcripts were reduced by ~40% in Rel−/− relative to wild-type BMDC Quantitative RT-PCR validated the requirements of RelB and c-Rel in activating Cxcl2, Cd40 and Il1b gene expression PMID:25305492 p19 and p40 subunits of IL-23, a c-Rel-dependent cytokine, was enhanced in p100-deficient cells, although expression of a RelA-dependent cytokine, TNF-α, was reduced. Nuclear translocation of c-Rel was enhanced in p100-deficient cells. p100, and not the processed p52 form, associated with c-Rel in the steady state and dissociated immediately after lipopolysaccharide stimulation in wild-type dendritic cells. Four hours after the stimulation, p100 was newly synthesized and associated with c-Rel again. In cells expressing both c-Rel and RelA, c-Rel is preferentially suppressed by p100. References_end </body> </html> </notes> <label text="cREL*"/> <bbox w="80.0" h="40.0" x="12712.5" y="4017.5"/> </glyph> <glyph class="macromolecule" id="s3494_sa2045"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 HUGO:NFKBIB HUGO:NFKBIE Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL13 CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε PMID:10607713 Maturation of dendritic cells correlates with an increase in IκBα, IκBε, and Bcl-3 PMID:17550372, PMID:9743347 IL13 inhibits NFBB activation via inhibition of p65 nuclear migration in inflammatory macrophages and via prevention of degradation of IkBa ( References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="12712.5" y="3967.5"/> <glyph class="state variable" id="_3d5d9097-582b-4fbf-a542-7acf498075ca"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12705.0" y="3982.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s47_csa266" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IKBKG:IKK_beta_*:MHC_class_I* Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL13 CASCADE:VEGFA CASCADE:STING CASCADE:TLR2_4 CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF Maps_Modules_end References_begin: complex PMID‭:15145317, PMID:15573129 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 PMID:15573129 NF-B is required for the development of DCs Blocking NF-B activity been shown to prevent DC differentiation from progenitor cells in vitro. PMID:24766893 Cytosolic DNA induces type I IFNs through the endoplasmic reticulum membrane protein STING, which subsequently activates the transcription factors NF-κB and IRF3 through the kinases IKK and TBK1, respectively PMID:11438547, PMID:24378531 in macrophages Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. References_end </body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="12925.0" y="3318.0"/> <glyph class="macromolecule" id="s650_sa2026"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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. PMID:22435554, PMID:15485931, PMID:21217011, PMID:15199157 Agonist stimulation induces IKK2, a catalytic subunit of the IKK complex, to phosphorylate p105. These phosphorylations create a binding site for the ubiquitin E3 ligase complex SCF-bTrCP which catalyzes K48-linked polyubiquitination of p105, followed by its proteasomal degradatio. This releases TPL-2 from p105 inhibition and allows TPL-2 to access its substrate MEK References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="12935.0" y="3370.0"/> <glyph class="state variable" id="_8136c603-3d6a-466c-92a4-2efea451a65e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12927.5" y="3385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s649_sa2027"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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="12933.0" y="3325.0"/> <glyph class="state variable" id="_4746f336-8250-44a8-b664-03296b675050"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="13003.0" y="3340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s58_sa2028"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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. PMID:17237376, PMID:21807870 Alternative pathways involeved IKKa activation by NIK. This signaling is important for DC maturation and T-cell activation (). NIK signaling is required in DCs to deliver co-stimulatory signals to CD4+ T cells PMID:23086447 Alternative NFkB pathway induces via phosphorylation of IκB-specific kinase α (IKK-α) the cleavage of p100-RelB to p52-RelB, which then translocates as heterodimer into the nucleus. Both complete p100 degradation and p100 processing to p52 may occur in Dcs and expression of IKKa, the kinase determining the activity of noncanonical NF-κB pathway, gradually increased during DC differentiation with concomitant p100 processing to p52  PMID:2649237 In macrophages RELB /p52 pathway is associated with M1 polarization PMID:23422957 IKKa could regulate IRF3 activity and IRF3-dependent IFNβ and IL-12 production by DC. TAK1 (MAP3K7)-mediated IKKα/β activation is required for IRF3-dependent IFNβ expression in DC. At the same time IKKα regulates IRF3-mediated transcription downstream of IKKɛ/TBK1mediated IRF3 phosphorylation. IKKa increases the association of IRF3 with the transcriptional co-activator CBP. The increased recruitment of CBP after overexpression of IKKα was also associated with increased transcription of endogenous IFNβ mRNA. PMID:17254973 NfkB heterodiners could be also bloked by p52 precursor, protein p100. Dissosiation of p100 from the comprex reactivate NF-kB signaling NIK and IKK1 regulates the degradation of nfkb2 p100 to effect NF-κB/RelA activation. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="40.0" x="12935.0" y="3420.0"/> <glyph class="state variable" id="_ff1468c9-4607-4d74-af14-fb8ee90c1b0f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12930.0" y="3435.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s54_csa275" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:RELA:p100 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:17254973 NfkB heterodiners could be also bloked by p52 precursor, protein p100. Dissosiation of p100 from the comprex reactivate NF-kB signaling NIK and IKK1 regulates the degradation of nfkb2 p100 to effect NF-κB/RelA activation. References_end </body> </html> </notes> <label text="s54"/> <bbox w="110.0" h="160.0" x="12295.0" y="3790.0"/> <glyph class="macromolecule" id="s55_sa2052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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:RELA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF CASCADE:IFNG Maps_Modules_end References_begin: 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="12307.5" y="3848.25"/> </glyph> <glyph class="macromolecule" id="s56_sa2053"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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:NFKB1 MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF 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. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="12305.0" y="3890.0"/> <glyph class="unit of information" id="_b57e0e41-c026-4680-97b0-d0a1be839f1d"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12320.0" y="3885.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3513_sa2054"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:23086447 Alternative NFkB pathway induces via phosphorylation of IκB-specific kinase α (IKK-α) the cleavage of p100-RelB to p52-RelB, which then translocates as heterodimer into the nucleus. Both complete p100 degradation and p100 processing to p52 may occur in Dcs and expression of IKKa, the kinase determining the activity of noncanonical NF-κB pathway, gradually increased during DC differentiation with concomitant p100 processing to p52  PMID:2649237 In macrophages RELB /p52 pathway is associated with M1 polarization () References_end </body> </html> </notes> <label text="p100"/> <bbox w="80.0" h="40.0" x="12305.0" y="3800.0"/> </glyph> </glyph> <glyph class="complex" id="s61_csa62" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD247:NKp30* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A CASCADE:KLRB1 MAP:NATURAL_KILLER CASCADE:NKP30 References_end </body> </html> </notes> <label text="s61"/> <bbox w="103.75" h="130.0" x="10643.125" y="1345.0"/> <glyph class="macromolecule" id="s65_sa599"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP30 CASCADE:TGFB 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="10660.625" y="1402.5"/> <glyph class="unit of information" id="_dc66ee6f-94fc-432f-87be-20b559a491eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10678.125" y="1397.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4353_sa2874"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="10655.0" y="1355.0"/> <glyph class="state variable" id="_7de8cb80-30ac-45d7-a964-71e0be4a4c3a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10650.0" y="1375.0"/> </glyph> <glyph class="unit of information" id="_e7456b4f-a80e-47a8-9113-057142c5d476"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10672.5" y="1350.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s70_csa69" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD247:NKp30* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER CASCADE:NKP30 References_end </body> </html> </notes> <label text="s61"/> <bbox w="120.0" h="140.0" x="10725.0" y="1560.0"/> <glyph class="macromolecule" id="s3532_sa615"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCR3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP30 CASCADE:TGFB 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="10745.0" y="1625.0"/> <glyph class="unit of information" id="_c83362d7-947e-4695-a75f-6a0eb1d96a04"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10762.5" y="1620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3533_sa616"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="10745.0" y="1585.0"/> <glyph class="state variable" id="_56b4d6c3-31bc-4cf3-ae19-f50f148ce790"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10737.5" y="1605.0"/> </glyph> <glyph class="unit of information" id="_78319dc1-4fce-48a4-9b73-92435890932c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10762.5" y="1580.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s94_csa105" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RAC1_2* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 MAP:DENDRITIC_CELL MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s94"/> <bbox w="100.0" h="110.0" x="7990.0" y="3935.0"/> <glyph class="simple chemical" id="s96_sa701"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="8008.75" y="3991.875"/> </glyph> <glyph class="macromolecule" id="s3771_sa2240"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RAC1 HUGO:RAC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. 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. PMID:14697347, PMID: 11146654 Integrin αvβ5 regulates phagocytosis via CRK /DOCK1 (DOCK180) /RAC1 pathway downstream of. Integrin αvβ5 activation results in recruitment of the p130cas–CrkII–Dock180 complex and RAC1 activation. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="8000.0" y="3940.0"/> </glyph> </glyph> <glyph class="complex" id="s97_csa104" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RAC1_2* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 MAP:DENDRITIC_CELL MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s94"/> <bbox w="90.0" h="105.0" x="8235.0" y="3937.5"/> <glyph class="simple chemical" id="s2985_sa699"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="8250.0" y="3990.0"/> </glyph> <glyph class="macromolecule" id="s3772_sa2241"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 HUGO:RAC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. 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. PMID:14697347, PMID: 11146654 Integrin αvβ5 regulates phagocytosis via CRK /DOCK1 (DOCK180) /RAC1 pathway downstream of. Integrin αvβ5 activation results in recruitment of the p130cas–CrkII–Dock180 complex and RAC1 activation. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="8240.0" y="3940.0"/> </glyph> </glyph> <glyph class="complex" id="s176_csa265" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IKBKG:IKK_alpha_*:IKK_beta_*:TNIP3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: complex 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. PMID:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 References_end </body> </html> </notes> <label text="IKK/TNIP3 complex"/> <bbox w="189.0" h="158.0" x="12450.5" y="2981.0"/> <glyph class="macromolecule" id="s648_sa2019"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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. PMID:17237376, PMID:21807870 Alternative pathways involeved IKKa activation by NIK. This signaling is important for DC maturation and T-cell activation (). NIK signaling is required in DCs to deliver co-stimulatory signals to CD4+ T cells PMID:23086447 Alternative NFkB pathway induces via phosphorylation of IκB-specific kinase α (IKK-α) the cleavage of p100-RelB to p52-RelB, which then translocates as heterodimer into the nucleus. Both complete p100 degradation and p100 processing to p52 may occur in Dcs and expression of IKKa, the kinase determining the activity of noncanonical NF-κB pathway, gradually increased during DC differentiation with concomitant p100 processing to p52  PMID:2649237 In macrophages RELB /p52 pathway is associated with M1 polarization PMID:23422957 IKKa could regulate IRF3 activity and IRF3-dependent IFNβ and IL-12 production by DC. TAK1 (MAP3K7)-mediated IKKα/β activation is required for IRF3-dependent IFNβ expression in DC. At the same time IKKα regulates IRF3-mediated transcription downstream of IKKɛ/TBK1mediated IRF3 phosphorylation. IKKa increases the association of IRF3 with the transcriptional co-activator CBP. The increased recruitment of CBP after overexpression of IKKα was also associated with increased transcription of endogenous IFNβ mRNA. PMID:17254973 NfkB heterodiners could be also bloked by p52 precursor, protein p100. Dissosiation of p100 from the comprex reactivate NF-kB signaling NIK and IKK1 regulates the degradation of nfkb2 p100 to effect NF-κB/RelA activation. References_end </body> </html> </notes> <label text="IKKα*"/> <bbox w="80.0" h="40.0" x="12465.0" y="3070.0"/> <glyph class="state variable" id="_f87c696d-06cc-443f-9900-6c62704a116c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12460.0" y="3085.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s104_sa2020"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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. PMID:22435554, PMID:15485931, PMID:21217011, PMID:15199157 Agonist stimulation induces IKK2, a catalytic subunit of the IKK complex, to phosphorylate p105. These phosphorylations create a binding site for the ubiquitin E3 ligase complex SCF-bTrCP which catalyzes K48-linked polyubiquitination of p105, followed by its proteasomal degradatio. This releases TPL-2 from p105 inhibition and allows TPL-2 to access its substrate MEK References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="12465.0" y="3030.0"/> <glyph class="state variable" id="_289d31e7-6f92-4e0d-b08b-fb95c0e8034c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12460.0" y="3045.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s105_sa2024"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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="12466.5" y="2987.0"/> <glyph class="state variable" id="_0d64533c-c03f-4661-bd4b-390fe66332dc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12541.5" y="3002.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s107_sa2025"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNIP3 CASCADE:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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. PMID:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 References_end </body> </html> </notes> <label text="TNIP3"/> <bbox w="80.0" h="40.0" x="12552.5" y="2987.0"/> </glyph> </glyph> <glyph class="complex" id="s178_csa278" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:RELA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF 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="140.0" h="174.5" x="13185.0" y="4292.75"/> <glyph class="macromolecule" id="s235_sa2059"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NFKB1 MAP: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 MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF 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. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="118.5" h="66.5" x="13195.75" y="4374.0"/> <glyph class="unit of information" id="_45217bf1-bee4-44f2-9b12-15665959f5c1"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="13230.0" y="4369.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s20_sa2060"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF CASCADE:IFNG Maps_Modules_end References_begin: 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="120.5" h="58.5" x="13195.0" y="4308.75"/> </glyph> </glyph> <glyph class="complex" id="s241_csa254" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL13RA1:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE 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="IL4/IL13_receptor- TYPE 2"/> <clone/> <bbox w="200.0" h="90.0" x="15965.0" y="5240.0"/> <glyph class="macromolecule" id="s3273_sa1904"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MODULE:MARKERS_MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:IL13 CASCADE:IL10 CASCADE:SCF2 Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, 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 PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). 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References_end </body> </html> </notes> <label text="IL4R"/> <clone/> <bbox w="80.0" h="50.0" x="665.0" y="4658.6875"/> <glyph class="state variable" id="_d191dedd-6cbc-47ec-8ba3-83582332f9b8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="740.0" y="4693.0767"/> </glyph> <glyph class="unit of information" id="_a3e05cf6-b141-4f9b-98c9-b96c68aaecfc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="682.5" y="4653.6875"/> </glyph> </glyph> <glyph class="macromolecule" id="s3274_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> MAP:MACROPHAGE HUGO:IL13RA1 ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:IL13 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="IL13RA1"/> <clone/> <bbox w="80.0" h="50.0" x="665.0" y="4708.6875"/> <glyph class="state variable" id="_2adc49d2-b2d8-4275-9fb9-e15abb3812f2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="740.0" y="4742.4443"/> </glyph> <glyph class="unit of information" id="_346f4814-24a5-45d0-aae5-877f21112337"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="682.5" y="4703.6875"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s242_csa251" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL2RG:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE: 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="IL4_receptor_TYPE1"/> <clone/> <bbox w="195.5" h="79.125" x="15912.25" y="4835.4375"/> <glyph class="macromolecule" id="s3259_sa1893"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MODULE:MARKERS_MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:IL13 CASCADE:IL10 CASCADE:SCF2 Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, 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 PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). 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References_end </body> </html> </notes> <label text="IL4R"/> <clone/> <bbox w="80.0" h="50.0" x="921.8571" y="5248.643"/> <glyph class="state variable" id="_0ae839e9-3344-4c28-8587-851a0baff99e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="996.8571" y="5283.032"/> </glyph> <glyph class="unit of information" id="_9374458a-72f9-4b00-9f79-4ff703b38b4a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="939.3571" y="5243.643"/> </glyph> </glyph> <glyph class="macromolecule" id="s3260_sa1032"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <clone/> <bbox w="80.0" h="50.0" x="920.0" y="5200.0"/> <glyph class="unit of information" id="_21bec76e-d55f-4138-89c4-306340f382fc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="937.5" y="5195.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s470_csa323" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PPARG:STAT6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:17681149 STAT6, by interacting with PPARγ, facilitates and is required for efficient endogenous PPARγ binding. 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PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL3, TNF, and CCL2(MCP1) References_end </body> </html> </notes> <label text="PPARG"/> <bbox w="80.0" h="40.0" x="2712.25" y="4020.0"/> </glyph> <glyph class="macromolecule" id="s4026_sa2483"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAT6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. 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PMID:12244147 GM-CSF can activate STAT6 in murine BM-DC PMID:12244147, PMID:24204259 Additionally IL4 via IL-4R type I JAK3 and STAT6 (but not IL13) upregulates production of IL12p70 References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="80.0" h="40.0" x="2710.25" y="3967.0"/> <glyph class="state variable" id="_fbed1e1e-07ee-4491-adf7-1f5546547cb8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2702.75" y="3982.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s479_csa326" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PPARG:SUMO* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <label text="PPARG/SUMO"/> <bbox w="100.0" h="120.0" x="3170.0" y="4190.0"/> <glyph class="macromolecule" id="s480_sa2529"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4. 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References_end </body> </html> </notes> <label text="IFNGR2"/> <bbox w="80.0" h="50.0" x="16095.0" y="2860.0"/> <glyph class="unit of information" id="_630344e4-567f-4cea-9fb0-5d6eeb1f6607"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16112.5" y="2855.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s709_sa1632"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNGR1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="16095.0" y="2820.0"/> <glyph class="state variable" id="_ea4bcd9b-0ccf-4f22-81ac-2b3a85e4f2bf"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16090.0" y="2839.9602"/> </glyph> <glyph class="unit of information" id="_f608648a-eaf7-4b25-a4fe-2f948f33deaf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16112.5" y="2815.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s540_csa325" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IRF4:MIR125B1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:16243976 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 ion resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR References_end </body> </html> </notes> <label text="IRF4/MIR125B1"/> <bbox w="100.0" h="120.0" x="3010.0" y="4750.0"/> <glyph class="nucleic acid feature" id="s541_sa2514"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:20729857 KDM6B ( Jmjd3) demethylates promoter region of IRF4 and upregulates its expression References_end </body> </html> </notes> <label text="IRF4"/> <bbox w="90.0" h="25.0" x="3015.0" y="4767.5"/> <glyph class="unit of information" id="_17b0d9a6-b01b-4e90-8730-784404926d10"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3050.0" y="4762.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s542_sa2515"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR125B1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: PMID:16243976 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 ion resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR References_end </body> </html> </notes> <label text="MIR125B1"/> <bbox w="90.0" h="25.0" x="3015.0" y="4797.5"/> <glyph class="unit of information" id="_28470e3b-b364-4fc8-b7a0-c43aa7feb9ac"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3045.0" y="4792.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s582_csa175" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CXCL12:CXCR4 Identifiers_end </body> </html> </notes> <label text="s582"/> <bbox w="100.0" h="120.0" x="5160.0" y="1655.0"/> <glyph class="macromolecule" id="s590_sa1182"> <notes> <html xmlns="http://www.w3.org/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:RECRUITMENT_OF_IMMUNE_CELLS MAP:MDSC MAP:NEUTROPHIL MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:PGE2 CASCADE:CXCL12 CASCADE:TLR2_4 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. PMID:22025564 PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. PMID:17035340 The secretion of HMGB1 is required for the migration of maturing dendritic cells. myeloid DC, which rapidly secrete upon maturation induction their own HMGB1, remodel their actin-based cytoskeleton, up-regulate the CCR7 and the CXCR4 chemokine receptors, and acquire the ability to migrate in response to chemokine receptor ligands. The events are apparently causally related: DC challenged with LPS in the presence of HMGB1-specific antibodies fail to up-regulate the expression of the CCR7 and CXCR4 receptors and to rearrange actin-rich structures. Moreover, DC matured in the presence of anti-HMGB1 antibodies fail to migrate in response to the CCR7 ligand CCL19 and to the CXCR4 ligand CXCL12 References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="80.0" h="50.0" x="5170.0" y="1710.0"/> <glyph class="unit of information" id="_14031d3f-11aa-476f-befa-bf5f648b2173"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5187.5" y="1705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s583_sa1183"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL12 CASCADE:PGE2 CASCADE:CXCL12 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:20644254 CXCR4, the receptor for the chemokine CXCL12 (also known as SDF-1), also plays an important role in facilitating macrophage migration in vivo. PMID:22025564 PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12 by tumor cells. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. PMID:17035340 The secretion of HMGB1 is required for the migration of maturing dendritic cells. myeloid DC, which rapidly secrete upon maturation induction their own HMGB1, remodel their actin-based cytoskeleton, up-regulate the CCR7 and the CXCR4 chemokine receptors, and acquire the ability to migrate in response to chemokine receptor ligands. The events are apparently causally related: DC challenged with LPS in the presence of HMGB1-specific antibodies fail to up-regulate the expression of the CCR7 and CXCR4 receptors and to rearrange actin-rich structures. Moreover, DC matured in the presence of anti-HMGB1 antibodies fail to migrate in response to the CCR7 ligand CCL19 and to the CXCR4 ligand CXCL12 References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="5170.0" y="1665.0"/> </glyph> </glyph> <glyph class="complex" id="s599_csa346"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:VEGFA:trVEGFR1* Identifiers_end </body> </html> </notes> <label text="s599"/> <bbox w="100.0" h="120.0" x="3780.0" y="8150.0"/> <glyph class="macromolecule" id="s602_sa2700"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:CSF2 Maps_Modules_end References_begin: PMID:21765015, PMID:22869907 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production. CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. specific inhibition of PHD3 increases VEGF production. References_end </body> </html> </notes> <label text="trVEGFR1*"/> <bbox w="80.0" h="40.0" x="3790.0" y="8160.0"/> <glyph class="unit of information" id="_7187d601-24da-40f3-b031-dae5c037cf6b"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3805.0" y="8155.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s600_sa2701"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:VEGFA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL CASCADE:VEGFA CASCADE:LACTIC CASCADE:MIF CASCADE:IL4 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:IFNAB MAP:NEUTROPHIL PMID:15573129, PMID:8837607 Vascular endothelial growth factor (VEGF) was the first tumour-derived factor shown to inhibit DC differentiation. The involvement of VEGF in tumour-induced defects in DC differentiation was indicated by in vitro experiments in which neutralizing VEGF-specific antibody abrogated the negative effect of tumour-cell-conditioned medium on the differentiation of DCs from HPCs. (VEGF) inhibit the activation of NF-B by blocking IB phosphorylation55, 101, 102, possibly through activation of STAT3 (signal transducer and activator of transcription 3). Recent data have shown that STAT3 might also bind p65 subunits of NF-B, thereby directly inhibiting NF-B activity PMID:9570538 VEGF inhibits TNF-α inducible activation of NF-κB in HPC, resulting in inhibition of DC differentiation The presence of VEGF significantly decreased the specific DNA binding of NF-kappa B as early as 30 min after induction with TNF-alpha. This was followed on days 7 to 10 by decreases in the mRNA for RelB and c-Rel, two subunits of NF-kappa B. PMID:16002046 Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. PMID:17086423 Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2 (KDR) PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis probavly via upregulation of MMP9, VEGF expression in macrophages and activates tumor invasion PMID:21372296 HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms. PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, PMID:15520864 MC-derived Ang-1 and VEGF-A promotes growth of plasmocytomas by stimulating neovascularization. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="80.0" h="40.0" x="3790.0" y="8215.0"/> </glyph> </glyph> <glyph class="complex" id="s610_csa219" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CSF2RA:CSF2RB Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:CSF2 Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits References_end </body> </html> </notes> <label text="s610"/> <bbox w="195.0" h="90.0" x="15937.5" y="5445.0"/> <glyph class="macromolecule" id="s613_sa1648"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2RB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:MACROPHAGE CASCADE:CSF2 MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL3 Maps_Modules_end References_begin: PMID:12393492, PMID:22323450 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits anf use JAK2 kinase PMID:23046136 The receptor for IL-3 comprises the cytokine-specific α subunit IL3Rα and the βc subunit (CSF2RB) ( References_end </body> </html> </notes> <label text="CSF2RB"/> <bbox w="80.0" h="50.0" x="16040.0" y="5470.0"/> <glyph class="unit of information" id="_9f579367-ea7f-4614-8d38-813260e869cd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16057.5" y="5465.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s612_sa1649"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2RA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:CSF2 Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits PMID:11306493 IL4 induces surface expression of CD116 (CSF2RA) in DC end prevents the blockade of dendritic cell differentiation induced by tumor cells. References_end </body> </html> </notes> <label text="CSF2RA"/> <bbox w="80.0" h="50.0" x="15940.0" y="5470.0"/> <glyph class="unit of information" id="_77c6403f-af17-4bef-b7c8-f97905a46e56"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15957.5" y="5465.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s632_csa112" compartmentRef="c45_ca46"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE 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="5862.0" y="3777.5"/> <glyph class="macromolecule" id="s404_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: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:405731 KEGG:3708 ATLASONC:GC_ITPR1 WIKI:ITPR1 REACTOME:405722 KEGG:3709 ATLASONC:GC_ITPR2 WIKI:ITPR2 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="5864.125" y="3823.0"/> <glyph class="unit of information" id="_8c32f103-cca0-467e-8cb0-5850d832f47f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5881.625" y="3818.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s403_sa717"> <label text="IP3"/> <bbox w="70.0" h="25.0" x="5869.125" y="3799.0"/> </glyph> </glyph> <glyph class="complex" id="s647_csa264" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IKBKG:IKK_alpha_*:IKK_beta_* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL13 CASCADE:VEGFA CASCADE:STING CASCADE:TLR2_4 CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF 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 PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation.Ser536 is phoshorylated downstream of RAGE signaling in MDSC. PMID:24766893 Cytosolic DNA induces type I IFNs through the endoplasmic reticulum membrane protein STING, which subsequently activates the transcription factors NF-κB and IRF3 through the kinases IKK and TBK1, respectively References_end </body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="12925.0" y="3028.0"/> <glyph class="macromolecule" id="s89_sa2021"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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="12933.0" y="3035.0"/> <glyph class="state variable" id="_5663ab45-f179-48a5-84b8-507b1bd86a93"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13008.0" y="3050.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3611_sa2136"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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. PMID:22435554, PMID:15485931, PMID:21217011, PMID:15199157 Agonist stimulation induces IKK2, a catalytic subunit of the IKK complex, to phosphorylate p105. These phosphorylations create a binding site for the ubiquitin E3 ligase complex SCF-bTrCP which catalyzes K48-linked polyubiquitination of p105, followed by its proteasomal degradatio. This releases TPL-2 from p105 inhibition and allows TPL-2 to access its substrate MEK References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="12935.0" y="3080.0"/> <glyph class="state variable" id="_885a3f01-fa45-4f12-a4c3-6363bad1749a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12930.0" y="3095.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3610_sa2137"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:STING CASCADE:TLR2_4 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. PMID:17237376, PMID:21807870 Alternative pathways involeved IKKa activation by NIK. This signaling is important for DC maturation and T-cell activation (). NIK signaling is required in DCs to deliver co-stimulatory signals to CD4+ T cells PMID:23086447 Alternative NFkB pathway induces via phosphorylation of IκB-specific kinase α (IKK-α) the cleavage of p100-RelB to p52-RelB, which then translocates as heterodimer into the nucleus. Both complete p100 degradation and p100 processing to p52 may occur in Dcs and expression of IKKa, the kinase determining the activity of noncanonical NF-κB pathway, gradually increased during DC differentiation with concomitant p100 processing to p52  PMID:2649237 In macrophages RELB /p52 pathway is associated with M1 polarization PMID:23422957 IKKa could regulate IRF3 activity and IRF3-dependent IFNβ and IL-12 production by DC. TAK1 (MAP3K7)-mediated IKKα/β activation is required for IRF3-dependent IFNβ expression in DC. At the same time IKKα regulates IRF3-mediated transcription downstream of IKKɛ/TBK1mediated IRF3 phosphorylation. IKKa increases the association of IRF3 with the transcriptional co-activator CBP. The increased recruitment of CBP after overexpression of IKKα was also associated with increased transcription of endogenous IFNβ mRNA. PMID:17254973 NfkB heterodiners could be also bloked by p52 precursor, protein p100. Dissosiation of p100 from the comprex reactivate NF-kB signaling NIK and IKK1 regulates the degradation of nfkb2 p100 to effect NF-κB/RelA activation. References_end </body> </html> </notes> <label text="IKKα*"/> <bbox w="80.0" h="40.0" x="12936.0" y="3125.0"/> <glyph class="state variable" id="_318350a6-530c-400e-9573-45ff3b832799"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12931.0" y="3140.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s651_csa207" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MAP3K7:TAB2:TAB3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:TNF Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1. PMID:23681101, PMID:11477091 There are three main signaling pathways could be activated downstream of TRR4/MyD88/TAK1 signaling : p38 (via MKK3 or MKK6), JNK (via MKK4 or MKK7) and NfkB ) IN DC all these signaling pathways are activated downstream of TLR4 and TLR2 signaling ) PMID:21232017, PMID:21133840 PMID:17301840, PMID:18641653, PMID:24958845, PMID:16603398, PMID:14633987 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modieed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. References_end </body> </html> </notes> <label text="s651"/> <bbox w="110.0" h="165.0" x="11455.0" y="2815.0"/> <glyph class="macromolecule" id="s3538_sa1606"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MAP3K7 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:TNF Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. PMID:21232017, PMID:21133840 PMID:17301840, PMID:18641653, PMID:24958845, PMID:16603398, PMID:14633987 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modieed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation References_end </body> </html> </notes> <label text="MAP3K7"/> <bbox w="80.0" h="40.0" x="11465.0" y="2830.0"/> </glyph> <glyph class="macromolecule" id="s645_sa1607"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAB2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:TNF Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TAB2"/> <bbox w="80.0" h="40.0" x="11465.0" y="2880.0"/> </glyph> <glyph class="macromolecule" id="s4154_sa2671"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAB3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:23681101 References_end </body> </html> </notes> <label text="TAB3"/> <bbox w="80.0" h="40.0" x="11465.0" y="2920.0"/> </glyph> </glyph> <glyph class="complex" id="s654_csa206" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD14:LY96:MYD88:TIRAP:TLR2/4* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:17704786, PMID:20547845 HMGB1 interacts with TLR4/LY96(MD2) complex and is internalized with the TLR4 complex after cell surface binding. PMID:16267105 HMGB1 interacts with TLR2. TLR2/TLR4 signaling downstream of HMGB1 acts via MYD88 pathway. PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. Transfection of dominant negative MyD88 or TIRAP inhibited almost all of the HMGB1- and LPS-induced NF-κB activation. MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="s654"/> <bbox w="198.75" h="180.0" x="15460.625" y="1315.0"/> <glyph class="macromolecule" id="s706_sa1601"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD14 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_DC MODULE:MARKERS_MDSC MODULE:MARKERS_NEUTROPHIL MODULE:MARKERS_MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 The surface markers of myeloid cells PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="CD14"/> <bbox w="80.0" h="40.0" x="15469.375" y="1375.0"/> </glyph> <glyph class="macromolecule" id="s674_sa1602"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TIRAP Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. References_end </body> </html> </notes> <label text="TIRAP"/> <bbox w="80.0" h="40.0" x="15549.375" y="1425.0"/> </glyph> <glyph class="macromolecule" id="s673_sa1603"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL18 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG CASCADE:IL15 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:23811849 HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and iactivates TLR4/MyD88 pathway in dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. PMID:17704786 DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="15469.375" y="1425.0"/> </glyph> <glyph class="macromolecule" id="s672_sa1604"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LY96 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="80.0" h="40.0" x="15469.375" y="1325.0"/> </glyph> <glyph class="macromolecule" id="s671_sa1605"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TLR2 HUGO:TLR4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:21826665 TLR4/PI3K signaling in TAN promotes motility of cancer cells References_end </body> </html> </notes> <label text="TLR2/4*"/> <bbox w="80.0" h="50.0" x="15549.375" y="1370.0"/> <glyph class="unit of information" id="_e18a2ecf-fc3b-444b-a8b7-d749ddbb1f2d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15566.875" y="1365.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s660_csa205" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD14:IRAK2:IRAK4:LY96:MYD88:TIRAP:TLR2/4* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. Transfection of dominant negative MyD88 or TIRAP inhibited almost all of the HMGB1- and LPS-induced NF-κB activation. MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 PMID:21372296 HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms. References_end </body> </html> </notes> <label text="s654"/> <bbox w="227.5" h="220.625" x="15541.25" y="1659.6875"/> <glyph class="macromolecule" id="s707_sa1594"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD14 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_DC MODULE:MARKERS_MDSC MODULE:MARKERS_NEUTROPHIL MODULE:MARKERS_MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 The surface markers of myeloid cells PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="CD14"/> <bbox w="80.0" h="40.0" x="15565.0" y="1720.0"/> </glyph> <glyph class="macromolecule" id="s682_sa1595"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IL18 Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 PMID:12682231 IL18 signaling induces IRAK4 activation (phosphorylation) and activate JNK/AP1 pathway via IRAK4 References_end </body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="15565.0" y="1810.0"/> </glyph> <glyph class="macromolecule" id="s681_sa1596"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TLR2 HUGO:TLR4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:21826665 TLR4/PI3K signaling in TAN promotes motility of cancer cells References_end </body> </html> </notes> <label text="TLR2/4*"/> <bbox w="80.0" h="50.0" x="15655.0" y="1715.0"/> <glyph class="unit of information" id="_c7df87c9-8e37-4283-b4f7-abd962ff0302"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15672.5" y="1710.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s680_sa1597"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LY96 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="80.0" h="40.0" x="15565.0" y="1670.0"/> </glyph> <glyph class="macromolecule" id="s679_sa1598"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL18 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG CASCADE:IL15 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:23811849 HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and iactivates TLR4/MyD88 pathway in dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. PMID:17704786 DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="15565.0" y="1770.0"/> </glyph> <glyph class="macromolecule" id="s678_sa1599"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TIRAP Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. References_end </body> </html> </notes> <label text="TIRAP"/> <bbox w="80.0" h="40.0" x="15655.0" y="1770.0"/> </glyph> <glyph class="macromolecule" id="s676_sa1600"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRAK2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. References_end </body> </html> </notes> <label text="IRAK2"/> <bbox w="80.0" h="40.0" x="15655.0" y="1810.0"/> </glyph> </glyph> <glyph class="complex" id="s747_csa63" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD247:FCER1G:NKp46* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A CASCADE:KLRB1 CASCADE:KIR2DL4 MAP:NATURAL_KILLER CASCADE:NKP46 References_end </body> </html> </notes> <label text="s747"/> <bbox w="200.0" h="160.0" x="11105.0" y="1320.0"/> <glyph class="macromolecule" id="s749_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:NCR1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:IL2 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="11162.5" y="1395.0"/> <glyph class="unit of information" id="_1d029850-8b64-438a-a0a0-a55356dcda53"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11180.0" y="1390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s750_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:FCER1G Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RIII CASCADE:NKP46 CASCADE:FCAR 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:15081523 FcαRI is dependent on association with the FcRγ chain for signalling and function References_end </body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="11125.0" y="1345.0"/> <glyph class="state variable" id="_3384e613-07eb-45c2-937c-49ff307be8b2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11120.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_b8a09699-a8e5-4401-bdcd-61f509e11186"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11142.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s751_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:CD247 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="11205.0" y="1345.0"/> <glyph class="state variable" id="_fea2018d-a1d8-4c78-81a2-d42f9ad8e935"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11200.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_9509c4cd-94ee-42aa-9652-d149ff5988ba"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11222.5" y="1340.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s752_csa73" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD247:FCER1G:NKp46* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRB1 CASCADE:NKG2A CASCADE:KIR2DL4 MAP:NATURAL_KILLER CASCADE:NKP46 References_end </body> </html> </notes> <label text="s747"/> <bbox w="200.0" h="160.0" x="11025.0" y="1610.0"/> <glyph class="macromolecule" id="s3534_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:CD247 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="11125.0" y="1635.0"/> <glyph class="state variable" id="_fa9756dd-67af-456b-b357-d7ef0fde62fb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11120.0" y="1655.0"/> </glyph> <glyph class="unit of information" id="_fd8f36ac-a5d3-4081-be40-1b6a719a7892"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11142.5" y="1630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s753_sa625"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:MARKERS_NK MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:IL2 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="11082.5" y="1685.0"/> <glyph class="unit of information" id="_edef37ce-b941-4db0-87b0-fdf8cb91838b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11100.0" y="1680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s755_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:FCER1G Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RIII CASCADE:NKP46 CASCADE:FCAR 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:15081523 FcαRI is dependent on association with the FcRγ chain for signalling and function References_end </body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="11045.0" y="1635.0"/> <glyph class="state variable" id="_1ba48dbc-bc6d-4282-87b7-c550e4bb0a8b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11040.0" y="1655.0"/> </glyph> <glyph class="unit of information" id="_aae1fd05-52d8-410b-ac95-6871db976d10"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11062.5" y="1630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s756_sa627"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="11125.0" y="1635.0"/> <glyph class="state variable" id="_d0c06539-580c-4206-a4ab-0e4b48dd63b6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11117.5" y="1655.0"/> </glyph> <glyph class="unit of information" id="_4ea52c9a-628a-4b69-ab30-f19d328a11b6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11142.5" y="1630.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s762_csa119" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:NKp44* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP44 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="11605.0" y="1315.0"/> <glyph class="macromolecule" id="s765_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:TYROBP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:KLRC2 CASCADE:KLRC3 CASCADE:NKP44 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="11615.0" y="1330.0"/> <glyph class="state variable" id="_d181fb27-85df-4228-b59a-dfb6511b13b7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11610.0" y="1350.0"/> </glyph> <glyph class="unit of information" id="_3f76a646-b408-42f7-8060-c69af6a45acc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11632.5" y="1325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3137_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:NCR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP44 CASCADE:IL2 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="11615.0" y="1375.0"/> <glyph class="unit of information" id="_7e97525b-0244-42c4-be69-8b5ae4129411"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11632.5" y="1370.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s766_csa121" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:NKp44* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP44 References_end </body> </html> </notes> <label text="s762"/> <bbox w="100.0" h="150.0" x="11625.0" y="1535.0"/> <glyph class="macromolecule" id="s3136_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:NCR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP44 CASCADE:IL2 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="11635.0" y="1595.0"/> <glyph class="unit of information" id="_1a0e4bd3-6e76-4d0c-a4e2-aa8e0c26ba23"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11652.5" y="1590.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s768_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:TYROBP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:KLRC2 CASCADE:KLRC3 CASCADE:NKP44 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="11635.0" y="1550.0"/> <glyph class="state variable" id="_2a9d2a3a-a4c6-4cf5-98d0-6df244797ac2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11627.5" y="1570.0"/> </glyph> <glyph class="unit of information" id="_f8d6d7e7-8c10-4e05-8b18-2602d94f1573"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11652.5" y="1545.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s771_csa71" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP10:NKG2D* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D References_end </body> </html> </notes> <label text="s771"/> <bbox w="110.0" h="140.0" x="12840.0" y="1300.0"/> <glyph class="macromolecule" id="s773_sa620"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:TGFB CASCADE:MIF CASCADE:IL15 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="12850.0" y="1365.0"/> <glyph class="unit of information" id="_1cea6e02-0a8e-430c-93bc-11b0aa017f4a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12867.5" y="1360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s774_sa621"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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, 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="12850.0" y="1315.0"/> <glyph class="state variable" id="_ca196bdd-06c0-4adf-a4e7-d94152d55dc1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12845.0" y="1335.0"/> </glyph> <glyph class="unit of information" id="_3516f0e3-4e41-47df-a820-ce80a3fcaec4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12867.5" y="1310.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s782_csa72" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP10:GRB2:NKG2D* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRB1 CASCADE:KIR2DL2 MAP:NATURAL_KILLER CASCADE:NKG2D References_end </body> </html> </notes> <label text="s771"/> <bbox w="115.0" h="190.0" x="13057.5" y="1685.0"/> <glyph class="macromolecule" id="s783_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: HUGO:KLRK1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:TGFB CASCADE:MIF CASCADE:IL15 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="13067.5" y="1800.0"/> <glyph class="unit of information" id="_1152b99c-788b-402e-81f8-a02df6c9117f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13085.0" y="1795.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s784_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: HUGO:DAP10 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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, 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="13067.5" y="1750.0"/> <glyph class="state variable" id="_26784979-5ecb-4c60-830d-fd3f2a71e7ad"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13060.0" y="1770.0"/> </glyph> <glyph class="unit of information" id="_bfb6e91b-97d9-4f3c-8a1b-7591a5d0ee66"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13085.0" y="1745.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s786_sa624"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:IL4 CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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="13065.0" y="1700.0"/> </glyph> </glyph> <glyph class="complex" id="s791_csa216" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TNF:TNFR2*:TRAF1:TRAF2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors.TNFR2 interacts with TRAF2 and TRAF1. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. PMID:24378531 TNF via TNFR2  induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TNFR2"/> <bbox w="190.0" h="120.0" x="15910.0" y="3470.0"/> <glyph class="macromolecule" id="s795_sa1636"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MAST_CELL MAP:MDSC MAP:NEUTROPHIL MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:MIF CASCADE:IL10 CASCADE:KLRG1 CASCADE:FCAR CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 CASCADE:IL15 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF CASCADE:IFNG PMID:19732719  Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, 14625680 TNF and IFNG cooperate in the activation of macrophages. PMID:18633355 TNF is pro-angiogenic facror. PMID:23510023, PMID:23170255 TRAIL, FASL and TNF provides Dendritic cell tumor killing activity.()  L10 stimulates HO1 expression via MAPK p38 stimulation. HO-1 mediates IL-10-induced suppression of TNF- production and IL-10-induced suppression of MMP9 and INOS expression PMID:22955274 SHIP inhibit MAPKp38 activation and prevent MNK1 phosphorylation by inhibiting the p38 MAPK pathway downstream of IL10. MNK1 regulates TNFa mRNA polysome assembly and upregulates TNFa translation.IL-10 Inhibits TNF Translation through SHIP1-mediated Inhibition of Mnk1 PMID:15699106, PMID:12646658 Phosphorylated STAT1 binds to TNF promoter end induces TNF expression downstream of IFNG. PMID:15099563 Mast cells produce cytokines TNF-a, TGF-b, IFN-a, IL-1a, IL-1b, IL-5, IL-6, IL-13, IL-16, IL-18 PMID:24092389 TANs from early tumors are more cytotoxic toward tumor cells and produce higher levels of TNF-α, NO, and H2O2 and, in established tumors, these functions are downregulated and TAN acquire a more protumorigenic phenotype PMID:21826665 TANs produce TNF and IL1B, probably downstream of TLR4 References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="16005.0" y="3480.0"/> </glyph> <glyph class="macromolecule" id="s3126_sa1637"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2  induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="15915.0" y="3530.0"/> <glyph class="state variable" id="_0333e45b-e610-42be-89d2-f115b824b091"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15990.0" y="3543.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s3127_sa1638"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21133840 TNFR2 interacts with TRAF2 and TRAF1. References_end </body> </html> </notes> <label text="TRAF1"/> <bbox w="80.0" h="40.0" x="15915.0" y="3480.0"/> </glyph> <glyph class="macromolecule" id="s792_sa1639"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFRSF1B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR2*"/> <bbox w="80.0" h="50.0" x="16010.0" y="3525.0"/> <glyph class="unit of information" id="_4c56c801-75d1-40ef-a534-0462676b8a04"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16027.5" y="3520.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s804_csa347" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:RBCK1:RNF31:SHARPIN Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises  SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modified RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. PMID:24958845 NFkB activation (IkBa degradation) downstream of TNF is LUBAC-dependent. References_end </body> </html> </notes> <label text="LUBAC"/> <bbox w="110.0" h="150.0" x="14920.0" y="3145.0"/> <glyph class="macromolecule" id="s4195_sa2726"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RNF31 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises  SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1. References_end </body> </html> </notes> <label text="RNF31"/> <bbox w="80.0" h="40.0" x="14940.0" y="3155.0"/> </glyph> <glyph class="macromolecule" id="s806_sa2727"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SHARPIN Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises  SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 References_end </body> </html> </notes> <label text="SHARPIN"/> <bbox w="80.0" h="40.0" x="14940.0" y="3195.0"/> </glyph> <glyph class="macromolecule" id="s4196_sa2728"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RBCK1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises  SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 References_end </body> </html> </notes> <label text="RBCK1"/> <bbox w="80.0" h="40.0" x="14940.0" y="3235.0"/> </glyph> </glyph> <glyph class="complex" id="s810_csa97" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RHOA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 References_end </body> </html> </notes> <label text="RHOA:GDP"/> <bbox w="100.0" h="120.0" x="7335.0" y="3430.0"/> <glyph class="macromolecule" id="s3132_sa684"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RHOA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR3 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:12740575 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:12194823 Rho-kinase and myosin-II control phagocytic cup formation during CR3, but not FcgammaR, phagocytosis. inhibition of the Rho --> ROK --> myosin-II pathway caused a decreased accumulation of Arp2/3 complex and F-actin around bound particles, which led to a reduction in CR-mediated phagocytic engulfment. FcgammaR-mediated phagocytosis, in contrast, was independent of Rho or ROK activity and was only dependent on myosin-II for particle internalization, not for actin cup formation. While myosins have been previously implicated in FcgammaR phagocytosis, to our knowledge, this is the first demonstration of a role for myosin-II in CR phagocytosis. References_end </body> </html> </notes> <label text="RHOA"/> <bbox w="80.0" h="40.0" x="7345.0" y="3450.0"/> </glyph> <glyph class="simple chemical" id="s3133_sa685"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="7353.75" y="3496.875"/> </glyph> </glyph> <glyph class="complex" id="s813_csa98" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RHOA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 References_end </body> </html> </notes> <label text="RHOA:GTP"/> <bbox w="100.0" h="120.0" x="7165.0" y="3430.0"/> <glyph class="macromolecule" id="s790_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:RHOA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR3 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:12740575 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:12194823 Rho-kinase and myosin-II control phagocytic cup formation during CR3, but not FcgammaR, phagocytosis. inhibition of the Rho --> ROK --> myosin-II pathway caused a decreased accumulation of Arp2/3 complex and F-actin around bound particles, which led to a reduction in CR-mediated phagocytic engulfment. FcgammaR-mediated phagocytosis, in contrast, was independent of Rho or ROK activity and was only dependent on myosin-II for particle internalization, not for actin cup formation. While myosins have been previously implicated in FcgammaR phagocytosis, to our knowledge, this is the first demonstration of a role for myosin-II in CR phagocytosis. References_end </body> </html> </notes> <label text="RHOA"/> <bbox w="80.0" h="40.0" x="7176.0" y="3440.0"/> </glyph> <glyph class="simple chemical" id="s3134_sa687"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="7180.0" y="3487.5"/> </glyph> </glyph> <glyph class="complex" id="s868_csa38" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TRIP10:WASP* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER 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="s868"/> <bbox w="105.0" h="140.0" x="8737.5" y="5780.0"/> <glyph class="macromolecule" id="s1691_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:WAS Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:KIR2DL1 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. PMID:19741094 t Cdc42 is essential for the activation of WASP and N-WASP, leading to actin assembly and phagocytic cup formation by macrophages during Fc(gamma)R-mediated phagocytosis. Cdc42 Is Required for Activation and Tyrosine Phosphorylation of WASP/N-WASP 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="WASP*"/> <bbox w="80.0" h="40.0" x="8747.5" y="5840.0"/> <glyph class="state variable" id="_fe1b5a99-30ab-4402-8f53-311cc9f0ee6c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8740.0" y="5855.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1692_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:TRIP10 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER 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="8747.5" y="5800.0"/> </glyph> </glyph> <glyph class="complex" id="s879_csa33" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ACTR2:ACTR3:ARPC1*:ARPC2:ARPC3:ARPC4:ARPC5 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9565.0" y="5465.0"/> <glyph class="macromolecule" id="s947_sa256"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9660.0" y="5480.0"/> </glyph> <glyph class="macromolecule" id="s948_sa257"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9660.0" y="5520.0"/> </glyph> <glyph class="macromolecule" id="s1693_sa259"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9660.0" y="5560.0"/> </glyph> <glyph class="macromolecule" id="s3805_sa285"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9570.0" y="5600.0"/> </glyph> <glyph class="macromolecule" id="s3804_sa286"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9570.0" y="5560.0"/> </glyph> <glyph class="macromolecule" id="s3803_sa287"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9570.0" y="5520.0"/> </glyph> <glyph class="macromolecule" id="s3802_sa288"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9570.0" y="5480.0"/> </glyph> </glyph> <glyph class="complex" id="s894_csa39" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ACTR2:ACTR3:ARPC1*:ARPC2:ARPC3:ARPC4:ARPC5:WASP* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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. PMID:10783245; PMID:12194823 Arp2/3 complex regulates phagocytosis mediated by FcγR (Fc_gamma_RII) or CR3. References_end </body> </html> </notes> <label text="Arp2/3"/> <bbox w="220.0" h="205.0" x="9160.0" y="6047.5"/> <glyph class="macromolecule" id="s1690_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:ACTR2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9170.0" y="6140.0"/> </glyph> <glyph class="macromolecule" id="s895_sa254"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9170.0" y="6182.5"/> </glyph> <glyph class="macromolecule" id="s1689_sa255"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9170.0" y="6102.5"/> </glyph> <glyph class="macromolecule" id="s1688_sa258"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9170.0" y="6062.5"/> </glyph> <glyph class="macromolecule" id="s3801_sa289"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9270.0" y="6062.5"/> </glyph> <glyph class="macromolecule" id="s3800_sa290"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9270.0" y="6110.0"/> </glyph> <glyph class="macromolecule" id="s901_sa291"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 CASCADE:Fc_gamma_RII 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="9270.0" y="6142.5"/> </glyph> <glyph class="macromolecule" id="s1687_sa292"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:KIR2DL1 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. PMID:19741094 t Cdc42 is essential for the activation of WASP and N-WASP, leading to actin assembly and phagocytic cup formation by macrophages during Fc(gamma)R-mediated phagocytosis. Cdc42 Is Required for Activation and Tyrosine Phosphorylation of WASP/N-WASP 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="WASP*"/> <bbox w="80.0" h="40.0" x="9270.0" y="6182.5"/> <glyph class="state variable" id="_57eefe23-5024-41c9-9cfb-dfdf5ad0d1a3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9262.5" y="6197.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s902_csa348" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CBP*:RELA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:16007092 GSK3B induces RELA (p65) interaction with CBP and activates downstream NF-kB signaling end expression of proinflammatory cytokines. References_end </body> </html> </notes> <label text="s902"/> <bbox w="100.0" h="150.0" x="13445.0" y="3885.0"/> <glyph class="macromolecule" id="s906_sa2743"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF CASCADE:IFNG Maps_Modules_end References_begin: 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="80.125" h="49.625" x="13454.9375" y="3890.1875"/> </glyph> <glyph class="macromolecule" id="s905_sa2744"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CREBBP Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:19879327 STAT1 is acetylated by CBP at the lysine residues K410 and K413. PMID:16007092 GSK3B induces RELA (p65) interaction with CBP and activates downstream NF-kB signaling end expression of proinflammatory cytokines. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator in macrophages. References_end </body> </html> </notes> <label text="CBP*"/> <bbox w="80.0" h="40.0" x="13455.0" y="3945.0"/> </glyph> </glyph> <glyph class="complex" id="s912_csa46" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:WASP*:WIPF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DL1 PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor References_end </body> </html> </notes> <label text="WASP*:WIPF1"/> <bbox w="110.0" h="140.0" x="10075.0" y="6107.5"/> <glyph class="macromolecule" id="s913_sa307"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DL1 PMID:16606694 WIPF1 forms complex with WASP. WIPF1 (WIP) phosphorylation in NK cells is mediated by PRKCQ (PKC theta) PMID:17890224 in macrophages WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation. References_end </body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="10095.0" y="6177.5"/> <glyph class="state variable" id="_4efa833e-04eb-4014-8655-b46507086365"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10090.0" y="6192.4683"/> </glyph> </glyph> <glyph class="macromolecule" id="s914_sa308"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:KIR2DL1 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. PMID:19741094 t Cdc42 is essential for the activation of WASP and N-WASP, leading to actin assembly and phagocytic cup formation by macrophages during Fc(gamma)R-mediated phagocytosis. Cdc42 Is Required for Activation and Tyrosine Phosphorylation of WASP/N-WASP 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="WASP*"/> <bbox w="80.0" h="40.0" x="10095.0" y="6117.5"/> <glyph class="state variable" id="_d01d0046-4bc4-4de7-a4de-b9e084d6265f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10087.5" y="6132.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s920_csa47" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:WASP*:WIPF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:KIR2DL1 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. 17890224 in macrophages WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation. References_end </body> </html> </notes> <label text="WASP*:WIPF1"/> <bbox w="110.0" h="140.0" x="10075.0" y="6380.0"/> <glyph class="macromolecule" id="s921_sa309"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:KIR2DL1 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. PMID:19741094 t Cdc42 is essential for the activation of WASP and N-WASP, leading to actin assembly and phagocytic cup formation by macrophages during Fc(gamma)R-mediated phagocytosis. Cdc42 Is Required for Activation and Tyrosine Phosphorylation of WASP/N-WASP 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="WASP*"/> <bbox w="80.0" h="40.0" x="10095.0" y="6390.0"/> <glyph class="state variable" id="_ab21590e-4b5a-4591-8b95-445dc97e0d46"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10087.5" y="6405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s922_sa310"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DL1 PMID:16606694 WIPF1 forms complex with WASP. WIPF1 (WIP) phosphorylation in NK cells is mediated by PRKCQ (PKC theta) PMID:17890224 in macrophages WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation. References_end </body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="10090.0" y="6450.0"/> <glyph class="state variable" id="_d0914299-dd09-457a-a56d-2303112ca95d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10082.5" y="6464.9683"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s926_csa59" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CLEC2B:NKp80* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKP80 MAP:NATURAL_KILLER 20663776, 17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. 20663776 Blocking of CLEC2B (AICL) partially inhibits NK cell degranulation (LAMP1/CD107a presentation). 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="13292.5" y="1470.0"/> <glyph class="macromolecule" id="s928_sa593"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CLEC2B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKP80 MAP:NATURAL_KILLER PMID:20663776, 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="13307.5" y="1480.0"/> </glyph> <glyph class="macromolecule multimer" id="s934_sa594"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRF1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKP80 MAP:NATURAL_KILLER 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. PMID:21149606 Nkp80 signaling induces marked IFNG production References_end </body> </html> </notes> <label text="NKp80*"/> <bbox w="86.0" h="56.0" x="13304.5" y="1522.0"/> <glyph class="unit of information" id="_2a029ac9-bf7f-423e-a0d9-c272ab078c28"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="13337.5" y="1517.0"/> </glyph> <glyph class="state variable" id="_55528539-2d8d-4ebc-a159-fd570f4015b0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13299.5" y="1545.0"/> </glyph> <glyph class="unit of information" id="_de131cdf-6236-4165-a6ed-b990e21fa329"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13325.0" y="1517.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s935_csa67" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CLEC2B:NKp80* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKP80 MAP:NATURAL_KILLER 20663776, 17057721 C-type lectin (AICL) is a unique KLRF1 ligand expressed on tumor cell lines of hematopoietic and non-hematopoietic origins. 20663776 Blocking of CLEC2B (AICL) partially inhibits NK cell degranulation (LAMP1/CD107a presentation). 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="13280.0" y="1690.0"/> <glyph class="macromolecule" id="s936_sa611"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKP80 MAP:NATURAL_KILLER PMID:20663776, 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="13295.0" y="1770.0"/> </glyph> <glyph class="macromolecule multimer" id="s937_sa612"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRF1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKP80 MAP:NATURAL_KILLER 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. PMID:21149606 Nkp80 signaling induces marked IFNG production References_end </body> </html> </notes> <label text="NKp80*"/> <bbox w="86.0" h="56.0" x="13292.0" y="1712.0"/> <glyph class="unit of information" id="_8428a8fc-4dee-46ad-8cf8-ce1336a699bd"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="13325.0" y="1707.0"/> </glyph> <glyph class="state variable" id="_13fc1115-731b-4df4-b23f-6a55a2c4bae1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13284.5" y="1735.0"/> </glyph> <glyph class="unit of information" id="_1d3ea74f-0e95-4352-98eb-9462ae41ba7d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13312.5" y="1707.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s978_csa334" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PKA*:PKA_R* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s978"/> <bbox w="100.0" h="140.0" x="4150.0" y="3610.0"/> <glyph class="macromolecule" id="s981_sa2564"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKACA HGNC:9380 ENTREZ:5566 UNIPROT:P17612 GENECARDS:PRKACA HUGO:PRKACB HGNC:9381 ENTREZ:5567 UNIPROT:P22694 GENECARDS:PRKACB HUGO:PRKACG HGNC:9382 ENTREZ:5568 UNIPROT:P22612 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: REACTOME:57845 KEGG:5566 ATLASONC:GC_PRKACA WIKI:PRKACA REACTOME:57847 KEGG:5567 ATLASONC:GC_PRKACB WIKI:PRKACB PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway PMID:10925299 IL13 activates Arginase activity downstream of cAMP/PKA References_end </body> </html> </notes> <label text="PKA*"/> <bbox w="80.0" h="40.0" x="4160.0" y="3680.0"/> </glyph> <glyph class="macromolecule" id="s979_sa2565"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKAB1 HGNC:9378 ENTREZ:5564 UNIPROT:Q9Y478 GENECARDS:PRKAB1 REACTOME:49384 KEGG:5564 ATLASONC:PRKAB1ID44100ch12q24 WIKI:PRKAB1 HUGO:PRKAB2 HGNC:9379 ENTREZ:5565 UNIPROT:O43741 GENECARDS:PRKAB2 REACTOME:49386 ATLASONC:GC_PRKAB2 WIKI:PRKAB2 HUGO:PRKAG1 HGNC:9385 ENTREZ:5571 UNIPROT:P54619 GENECARDS:PRKAG1 REACTOME:49388 KEGG:5571 ATLASONC:GC_PRKAG1 WIKI:PRKAG1 HUGO:PRKAG2 HGNC:9386 ENTREZ:51422 UNIPROT:Q9UGJ0 GENECARDS:PRKAG2 REACTOME:49390 KEGG:51422 ATLASONC:GC_PRKAG2 WIKI:PRKAG2 HUGO:PRKAG3 HGNC:9387 ENTREZ:53632 UNIPROT:Q9UGI9 GENECARDS:PRKAG3 REACTOME:49392 KEGG:53632 ATLASONC:GC_PRKAG3 WIKI:PRKAG3 HUGO:PRKAR1A HGNC:9388 ENTREZ:5573 UNIPROT:P10644 GENECARDS:PRKAR1A REACTOME:57837 KEGG:5573 ATLASONC:PRKAR1AID387 WIKI:PRKAR1A HUGO:PRKAR1B HGNC:9390 ENTREZ:5575 UNIPROT:P31321 GENECARDS:PRKAR1B REACTOME:57839 KEGG:5575 ATLASONC:GC_PRKAR1B WIKI:PRKAR1B HUGO:PRKAR2A HGNC:9391 ENTREZ:5576 UNIPROT:P13861 GENECARDS:PRKAR2A REACTOME:57841 KEGG:5576 ATLASONC:GC_PRKAR2A WIKI:PRKAR2A HUGO:PRKAR2B HGNC:9392 ENTREZ:5577 UNIPROT:P31323 GENECARDS:PRKAR2B REACTOME:57843 KEGG:5577 ATLASONC:GC_PRKAR2B WIKI:PRKAR2B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway References_end </body> </html> </notes> <label text="PKA_R*"/> <bbox w="80.0" h="40.0" x="4160.0" y="3630.0"/> </glyph> </glyph> <glyph class="complex" id="s987_csa336" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PKA_R*:cAMP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MAP:MACROPHAGE Maps_Modules_end </body> </html> </notes> <label text="s978"/> <bbox w="105.0" h="119.0" x="4587.5" y="3595.5"/> <glyph class="simple chemical" id="s988_sa2569"> <notes> <html xmlns="http://www.w3.org/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:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. </body> </html> </notes> <label text="cAMP"/> <bbox w="70.0" h="25.0" x="4605.0" y="3612.5"/> </glyph> <glyph class="macromolecule" id="s989_sa2570"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKAB1 HGNC:9378 ENTREZ:5564 UNIPROT:Q9Y478 GENECARDS:PRKAB1 REACTOME:49384 KEGG:5564 ATLASONC:PRKAB1ID44100ch12q24 WIKI:PRKAB1 HUGO:PRKAB2 HGNC:9379 ENTREZ:5565 UNIPROT:O43741 GENECARDS:PRKAB2 REACTOME:49386 ATLASONC:GC_PRKAB2 WIKI:PRKAB2 HUGO:PRKAG1 HGNC:9385 ENTREZ:5571 UNIPROT:P54619 GENECARDS:PRKAG1 REACTOME:49388 KEGG:5571 ATLASONC:GC_PRKAG1 WIKI:PRKAG1 HUGO:PRKAG2 HGNC:9386 ENTREZ:51422 UNIPROT:Q9UGJ0 GENECARDS:PRKAG2 REACTOME:49390 KEGG:51422 ATLASONC:GC_PRKAG2 WIKI:PRKAG2 HUGO:PRKAG3 HGNC:9387 ENTREZ:53632 UNIPROT:Q9UGI9 GENECARDS:PRKAG3 REACTOME:49392 KEGG:53632 ATLASONC:GC_PRKAG3 WIKI:PRKAG3 HUGO:PRKAR1A HGNC:9388 ENTREZ:5573 UNIPROT:P10644 GENECARDS:PRKAR1A REACTOME:57837 KEGG:5573 ATLASONC:PRKAR1AID387 WIKI:PRKAR1A HUGO:PRKAR1B HGNC:9390 ENTREZ:5575 UNIPROT:P31321 GENECARDS:PRKAR1B REACTOME:57839 KEGG:5575 ATLASONC:GC_PRKAR1B WIKI:PRKAR1B HUGO:PRKAR2A HGNC:9391 ENTREZ:5576 UNIPROT:P13861 GENECARDS:PRKAR2A REACTOME:57841 KEGG:5576 ATLASONC:GC_PRKAR2A WIKI:PRKAR2A HUGO:PRKAR2B HGNC:9392 ENTREZ:5577 UNIPROT:P31323 GENECARDS:PRKAR2B REACTOME:57843 KEGG:5577 ATLASONC:GC_PRKAR2B WIKI:PRKAR2B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway References_end </body> </html> </notes> <label text="PKA_R*"/> <bbox w="80.0" h="40.0" x="4600.0" y="3645.0"/> </glyph> </glyph> <glyph class="complex" id="s990_csa103" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD11a*:CD18* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:LFA1 CASCADE:NKG2D 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="8957.5" y="1390.0"/> <glyph class="macromolecule" id="s992_sa696"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR4 CASCADE:CR3 CASCADE:LFA1 CASCADE:IFNG MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:24343663, PMID:9712030, PMID:10591186 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="8967.5" y="1395.0"/> <glyph class="unit of information" id="_8b57cb2c-cd35-4c0e-be5e-4a831972432c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8985.0" y="1390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s993_sa697"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:LFA1 MAP:NATURAL_KILLER PMID:10591186, PMID:24440149 LFA1 physically associates with DNAM1 in NK cells. Phosphorylated by PKC S329 probably plays a critical role in this association. References_end </body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="8972.5" y="1455.0"/> <glyph class="unit of information" id="_87565621-6020-4662-8a37-460208b149f1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8990.0" y="1450.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s994_csa111" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD11a*:CD18*:DNAM1* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:LFA1 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="110.0" h="187.5" x="9247.5" y="1396.25"/> <glyph class="macromolecule" id="s2771_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:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR4 CASCADE:CR3 CASCADE:LFA1 CASCADE:IFNG MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:24343663, PMID:9712030, PMID:10591186 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="9267.5" y="1418.75"/> <glyph class="unit of information" id="_e86f3f70-1cf4-475f-803a-2daad7cd4d9e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9285.0" y="1413.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s2772_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:ITGAL Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:LFA1 MAP:NATURAL_KILLER PMID:10591186, PMID:24440149 LFA1 physically associates with DNAM1 in NK cells. Phosphorylated by PKC S329 probably plays a critical role in this association. References_end </body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="9272.5" y="1471.25"/> <glyph class="unit of information" id="_719b924c-c377-4575-950e-ca3401064a4a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9290.0" y="1466.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s999_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:CD226 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:LFA1 MAP:NATURAL_KILLER 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="9267.5" y="1511.25"/> <glyph class="state variable" id="_4ed7580e-e44c-41a5-8003-1a55604557dd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9262.5" y="1513.4545"/> </glyph> <glyph class="state variable" id="_c6d235db-7e53-4021-abca-660400fdd2a3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9260.0" y="1539.804"/> </glyph> <glyph class="unit of information" id="_1bc01d77-bf9a-47ca-83db-6a1c859cdc9c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9285.0" y="1506.25"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1000_csa116" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD11a*:CD18*:DNAM1* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:LFA1 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="106.25" h="195.625" x="9269.375" y="1652.1875"/> <glyph class="macromolecule" id="s1001_sa679"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR4 CASCADE:CR3 CASCADE:LFA1 CASCADE:IFNG MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:24343663, PMID:9712030, PMID:10591186 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="9279.375" y="1667.1875"/> <glyph class="unit of information" id="_5b39f079-6240-4567-9c87-66c98c619c66"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9296.875" y="1662.1875"/> </glyph> </glyph> <glyph class="macromolecule" id="s3718_sa728"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:LFA1 MAP:NATURAL_KILLER PMID:10591186, PMID:24440149 LFA1 physically associates with DNAM1 in NK cells. Phosphorylated by PKC S329 probably plays a critical role in this association. References_end </body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="9284.375" y="1717.1875"/> <glyph class="unit of information" id="_9572864c-d700-4f81-87d7-155e8d34f9bf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9301.875" y="1712.1875"/> </glyph> </glyph> <glyph class="macromolecule" id="s1003_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:CD226 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:LFA1 MAP:NATURAL_KILLER 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="9279.375" y="1757.1875"/> <glyph class="state variable" id="_2231cba9-f3f5-4386-a029-e39e1727c27c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9271.875" y="1759.392"/> </glyph> <glyph class="state variable" id="_ced878ad-e2ab-4c08-8811-f56c7b65f6b3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9271.875" y="1785.7415"/> </glyph> <glyph class="unit of information" id="_c88e6385-bc53-496c-9caa-9aa2452d3e10"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9296.875" y="1752.1875"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1054_csa168" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RAC1_2* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end </body> </html> </notes> <label text="s1054"/> <bbox w="100.0" h="120.0" x="5853.5938" y="6235.9375"/> <glyph class="simple chemical" id="s1055_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> CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="5868.5938" y="6303.4375"/> </glyph> <glyph class="macromolecule" id="s1051_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:RAC1 HUGO:RAC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. 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. PMID:14697347, PMID: 11146654 Integrin αvβ5 regulates phagocytosis via CRK /DOCK1 (DOCK180) /RAC1 pathway downstream of. Integrin αvβ5 activation results in recruitment of the p130cas–CrkII–Dock180 complex and RAC1 activation. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="5863.5938" y="6255.9375"/> </glyph> </glyph> <glyph class="complex" id="s1081_csa58" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD247:Fc_gamma_RIII* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="10310.0" y="1320.0"/> <glyph class="macromolecule" id="s1556_sa591"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD247 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="10320.0" y="1325.0"/> <glyph class="state variable" id="_d6da1a75-70af-48b1-b346-8dfe5ac9e974"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10315.0" y="1345.0"/> </glyph> <glyph class="unit of information" id="_48300a7e-19bd-49ab-a4ce-64cc2716de61"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10337.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1557_sa592"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:MARKERS_NK MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS MODULE:MARKERS_MDSC Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MAST_CELL MAP:NEUTROPHIL CASCADE:Fc_gamma_RIII http://www.biolegend.com/cell_markers PMID:24445665 Review 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 PMID:2139103 Fc gamma RI and Fc gamma RII on whichever cells they were expressed were capable of phagocytosing anti-Fc gamma R mAb-coated erythrocytes. Furthermore, Fc gamma RIII on mononuclear phagocytes, which appears to be a conventional integral membrane protein that spans the lipid bilayer, was capable of phagocytosing anti-Fc gamma RIII-coated erythrocytes References_end </body> </html> </notes> <label text="FcγRIII*"/> <bbox w="80.0" h="50.0" x="10321.0" y="1375.0"/> <glyph class="unit of information" id="_df154cc0-4467-4b36-b9dd-26b56f4090ae"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10338.5" y="1370.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1107_csa252" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL15RA:IL2RB:IL2RG Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 PMID:16815076 IL-15 receptor complex contains IL15RA, IL2RG, IL2RB subunits. References_end </body> </html> </notes> <label text="s1107"/> <bbox w="116.25" h="217.5" x="16001.875" y="3896.25"/> <glyph class="macromolecule" id="s1109_sa1895"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL 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. References_end </body> </html> </notes> <label text="IL15RA"/> <bbox w="80.0" h="50.0" x="16018.125" y="4031.25"/> <glyph class="unit of information" id="_1c4132dc-8cdd-4bb3-93cb-e48d893a5834"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16035.625" y="4026.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s1110_sa1896"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL2 PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. PMID:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) References_end </body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="16018.125" y="3971.25"/> <glyph class="state variable" id="_528bc1ca-d57d-40ed-826c-ea05957afb63"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16013.125" y="3991.25"/> </glyph> <glyph class="unit of information" id="_24eb15a6-497d-4aab-8b22-9d7a1a7a1e42"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16035.625" y="3966.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s1111_sa1897"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <bbox w="80.0" h="50.0" x="16014.375" y="3913.75"/> <glyph class="unit of information" id="_8031c71f-cb9d-40da-98d0-16234ebf27e4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16031.875" y="3908.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1108_csa247" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL15:IL15RA:IL2RB:IL2RG:JAK1:JAK3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 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. References_end </body> </html> </notes> <label text="s1107"/> <bbox w="195.0" h="180.0" x="15742.5" y="3895.0"/> <glyph class="macromolecule" id="s1106_sa1872"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <bbox w="80.0" h="50.0" x="15850.0" y="3910.0"/> <glyph class="unit of information" id="_642bda18-fee2-4e9d-9e2e-b1a28c294f97"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15867.5" y="3905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1105_sa1873"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL2 PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. PMID:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) References_end </body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="15850.0" y="3970.0"/> <glyph class="state variable" id="_58ead71a-cd9a-4aea-98a8-b887c3b74cac"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15842.5" y="3990.0"/> </glyph> <glyph class="unit of information" id="_ed9ef9b6-cc92-4574-b5aa-989dc20a5023"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15867.5" y="3965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1104_sa1874"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL 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. References_end </body> </html> </notes> <label text="IL15RA"/> <bbox w="80.0" h="50.0" x="15750.0" y="3970.0"/> <glyph class="unit of information" id="_c8a790df-f2ef-4be9-b41d-b5fc7a7601ff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15767.5" y="3965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4163_sa1875"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:IFNAB CASCADE:IL15 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 tumoricidal activity of NK cells. PMID:14607946 DCs activate resting NK cells by expressing MHC class I-related chain A and B (MICA/B), ligands for NKG2D, in response to IFN-alpha and IL15. IL-15- and type I IFN-mediated induction of MICA/B in healthy donors is completely inhibited when DCs are incubated in the presence of anti-IFN-alpha/betaR or anti-IL-15Ralpha, respectively, suggesting interdependent roles of these cytokines in MICA/B expression. Indeed, DCs produced IL-15 in response to type I IFN, whereas they directly produced IFN-beta, in response to IL-15, which was followed by the production of IFN-alpha. PMID:25582338 mIL-15 DCs secreted markedly greater amounts of proinflammatory cytokines, including IL-1α, IL-1β, IL-6, TNFα, TNFβ and IFN-γ, compared with mIL-4 DCs, suggesting that mIL-15 DCs are more proinflammatory than mIL-4 DCs. References_end </body> </html> </notes> <label text="IL15"/> <bbox w="80.0" h="40.0" x="15750.0" y="3915.0"/> </glyph> <glyph class="macromolecule" id="s2094_sa1877"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:JAK1 Identifiers_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 CASCADE:IFNAB ‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:7512720, PMID:7521688 Jak1 and Jak2 are activated by the G-CSFR References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="15755.0" y="4020.0"/> <glyph class="state variable" id="_6d5b82fc-270e-4ebb-908f-fa8211466e70"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15750.0" y="4035.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4815_sa1902"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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 ------ Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 Maps_Modules_end </body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="15845.0" y="4020.0"/> </glyph> </glyph> <glyph class="complex" id="s1115_csa96" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PDPK1:PIP3* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNG CASCADE:IL4 MAP:MACROPHAGE References_end </body> </html> </notes> <label text="s1115"/> <bbox w="100.0" h="120.0" x="8840.0" y="3590.0"/> <glyph class="macromolecule" id="s1116_sa682"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PDK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:IL4 PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with p85 subunit of PI3K and Grb2 and activates downstrean PI3K signaling ( phosphorylation of Akt on Ser473) 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="8850.0" y="3600.0"/> </glyph> <glyph class="simple chemical" id="s3588_sa2103"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:NATURAL_KILLER 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. </body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="8855.0" y="3657.5"/> </glyph> </glyph> <glyph class="complex" id="s1133_csa85" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GRB2:SHC1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MAST_CELL CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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. PMID:19909365 MAST cells References_end </body> </html> </notes> <label text="s1133"/> <bbox w="100.0" h="120.0" x="9360.0" y="3105.0"/> <glyph class="macromolecule" id="s1679_sa657"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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="9372.5" y="3115.0"/> <glyph class="state variable" id="_ace5ee78-87b6-415f-bb1e-d360a7aaf692"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9365.0" y="3130.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1134_sa658"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:IL4 CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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="9373.5" y="3157.0"/> </glyph> </glyph> <glyph class="complex" id="s1172_csa106" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TSC1:TSC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL15 CASCADE:CSF2 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="8860.0" y="3880.0"/> <glyph class="macromolecule" id="s1173_sa702"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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="8870.0" y="3900.0"/> </glyph> <glyph class="macromolecule" id="s1174_sa703"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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="8870.0" y="3950.0"/> <glyph class="state variable" id="_37ce2dfc-6d92-4bfb-aecf-8b3124b9f625"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8865.0" y="3965.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1176_csa110" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RHEB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:IL15 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="s1176"/> <bbox w="100.0" h="120.0" x="8730.0" y="4250.0"/> <glyph class="macromolecule" id="s1177_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:HREB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER 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="RHEB"/> <bbox w="80.0" h="40.0" x="8740.0" y="4270.0"/> </glyph> <glyph class="simple chemical" id="s1179_sa712"> <label text="GDP"/> <bbox w="70.0" h="25.0" x="8745.0" y="4317.5"/> </glyph> </glyph> <glyph class="complex" id="s1178_csa109" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RHEB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:CSF2 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="s1178"/> <bbox w="100.0" h="120.0" x="8490.0" y="4250.0"/> <glyph class="macromolecule" id="s1175_sa709"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HREB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER 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="RHEB"/> <bbox w="80.0" h="40.0" x="8500.0" y="4260.0"/> </glyph> <glyph class="simple chemical" id="s1180_sa710"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="8505.0" y="4317.5"/> </glyph> </glyph> <glyph class="complex" id="s1185_csa108" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TSC1:TSC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL15 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="9110.0" y="3880.0"/> <glyph class="macromolecule" id="s1186_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:TSC1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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="9120.0" y="3890.0"/> </glyph> <glyph class="macromolecule" id="s1187_sa708"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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="9120.0" y="3940.0"/> <glyph class="state variable" id="_0dae12ed-c478-4c02-a169-37a44855dcd1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9112.5" y="3955.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1225_csa257" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL12RB1:IL12RB2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="100.0" h="170.625" x="15980.0" y="3669.6875"/> <glyph class="macromolecule" id="s1709_sa1943"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL12 CASCADE:IL2 MAP:NATURAL_KILLER 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:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 References_end </body> </html> </notes> <label text="IL12RB1"/> <bbox w="80.0" h="50.0" x="15990.0" y="3694.0625"/> <glyph class="unit of information" id="_8c2f67f6-5b2c-48fa-9764-a14fea2b867e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16007.5" y="3689.0625"/> </glyph> </glyph> <glyph class="macromolecule" id="s1230_sa1944"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL12 CASCADE:IL2 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:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 References_end </body> </html> </notes> <label text="IL12RB2"/> <bbox w="80.0" h="50.0" x="15990.0" y="3764.0625"/> <glyph class="unit of information" id="_3122c362-47c5-4a0d-96b6-3439e2dc1b81"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16007.5" y="3759.0625"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1232_csa258" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL12*:IL12RB1:IL12RB2:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL12 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1225"/> <bbox w="215.0" h="177.5" x="15572.5" y="3676.25"/> <glyph class="macromolecule" id="s1233_sa1945"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL12 CASCADE:IL2 MAP:NATURAL_KILLER 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:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 References_end </body> </html> </notes> <label text="IL12RB1"/> <bbox w="80.0" h="50.0" x="15592.5" y="3736.25"/> <glyph class="unit of information" id="_3b6b4edd-5c86-45f7-b826-2878c77d991b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15610.0" y="3731.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s1234_sa1946"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL12 CASCADE:IL2 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:10807786 Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4 References_end </body> </html> </notes> <label text="IL12RB2"/> <bbox w="80.0" h="50.0" x="15682.5" y="3736.25"/> <glyph class="unit of information" id="_d9981738-7d4e-4a6a-a942-41fc13f6fae0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15700.0" y="3731.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s1231_sa1947"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:TLR2_4 CASCADE:IL12 CASCADE:CSF2 CASCADE:IL4 PMID:12244147, PMID:24204259 IL4 via IL-4R type I JAK3 and STAT6 (but not IL13) upregulates production of IL12p70 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: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 PMID:21042762 Inhibition of TGF-ß signalinginduced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner via SMADs. NK cells stimulated by IL12 induces IL10 production. References_end </body> </html> </notes> <label text="IL12*"/> <bbox w="80.0" h="40.0" x="15592.5" y="3686.25"/> </glyph> <glyph class="macromolecule" id="s4127_sa2642"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 References_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:IL12 CASCADE:IFNAB PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="15690.0" y="3795.0"/> <glyph class="state variable" id="_c563e43a-345a-4cfa-b472-2602859e5014"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15682.5" y="3810.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4128_sa2643"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:CSF3 CASCADE:CSF2 CASCADE:IL12 Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="15590.0" y="3795.0"/> <glyph class="state variable" id="_643b7deb-c70a-4d93-80a8-e2ce62d51ce0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15582.5" y="3810.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1263_csa232" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL18:IL18R1:IL18RAP:IRAK4:MYD88 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS 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="s1260"/> <bbox w="187.5" h="172.5" x="15651.25" y="2133.75"/> <glyph class="macromolecule" id="s3159_sa1704"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL18 CASCADE:IL15 CASCADE:IL21 MAP:DENDRITIC_CELL CASCADE:IFNG 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="15658.75" y="2191.25"/> <glyph class="unit of information" id="_dc614484-4e6e-4005-8ffa-e592ddf43b40"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15676.25" y="2186.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s3160_sa1705"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL18 CASCADE:IL15 CASCADE:IL21 CASCADE:IFNG 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="15748.75" y="2191.25"/> <glyph class="unit of information" id="_eafcacc4-ac07-4e3d-b8f4-0048b85dd748"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15766.25" y="2186.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s3161_sa1706"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MAST_CELL CASCADE:IL18 CASCADE:TLR2_4 CASCADE:IL4 CASCADE:IL13 PMID:9469432 IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells PMID:10679398 The role of IL-18 in innate immunity. PMID:15802534 Exposure to HMGB1 triggers DCs to produce pro-IL-1β, and pro-IL18 PMID:14504095, PMID:14662834 IL-18 induces chemotaxis of pDC. PMID:14662834 IL-18 had a direct migratory effect on MoDC as indicated by induction of filamentous actin polymerization and migration in Boyden chamber experiments (MoDC migrated toward an IL-18 gradient in Boyden chamber assays). In epidermal DC, IL-18 was also able to induce filamentous actin polymerization. Therefore,IL-18 might represent a novel mechanism to recruit DC to areas of inflammation. IL-18 up-regulated most strikingly the surface expression of CD54 (ICAM1) and induces F-actin polymerization PMID:11592085 ICAM-1 regulates the migration of dendritic cells into regional lymph nodes PMID:15099563 Mast cells produce cytokines TNF-a, TGF-b, IFN-a, IL-1a, IL-1b, IL-5, IL-6, IL-13, IL-16, IL-18 References_end </body> </html> </notes> <label text="IL18"/> <bbox w="80.0" h="40.0" x="15658.75" y="2146.25"/> </glyph> <glyph class="macromolecule" id="s3162_sa1707"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL18 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG CASCADE:IL15 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:23811849 HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and iactivates TLR4/MyD88 pathway in dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. PMID:17704786 DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="15658.75" y="2246.25"/> </glyph> <glyph class="macromolecule" id="s4158_sa2677"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:IRAK4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IL18 Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 PMID:12682231 IL18 signaling induces IRAK4 activation (phosphorylation) and activate JNK/AP1 pathway via IRAK4 References_end </body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="15745.0" y="2250.0"/> </glyph> </glyph> <glyph class="complex" id="s1282_csa224" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IFNAR1:IFNAR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB 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="110.0" h="147.5" x="16155.0" y="2480.0"/> <glyph class="macromolecule" id="s1297_sa1679"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB 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:21930769, PMID:21930765 Dcs dependent tumor rejection is regulated via I IFN receptor. DCs lacking IFNAR1 display defects in antigen cross-presentation to CD8(+) T cells. References_end </body> </html> </notes> <label text="IFNAR1"/> <bbox w="80.0" h="50.0" x="16165.0" y="2482.5"/> <glyph class="unit of information" id="_1e0829b9-9440-478a-9dfc-0df2e99ef557"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16182.5" y="2477.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1298_sa1680"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNAR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB 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="16165.0" y="2542.5"/> <glyph class="unit of information" id="_8a046d34-b2e8-4199-9ffe-126181f3d843"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16182.5" y="2537.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1300_csa226" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IFNAR1:IFNAR2:JAK1:TYK2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB 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:21930769, PMID:21930765, PMID:11964292, PMID:11698286, PMID: 11207245 I IFN receptor signaling regulates antigen cross-presentation to CD8(+) T cells. (), probably via upregulation of CD80, CD86, CD40, CD83 and MHC class II and CD11c, PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="s1282"/> <bbox w="202.5" h="130.0" x="15833.75" y="2535.0"/> <glyph class="macromolecule" id="s1301_sa1684"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNAR1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB 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:21930769, PMID:21930765 Dcs dependent tumor rejection is regulated via I IFN receptor. DCs lacking IFNAR1 display defects in antigen cross-presentation to CD8(+) T cells. References_end </body> </html> </notes> <label text="IFNAR1"/> <bbox w="80.0" h="50.0" x="15843.75" y="2550.0"/> <glyph class="unit of information" id="_f647a382-d808-4a32-8d71-169db8fed8ec"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15861.25" y="2545.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1302_sa1685"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNAR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB 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="15843.75" y="2600.0"/> <glyph class="unit of information" id="_ad657472-6c74-47de-a311-5827481c86d4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15861.25" y="2595.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4119_sa2640"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:JAK1 Identifiers_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 CASCADE:IFNAB ‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:7512720, PMID:7521688 Jak1 and Jak2 are activated by the G-CSFR References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="15931.25" y="2553.75"/> <glyph class="state variable" id="_e6279021-6888-470d-87b8-61b6f0e19549"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15926.25" y="2568.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s4120_sa2641"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 References_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:IL12 CASCADE:IFNAB PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="15931.25" y="2603.75"/> <glyph class="state variable" id="_8fe95a1f-2246-4a25-a49d-2c2d1252d5bb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15926.25" y="2618.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1345_csa66" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR1245A:NKG2D* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="12675.0" y="2020.0"/> <glyph class="nucleic acid feature" id="s1346_sa609"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:MIF 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. PMID:18490733 MIF inhibits NK cell activity through a transcriptional down-regulation of NKG2D References_end </body> </html> </notes> <label text="NKG2D*"/> <bbox w="90.0" h="25.0" x="12680.0" y="2037.5"/> <glyph class="unit of information" id="_b40ae9d1-3ea9-4f6a-8e27-02955faef9ac"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12715.0" y="2032.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1347_sa610"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="12680.0" y="2067.5"/> <glyph class="unit of information" id="_f7dec975-d052-4f74-b37f-debf30a1be97"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12710.0" y="2062.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1352_csa123" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:MIR183 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="11835.0" y="2015.0"/> <glyph class="nucleic acid feature" id="s1354_sa758"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="11840.0" y="2022.5"/> <glyph class="unit of information" id="_2a350b11-502a-4801-aabb-04a54800bc36"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="11870.0" y="2017.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1353_sa759"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB 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="11840.0" y="2052.5"/> <glyph class="unit of information" id="_10333c3f-098f-43a2-8dbb-4c181bc84528"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11875.0" y="2047.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1367_csa186" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:Caspase1*:NLRP3:PYCARD Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. References_end </body> </html> </notes> <label text="Inflammasome"/> <bbox w="110.0" h="150.0" x="5005.0" y="6425.0"/> <glyph class="macromolecule" id="s2914_sa1244"> <notes> <html xmlns="http://www.w3.org/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:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 CASCADE:TLR2_4 PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) References_end </body> </html> </notes> <label text="NLRP3"/> <bbox w="80.0" h="40.0" x="5015.0" y="6515.0"/> </glyph> <glyph class="macromolecule" id="s2915_sa1245"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 CASCADE:TLR2_4 PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) References_end </body> </html> </notes> <label text="PYCARD"/> <bbox w="80.0" h="40.0" x="5015.0" y="6475.0"/> </glyph> <glyph class="macromolecule" id="s2916_sa1246"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3).After 2 hours of incubation, monocytes display clear activation of caspase-1 regardless of LPS stimulation. References_end </body> </html> </notes> <label text="Caspase1*"/> <bbox w="80.0" h="40.0" x="5015.0" y="6435.0"/> </glyph> </glyph> <glyph class="complex" id="s1368_csa185" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NLRP3:PYCARD:cleaved Caspase1* Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 CASCADE:TLR2_4 19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) 20385749 The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. References_end </body> </html> </notes> <label text="Inflammasome"/> <bbox w="110.0" h="150.0" x="4845.0" y="6725.0"/> <glyph class="macromolecule" id="s3138_sa1241"> <notes> <html xmlns="http://www.w3.org/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:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 CASCADE:TLR2_4 PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) References_end </body> </html> </notes> <label text="NLRP3"/> <bbox w="80.0" h="40.0" x="4855.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s3139_sa1242"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 CASCADE:TLR2_4 PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) References_end </body> </html> </notes> <label text="PYCARD"/> <bbox w="80.0" h="40.0" x="4855.0" y="6775.0"/> </glyph> <glyph class="macromolecule" id="s2913_sa1243"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL CASCADE:P2RX7 CASCADE:TLR2_4 PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3). After 2 hours of incubation, monocytes display clear activation of caspase-1 regardless of LPS stimulation. References_end </body> </html> </notes> <label text="cleaved Caspase1*"/> <bbox w="80.0" h="40.0" x="4860.0" y="6730.0"/> <glyph class="unit of information" id="_50268c74-7601-4384-b661-35ceb4f337bf"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4875.0" y="6725.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1391_csa89" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RAP1A Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="s1391"/> <bbox w="100.0" h="120.0" x="7825.0" y="4480.0"/> <glyph class="macromolecule" id="s1392_sa666"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RAP1A Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="7835.0" y="4500.0"/> </glyph> <glyph class="simple chemical" id="s1393_sa667"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="7846.75" y="4546.875"/> </glyph> </glyph> <glyph class="complex" id="s1394_csa88" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RAP1A Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="s1394"/> <bbox w="100.0" h="120.0" x="8015.0" y="4480.0"/> <glyph class="macromolecule" id="s3135_sa664"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="8025.0" y="4500.0"/> </glyph> <glyph class="simple chemical" id="s1395_sa665"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="8033.0" y="4547.5"/> </glyph> </glyph> <glyph class="complex" id="s1416_csa65" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CRKL:PI3KR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D PMID:19454690 IP of p85 indicated constitutive p85-CrkL association. Disruption of this p85-CrkL complex would lead to impaired killing downstream of NKG2D, probably via RAPGEF1/RAP1 pathways. References_end </body> </html> </notes> <label text="s1416"/> <bbox w="120.0" h="130.0" x="7710.0" y="3955.0"/> <glyph class="macromolecule" id="s2692_sa607"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:NEUTROPHIL MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:LGALS3 CASCADE:IL4 CASCADE:SLAMF7 CASCADE:NKP80 CASCADE:NKG2D CASCADE:NKP46 CASCADE:Fc_gamma_RIII CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNAB CASCADE:IFNG PMID:24751819 IL21 signaling activates PI3K/AKT pathway PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:18250477 Galectin-3 mediate alternative activation of macrophages via activation of PI3K signaling and AKT posphorylation. And regulates expression of MRC1 probably via PI3K 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, 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. PMID:9314552 Syk- macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcgammaRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcgammaR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcgammaR-mediated phagocytosis. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with p85 subunit of PI3K and Grb2 and activates downstrean PI3K signaling ( phosphorylation of Akt on Ser473) PMID:20805416 In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF And this signaling is needful for DC differentiation. PMID:25960930 IFNα induces PKC-θ auto-phosphorylation in NK cells via P3K and PLC pathways and improves the degranulation via PKC-θ signaling PMID:16713974, PMID:11579131 INFG pathway inhibits activation (phosphorylation) of ERK, JNK, p38 kinases and PI3K pathway induced by TLR. Inhibition of AKT pathway by IFNG resulted in activation of GSK3. GSK3 inhibits downstream AP-1 and CREB1 signaling and downregulates IL10 expression induced by TLR.IFNG inhibits CREB activation via p38 induced by TLR signaling PMID:19909365 MAST cells PMID:21826665 TLR4/PI3K signaling in TAN promotes motility of cancer cells References_end </body> </html> </notes> <label text="PI3KR(p85)*"/> <bbox w="80.0" h="40.0" x="7721.25" y="3965.0"/> </glyph> <glyph class="macromolecule" id="s1417_sa608"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CRKL Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="7730.0" y="4030.0"/> <glyph class="state variable" id="_6f04c6a8-2234-4e6a-b72f-5918eff9d47c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7725.0" y="4045.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1478_csa122" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:HLA-E:KLRC2:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRC2 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1478"/> <bbox w="190.0" h="180.0" x="11820.0" y="1420.0"/> <glyph class="macromolecule" id="s1476_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:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER CASCADE:KLRC2 CASCADE:KLRC3 References_end </body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="11830.0" y="1525.0"/> <glyph class="unit of information" id="_4ed80214-d3ce-4ab3-bf87-c23a53fd7761"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11847.5" y="1520.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1477_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:HLA-E Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER CASCADE:KLRC2 CASCADE:KLRC3 PMID:2731048 HLA-E is a ligand of inhibitory receptor NKG2A. PMID:9486650, 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="11830.0" y="1430.0"/> </glyph> <glyph class="macromolecule" id="s1482_sa756"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRC2 MAP:NATURAL_KILLER PMID:9486650, 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="11830.0" y="1475.0"/> <glyph class="unit of information" id="_ad57ffe2-6339-4102-9adf-c9d5f1181464"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11847.5" y="1470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1483_sa757"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:KLRC2 CASCADE:KLRC3 CASCADE:NKP44 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="11925.0" y="1525.0"/> <glyph class="state variable" id="_36dbb405-ccc3-49ab-a9b4-e14df95228e7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11917.5" y="1545.0"/> </glyph> <glyph class="unit of information" id="_51363245-9524-49d4-8832-831040c952b0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11942.5" y="1520.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1484_csa60" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:KIR2DS2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DS2 References_end </body> </html> </notes> <label text="s1484"/> <bbox w="110.0" h="165.0" x="12490.0" y="1397.5"/> <glyph class="macromolecule" id="s2515_sa595"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:16238 KEGGCOMPOUND:C00016 CAS:146-14-5 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KIR2DS2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DS2 PMID:11015446, 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="12510.0" y="1462.5"/> <glyph class="unit of information" id="_2d37f450-4c7b-418d-855a-282384d76210"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12527.5" y="1457.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2516_sa596"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:KLRC2 CASCADE:KLRC3 CASCADE:NKP44 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="12510.0" y="1412.5"/> <glyph class="state variable" id="_f17753b8-8504-47e7-9955-942cc329232f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12505.0" y="1432.5"/> </glyph> <glyph class="unit of information" id="_d46e27e1-3e1c-45b2-a8ce-b1f5649c1551"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12527.5" y="1407.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1486_csa61" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:KIR3DS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR3DS1 References_end </body> </html> </notes> <label text="s1486"/> <bbox w="110.0" h="165.0" x="12340.0" y="1387.5"/> <glyph class="macromolecule" id="s2982_sa597"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR3DS1 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="12350.0" y="1452.5"/> <glyph class="unit of information" id="_8c897aeb-c7d9-420b-8584-f018ff85a156"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12367.5" y="1447.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1487_sa598"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:KLRC2 CASCADE:KLRC3 CASCADE:NKP44 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="12350.0" y="1402.5"/> <glyph class="state variable" id="_4b49712a-a2f1-4bf8-93c6-b1b2922edd07"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12345.0" y="1422.5"/> </glyph> <glyph class="unit of information" id="_c3db3e02-ae0b-4f1b-b28d-0d9ad79935d0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12367.5" y="1397.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1522_csa120" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:HLA-C:KIR2DS4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DS4 References_end </body> </html> </notes> <label text="s1522"/> <bbox w="100.0" h="130.0" x="11335.0" y="1615.0"/> <glyph class="macromolecule" id="s1523_sa750"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL3 CASCADE:KIR2DL2 CASCADE:KIR2DL1 MAP:NATURAL_KILLER CASCADE:KIR2DS4 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="11345.0" y="1625.0"/> </glyph> <glyph class="macromolecule" id="s1524_sa751"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DS4 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="11345.0" y="1670.0"/> <glyph class="unit of information" id="_c799868a-e036-45b0-9fe7-fd530571e7c1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11362.5" y="1665.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1534_csa259" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR212:STAT4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL12 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1534"/> <bbox w="100.0" h="120.0" x="14795.0" y="3840.0"/> <glyph class="nucleic acid feature" id="s1537_sa1948"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="14800.0" y="3897.5"/> <glyph class="unit of information" id="_863cc088-f965-4564-802a-74016649e669"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14835.0" y="3892.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1540_sa1949"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="14800.0" y="3867.5"/> <glyph class="unit of information" id="_fbcd7523-ce49-48d0-b2cd-f495c8fae48b"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="14830.0" y="3862.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1535_csa260" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR132:STAT4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL12 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1535"/> <bbox w="100.0" h="120.0" x="14905.0" y="3840.0"/> <glyph class="nucleic acid feature" id="s1538_sa1950"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="14910.0" y="3897.5"/> <glyph class="unit of information" id="_c5a53fc5-e353-409d-8ca3-602989b21383"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14945.0" y="3892.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1541_sa1951"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: CASCADE:IL12 MAP:NATURAL_KILLER 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="14910.0" y="3867.5"/> <glyph class="unit of information" id="_94016d3f-62f9-4c24-b858-b034e30082c0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="14940.0" y="3862.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1536_csa261" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR200A:STAT4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL12 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1536"/> <bbox w="100.0" h="120.0" x="15025.0" y="3840.0"/> <glyph class="nucleic acid feature" id="s1539_sa1952"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="15030.0" y="3897.5"/> <glyph class="unit of information" id="_8d534e5c-24bd-42d5-9c8d-378e17c5070d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15065.0" y="3892.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1542_sa1953"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 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="15030.0" y="3867.5"/> <glyph class="unit of information" id="_5077ed52-64f5-4c1e-bfd1-ff089274ea76"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="15060.0" y="3862.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1559_csa64" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD247:FCER1G:Fc_gamma_RIII*:Immunoglobulins* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:KLRB1 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="240.0" x="10370.0" y="1550.0"/> <glyph class="macromolecule" id="s1561_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:CD247 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:NKP46 CASCADE:NKP30 CASCADE:NKG2A CASCADE:Fc_gamma_RIII 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="10385.0" y="1605.0"/> <glyph class="state variable" id="_7d47d5f6-b6ec-4ca5-8c10-fd5f0356f450"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10377.5" y="1625.0"/> </glyph> <glyph class="unit of information" id="_cb5e7389-9501-4fd6-bf7d-4abbea37a636"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10402.5" y="1600.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1560_sa605"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCGR3A HUGO:FCGR3B Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS MODULE:MARKERS_MDSC Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MAST_CELL MAP:NEUTROPHIL CASCADE:Fc_gamma_RIII http://www.biolegend.com/cell_markers PMID:24445665 Review 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 PMID:2139103 Fc gamma RI and Fc gamma RII on whichever cells they were expressed were capable of phagocytosing anti-Fc gamma R mAb-coated erythrocytes. Furthermore, Fc gamma RIII on mononuclear phagocytes, which appears to be a conventional integral membrane protein that spans the lipid bilayer, was capable of phagocytosing anti-Fc gamma RIII-coated erythrocytes References_end </body> </html> </notes> <label text="FcγRIII*"/> <bbox w="80.0" h="50.0" x="10385.0" y="1655.0"/> <glyph class="unit of information" id="_1b5d2470-1457-4f55-9a10-03d276a8a392"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10402.5" y="1650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1558_sa606"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IGH HUGO:IGL HUGO:IGK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MAST_CELL CASCADE:FCGR2B CASCADE:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII PMID:15099567 The cross-linking of immunoglobulin E (IgE) with bivalent or multivalent antigen results in the aggregation of FceRI, which is sufficient for initiating down-stream signal transduction events that activate cell degranulation as well as the de novo synthesis and secretion of lipid mediators and cytokines References_end </body> </html> </notes> <label text="Immunoglobulins*"/> <bbox w="80.0" h="40.0" x="10380.0" y="1560.0"/> </glyph> <glyph class="macromolecule" id="s3768_sa2237"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RIII CASCADE:NKP46 CASCADE:FCAR 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:15081523 FcαRI is dependent on association with the FcRγ chain for signalling and function References_end </body> </html> </notes> <label text="FCER1G"/> <bbox w="80.0" h="50.0" x="10385.0" y="1705.0"/> <glyph class="state variable" id="_79742d87-ba6e-4078-b302-0eef0493ec68"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10377.5" y="1725.0"/> </glyph> <glyph class="unit of information" id="_8a8e8ae8-cabd-4bc4-87b0-fde354c6368f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10402.5" y="1700.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1571_csa138" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR155:SHIP1* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1571"/> <bbox w="100.0" h="100.0" x="2887.5" y="3050.0"/> <glyph class="nucleic acid feature" id="s1572_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:INPP5D Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:IL4 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. PMID:20435894 IL-10 inhibits miR-155 expression via STAT3. 3--UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. (). References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="90.0" h="25.0" x="2892.5" y="3067.5"/> <glyph class="unit of information" id="_7c0ed8bc-9a5e-442a-bf50-d33dfa992ade"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2927.5" y="3062.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1573_sa877"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:KLRB1 PMID:24227772 KLRB1 (NK1.1) ligation also induce MIR155 expression 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 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 PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES PMID:21385848 miR155 induction is required for efficient DC maturation and is critical for the ability of DCs to promote antigen-specific T-cell activation. miR155 expression was increased strongly in mature Mo-DCs relative to monocytes and immature Mo-DCs. References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="2892.5" y="3097.5"/> <glyph class="unit of information" id="_a15d5533-9978-4ef8-8082-3f9a08343a03"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2922.5" y="3092.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1637_csa262" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL21R:IL2RG Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL21 References_end </body> </html> </notes> <label text="s1637"/> <bbox w="100.0" h="150.0" x="16120.0" y="4180.0"/> <glyph class="macromolecule" id="s1641_sa1965"> <notes> <html xmlns="http://www.w3.org/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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL21 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="16130.0" y="4195.0"/> <glyph class="unit of information" id="_64ea019f-737b-4243-9411-78c91cd87e5b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16147.5" y="4190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1642_sa1966"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <bbox w="80.0" h="50.0" x="16130.0" y="4245.0"/> <glyph class="unit of information" id="_d473d198-5641-49a9-a7bf-c6b6b599a09b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16147.5" y="4240.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1644_csa263" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL21:IL21R:IL2RG:JAK1:JAK3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL21 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="186.25" h="160.0" x="15556.875" y="4215.0"/> <glyph class="macromolecule" id="s3344_sa1967"> <notes> <html xmlns="http://www.w3.org/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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL21 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="15653.125" y="4270.0"/> <glyph class="unit of information" id="_8ef60dcd-85ff-4df9-9667-e4a2d720e71b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15670.625" y="4265.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4161_sa1968"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <bbox w="80.0" h="50.0" x="15650.0" y="4320.0"/> <glyph class="unit of information" id="_68479e94-17f3-46ff-a6c7-8614600f6309"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15667.5" y="4315.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4162_sa1969"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL21 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="15635.0" y="4230.0"/> </glyph> <glyph class="macromolecule" id="s4130_sa2644"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 CASCADE:IFNAB ‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:7512720, PMID:7521688 Jak1 and Jak2 are activated by the G-CSFR References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="15563.125" y="4275.0"/> <glyph class="state variable" id="_8f96c94c-3f49-4fc8-845a-382a2863d866"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15555.625" y="4290.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4131_sa2645"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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 ------ Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 Maps_Modules_end </body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="15565.0" y="4320.0"/> </glyph> </glyph> <glyph class="complex" id="s1669_csa77" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GRB2:LAT Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1669"/> <bbox w="100.0" h="120.0" x="10195.0" y="3050.0"/> <glyph class="macromolecule" id="s1670_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:LAT Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MAST_CELL CASCADE:2B4 CASCADE:Fc_gamma_RIII 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. PMID:10781611 The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells. Co-immunoprecipitation experiments revealed a constitutive association of p36 LAT with both FcgammaRI and FcgammaRIIa immunoprecipitates, and an activation-induced association of LAT with PLCgamma1, Grb2, and the p85 subunit of phosphatidylinositol 3-kinase. bone marrow-derived macrophages from LAT-deficient mice displayed reduced phagocytic efficiency in comparison to the macrophages from wild-type mice. PMID:19909365 LAT is adaptor protein f Fc epsilon RI signaling in mast cells References_end </body> </html> </notes> <label text="LAT"/> <bbox w="80.0" h="50.0" x="10205.0" y="3105.0"/> <glyph class="state variable" id="_9647466e-eb85-450c-ae9c-bf715c0c0dae"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10197.5" y="3125.0"/> </glyph> <glyph class="unit of information" id="_f1a7206c-58a9-4418-a322-f50928bb636e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10222.5" y="3100.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1671_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:GRB2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:IL4 CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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="10205.0" y="3060.0"/> </glyph> </glyph> <glyph class="complex" id="s1700_csa99" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CDC42:GTP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1700"/> <bbox w="100.0" h="120.0" x="6550.0" y="3205.0"/> <glyph class="macromolecule" id="s1694_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:CDC42 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER 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:15001467 CD16 signaling activates cdc24 in NK cells probably via vav proteins. PMID:22126964 Cdc42 activation is downstream of PI3K pathway (probably via VAVs) PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. PMID:9831565, PMID:19741094 Inactivation of Cdc42, either by expression of a dominant-negative mutant or by knockdown, greatly inhibits phagocytosis PMID:19741094 t Cdc42 is essential for the activation of WASP and N-WASP, leading to actin assembly and phagocytic cup formation by macrophages during Fc(gamma)R-mediated phagocytosis. References_end </body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="6560.0" y="3225.0"/> </glyph> <glyph class="simple chemical" id="s1701_sa689"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="6565.0" y="3272.5"/> </glyph> </glyph> <glyph class="complex" id="s1703_csa100" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CDC42:GDP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1703"/> <bbox w="100.0" h="120.0" x="6740.0" y="3205.0"/> <glyph class="simple chemical" id="s1704_sa690"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="6758.75" y="3271.875"/> </glyph> <glyph class="macromolecule" id="s1702_sa691"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CDC42 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER 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:15001467 CD16 signaling activates cdc24 in NK cells probably via vav proteins. PMID:22126964 Cdc42 activation is downstream of PI3K pathway (probably via VAVs) PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. PMID:9831565, PMID:19741094 Inactivation of Cdc42, either by expression of a dominant-negative mutant or by knockdown, greatly inhibits phagocytosis PMID:19741094 t Cdc42 is essential for the activation of WASP and N-WASP, leading to actin assembly and phagocytic cup formation by macrophages during Fc(gamma)R-mediated phagocytosis. References_end </body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="6750.0" y="3215.0"/> </glyph> </glyph> <glyph class="complex" id="s1717_csa79" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:BCAR1:CBL:CRK:CRKL:RAPGEF1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:NKG2D References_end </body> </html> </notes> <label text="s1717"/> <bbox w="210.0" h="191.25" x="7325.0" y="4174.375"/> <glyph class="macromolecule" id="s1723_sa640"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER 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="7385.0" y="4184.375"/> </glyph> <glyph class="macromolecule" id="s1718_sa641"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:BCAR1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:INTEGRIN_AVB5 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="7345.0" y="4234.375"/> <glyph class="state variable" id="_1a31cf39-a8e8-4e1a-b0f9-2e2c3d055a12"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7337.5" y="4249.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1719_sa642"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CRK Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:INTEGRIN_AVB5 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL 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="7435.0" y="4284.375"/> <glyph class="state variable" id="_cc3c5e55-5168-4039-a6b0-24e8cbe7a430"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7430.0" y="4299.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1720_sa643"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CRKL Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="7345.0" y="4284.375"/> <glyph class="state variable" id="_a0026369-f5ac-4b46-823b-01928f90b17c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7340.0" y="4299.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1722_sa644"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D PMID:20189481, 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="7435.0" y="4234.375"/> <glyph class="state variable" id="_3703e2d1-e3fb-42f4-8c50-807b04356c7d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7427.5" y="4249.375"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1724_csa76" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:BCAR1:CBL:CRK:CRKL:RAPGEF1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:NKG2D References_end </body> </html> </notes> <label text="s1717"/> <bbox w="210.0" h="191.25" x="7045.0" y="4164.375"/> <glyph class="macromolecule" id="s1725_sa631"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER 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="7105.0" y="4174.375"/> </glyph> <glyph class="macromolecule" id="s1726_sa632"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:INTEGRIN_AVB5 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="7060.0" y="4220.0"/> <glyph class="state variable" id="_70567a37-f87a-43fd-915f-ae6fa4730d93"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7052.5" y="4235.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1729_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:CRK Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:INTEGRIN_AVB5 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL 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="7155.0" y="4274.375"/> <glyph class="state variable" id="_18d5df35-667a-41fe-b900-a522e4193cb5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7147.5" y="4289.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s1730_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:CRKL Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="7060.0" y="4280.0"/> <glyph class="state variable" id="_b7526706-7cdc-4001-a230-32825f36bad9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7052.5" y="4295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1728_sa635"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CBL Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D PMID:20189481, 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="7155.0" y="4224.375"/> <glyph class="state variable" id="_aabe78ca-2832-4e76-aff2-0954f59f0752"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7147.5" y="4239.375"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1736_csa94" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MST1:RASSF5 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D References_end </body> </html> </notes> <label text="s1736"/> <bbox w="100.0" h="120.0" x="8180.0" y="4640.0"/> <glyph class="macromolecule" id="s1739_sa677"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MST1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D 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="8190.0" y="4650.0"/> <glyph class="state variable" id="_e419625c-8783-4b1f-b843-026a446abf71"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8182.5" y="4665.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1738_sa678"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RASSF5 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D PMID:19454690 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="8190.0" y="4690.0"/> </glyph> </glyph> <glyph class="complex" id="s1747_csa75" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SLAMF7 MAP:NATURAL_KILLER INPUT_ACTIVATORS References_end </body> </html> </notes> <label text="s1747"/> <bbox w="100.0" h="120.0" x="14225.0" y="1390.0"/> <glyph class="macromolecule multimer" id="s1745_sa630"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SLAMF7 MAP:NATURAL_KILLER INPUT_ACTIVATORS 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="14232.0" y="1432.0"/> <glyph class="unit of information" id="_9dfc49b2-c0d4-4487-9ab3-4787a70717d1"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="14265.0" y="1427.0"/> </glyph> <glyph class="state variable" id="_01361456-4c36-40f3-b03a-c316809d3a98"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14227.0" y="1455.0"/> </glyph> <glyph class="unit of information" id="_768e5240-2a39-4fe1-9b8a-6c905f67f649"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14252.5" y="1427.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1758_csa57" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:2B4*:SH2D1B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 References_end </body> </html> </notes> <label text="s1758"/> <bbox w="110.0" h="140.0" x="13920.0" y="1740.0"/> <glyph class="macromolecule" id="s1756_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:SH2D1B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 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="13930.0" y="1810.0"/> <glyph class="state variable" id="_27f2a053-0246-42d3-ad6a-0458ca5e2406"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13925.0" y="1825.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1759_sa590"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:2B4 CASCADE:KIR2DL1 MAP:NATURAL_KILLER 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 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: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="13930.0" y="1755.0"/> <glyph class="state variable" id="_db67c15f-dae0-4ba7-bf99-5c94137241db"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13925.0" y="1775.0"/> </glyph> <glyph class="unit of information" id="_860a4edf-4ec6-4e8d-a9d4-bee45cb72261"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13947.5" y="1750.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1764_csa82" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SH2D1B:SLAMF7 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SLAMF7 MAP:NATURAL_KILLER INPUT_ACTIVATORS References_end </body> </html> </notes> <label text="s1747"/> <bbox w="110.0" h="180.0" x="14220.0" y="1540.0"/> <glyph class="macromolecule multimer" id="s1765_sa649"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SLAMF7 MAP:NATURAL_KILLER INPUT_ACTIVATORS 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="14237.0" y="1622.0"/> <glyph class="unit of information" id="_108ce087-def7-4033-91a1-9c9e25ef52cc"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="14270.0" y="1617.0"/> </glyph> <glyph class="state variable" id="_420d98ef-8f35-4114-aff6-8342900dd758"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14229.5" y="1645.0"/> </glyph> <glyph class="unit of information" id="_6486c6e7-f67d-4134-baf6-c72a9f13f4a6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14257.5" y="1617.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1766_sa650"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SH2D1B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 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="14230.0" y="1560.0"/> <glyph class="state variable" id="_caa490d0-6a05-4bd6-862f-c3eb6ef4eb85"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14222.5" y="1575.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1796_csa68" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:2B4*:CD48:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRB1 CASCADE:KIR2DL1 CASCADE:KIR2DL4 CASCADE:2B4 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="13695.0" y="1335.0"/> <glyph class="macromolecule" id="s2525_sa415"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:2B4 CASCADE:KIR2DL1 MAP:NATURAL_KILLER 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 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: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="13705.0" y="1345.0"/> <glyph class="state variable" id="_5ec0035b-3a84-4df6-9caf-1c7b9d2e55cc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13697.5" y="1365.0"/> </glyph> <glyph class="unit of information" id="_0b84e6b2-4622-4e2b-98dd-d5da8b34170d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13722.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1798_sa614"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 CASCADE:IFNAB CASCADE:IL12 CASCADE:IL2 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="13785.0" y="1350.0"/> </glyph> <glyph class="macromolecule" id="s4097_sa2626"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 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="13785.0" y="1400.0"/> </glyph> </glyph> <glyph class="complex" id="s1800_csa70" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:2B4*:3BP2*:CD48:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRB1 CASCADE:KIR2DL1 CASCADE:KIR2DL4 CASCADE:2B4 MAP:NATURAL_KILLER 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="13635.0" y="1705.0"/> <glyph class="macromolecule" id="s2527_sa417"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD244 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:2B4 CASCADE:KIR2DL1 MAP:NATURAL_KILLER 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 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: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="13725.0" y="1795.0"/> <glyph class="state variable" id="_cea61f78-5f9c-4cc8-a893-61cbf528881c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13717.5" y="1815.0"/> </glyph> <glyph class="unit of information" id="_0b06474d-bd74-4b4e-ba4f-f241873887ad"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13742.5" y="1790.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1802_sa617"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SH2D1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 CASCADE:IFNAB CASCADE:IL12 CASCADE:IL2 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="13645.0" y="1790.0"/> </glyph> <glyph class="macromolecule" id="s1801_sa618"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD48 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 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="13735.0" y="1730.0"/> </glyph> <glyph class="macromolecule" id="s1804_sa619"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SH3BP2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:2B4 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="13645.0" y="1730.0"/> <glyph class="state variable" id="_9ca3ef7c-597b-400f-875f-2d70eba428b9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13637.5" y="1745.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1817_csa118" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:Ca2+:Calmodulin* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="5910.0" y="4240.0"/> <glyph class="macromolecule" id="s2473_sa733"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="5920.0" y="4250.0"/> </glyph> <glyph class="simple chemical" id="s2474_sa734"> <notes> <html xmlns="http://www.w3.org/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="5947.5" y="4307.5"/> </glyph> </glyph> <glyph class="complex" id="s1822_csa286" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CNA*:CNB* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="5910.0" y="4440.0"/> <glyph class="macromolecule" id="s3590_sa2104"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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 Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_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 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="5920.0" y="4450.0"/> </glyph> <glyph class="macromolecule" id="s3591_sa2105"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="5920.0" y="4500.0"/> </glyph> </glyph> <glyph class="complex" id="s1823_csa113" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CNA*:CNB*:Ca2+:Calmodulin* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="6080.0" y="4320.0"/> <glyph class="simple chemical" id="s1824_sa718"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="6207.5" y="4397.5"/> </glyph> <glyph class="macromolecule" id="s1825_sa719"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="6180.0" y="4340.0"/> </glyph> <glyph class="macromolecule" id="s2472_sa720"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_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 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="6090.0" y="4340.0"/> </glyph> <glyph class="macromolecule" id="s1828_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: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER 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="6090.0" y="4390.0"/> </glyph> </glyph> <glyph class="complex" id="s1844_csa74" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SHC1:SHIP1* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="8465.0" y="3310.0"/> <glyph class="macromolecule" id="s1845_sa628"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SHC1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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="8475.0" y="3370.0"/> <glyph class="state variable" id="_511bda5a-e045-4609-addf-64b39fc200fd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8467.5" y="3385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1846_sa629"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL10 CASCADE:FCGR2B CASCADE:2B4 CASCADE:SLAMF7 CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII 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. PMID:1238444 FcgammaRIIa-mediated phagocytosis was significantly enhanced in THP-1 cells overexpressing dominant-negative form of SHIP in the absence of FcgammaRII(b). These results indicate that SHIP negatively regulates FcgammaR-mediated phagocytosis through all ITAM-containing IgG receptors PMID:20435894 IL-10 inhibits miR-155 expression via STAT3. 3--UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10 PMID:22955274 SHIP inhibit MAPKp38 activation and prevent MNK1 phosphorylation by inhibiting the p38 MAPK pathway downstream of IL10. MNK1 regulates TNFa mRNA polysome assembly and upregulates TNFa translation.IL-10 Inhibits TNF Translation through SHIP1-mediated Inhibition of Mnk1 PMID:21469115 IL4 signaling reduces SHIP protein levels and activity via PI3K correlating with M2 marker induction ( activation of arginase protein level and activity and inhibition of NO production). References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="8475.0" y="3320.0"/> <glyph class="state variable" id="_1b20e330-5e96-401f-a644-f1cae52eec9f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8467.5" y="3335.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1849_csa91" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:HRAS Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="9235.0" y="3560.0"/> <glyph class="simple chemical" id="s1850_sa671"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="9250.0" y="3617.5"/> </glyph> <glyph class="macromolecule" id="s2469_sa672"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HRAS Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="HRAS"/> <bbox w="80.0" h="40.0" x="9245.0" y="3570.0"/> </glyph> </glyph> <glyph class="complex" id="s1861_csa102" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ARF6:GDP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII References_end </body> </html> </notes> <label text="s1861"/> <bbox w="100.0" h="120.0" x="8765.0" y="2970.0"/> <glyph class="macromolecule" id="s1863_sa694"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="8775.0" y="2980.0"/> </glyph> <glyph class="simple chemical" id="s1862_sa695"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="8783.75" y="3026.875"/> </glyph> </glyph> <glyph class="complex" id="s1925_csa28" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD80:CD86 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="CD80:CD86"/> <bbox w="100.0" h="120.0" x="13920.0" y="7955.0"/> <glyph class="macromolecule" id="s1926_sa178"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CD80 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:MARKERS_DC MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL3 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:15197224, PMID:7523569, PMID:9359474 The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation. PMID:25582338 The expression levels of CD80 and CD83, the molecules involved in T-cell activation, was similar between the two DC subsets (IL4 and IL15) PMID:11964292, PMID:14764699 IFNAR signaling upregulates surface expression of CD80, CD86, CD40.Probably via STAT1 PMID:22437870 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:25215878 FLT3 ligand upregulates surface expression of CD80 in DCs. PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD23  15034038 IL3 induces CD80, CD86, CD40 surface expression in pDC PMID:7512027 IL-10 inhibits surface expression CD80 (B7) on monocytes, even following induction of these molecules by IL4 or IFNG and diminishes the antigen-presenting capacity of monocytes. PMID:20231889 Dcs Stat5-Tg mice are expressing ot surface high levels of MHC-II and costimulatory molecules such as CD80, CD86 and CD54 (ICAM1) and have increased level of I12 secretion (.) Expression of CD83, a and CD80 and was significantly enhanced by the FLT3L  11207245 I IFN receptor signaling regulates antigen cross-presentation to CD8(+) T cells. (), probably via upregulation of CD80, CD86, CD40, CD83 and MHC class II and CD11c, PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. References_end </body> </html> </notes> <label text="CD80"/> <bbox w="80.0" h="40.0" x="13930.0" y="8005.0"/> <glyph class="unit of information" id="_2935bb75-6f3a-4d9a-8fb0-1799815f79c2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13947.5" y="8000.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1927_sa179"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CD86 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:MARKERS_DC MAP:MACROPHAGE MAP:NEUTROPHIL MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL3 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:TNF CASCADE:FLT3LG CASCADE:IFNAB Maps_Modules_end References_begin: PMID:15197224, PMID:7523569, PMID:9359474 The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation. PMID:20805416 Expression of CD86, a critical costimulatory molecule for efficient T cell priming, is enhanced in activated MDSC during mTOR inhibition This phenotype was not observed in moDCs, in which surface expression of CD80 and CD86 was inhibited by rapamycin. PMID:11964292, PMID:14764699 IFNAR signaling upregulates surface expression of CD80, CD86, CD40.Probably via STAT1 PMID:22437870 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:10477595, PMID:8920882, PMID: 25215878 FLT3L induces Ag-presenting ability of Dcs. Probably via induction of surface expression of class II MHC and CD86. PMID:22076556, PMID:21220452 , PMID:24218453 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD23 PMID: 15034038 IL3 induces CD80, CD86, CD40 surface expression in pDC PMID:9359474 DC derived from progressing metastases do not express CD86, probably its expression is inhibited by IL10 released by melanoma cells, such cells induce T-cell anergy.(DC derived from progressing metastases do not express CD86, probably its expression is inhibited by IL10 released by melanoma cells, such cells induce T-cell anergy.(DC derived from progressing metastases do not express CD86, probably its expression is inhibited by IL10 released by melanoma cells, such cells induce T-cell anergy. PMID:20231889 Dcs Stat5-Tg mice are expressing ot surface high levels of MHC-II and costimulatory molecules such as CD80, CD86 and CD54 (ICAM1) and have increased level of I12 secretion (.) PMID:10477595, PMID:8920882, PMID:25215878 PMID: 11207245 I IFN receptor signaling regulates antigen cross-presentation to CD8(+) T cells. (), probably via upregulation of CD80, CD86, CD40, CD83 and MHC class II and CD11c, PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) PMID:25384214 the stimulatory effect of TANs was partially abrogated in the presence of anti-CD54 and -CD86 blocking Abs References_end </body> </html> </notes> <label text="CD86"/> <bbox w="80.0" h="40.0" x="13930.0" y="7965.0"/> <glyph class="state variable" id="_96059545-df88-4fd8-9995-8e0dca177633"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13925.0" y="7980.0"/> </glyph> <glyph class="unit of information" id="_e4327946-ff99-4757-913d-344807bc1b44"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13947.5" y="7960.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1931_csa192" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:INTEGRIN_AVB3 MAP:DENDRITIC_CELL PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. and cross-present Antigens to Cytotoxic T Lymphocytes The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="s1931"/> <bbox w="100.0" h="130.0" x="8102.5" y="1295.0"/> <glyph class="macromolecule" id="s1929_sa1457"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAV Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB5 CASCADE:INTEGRIN_AVB3 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGAV"/> <bbox w="80.0" h="50.0" x="8112.5" y="1300.0"/> <glyph class="unit of information" id="_0156793d-7ea4-4d47-9f5c-71dd9e2c0b9d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8130.0" y="1295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1930_sa1458"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB3 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGB3"/> <bbox w="80.0" h="50.0" x="8112.5" y="1350.0"/> <glyph class="unit of information" id="_dcd64d1d-55fd-42f2-80ee-6ea420026545"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8130.0" y="1345.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1934_csa194" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB5 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. Cross-present Antigens to Cytotoxic T Lymphocytes. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="s1934"/> <bbox w="100.0" h="120.0" x="8302.5" y="1310.0"/> <glyph class="macromolecule" id="s2201_sa1461"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGB5"/> <bbox w="80.0" h="50.0" x="8312.5" y="1365.0"/> <glyph class="unit of information" id="_1ccbb751-4d4c-4172-991f-4b4ab030df63"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8330.0" y="1360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2202_sa1462"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAV Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB5 CASCADE:INTEGRIN_AVB3 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGAV"/> <bbox w="80.0" h="50.0" x="8312.5" y="1315.0"/> <glyph class="unit of information" id="_6987dc20-cba1-4c50-8009-fb23fbde9683"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8330.0" y="1310.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1951_csa180" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CCL19:CCR7 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CCR7 PMID:11698286 IFNA induces mRNA expression both CCR7 and it's ligand CCL19 in Dcs and induces Dcs migration PMID:19759904 Jak3 is important for DC maturation, migration and function, through a CCR7-mediated signalling pathway. References_end </body> </html> </notes> <label text="s1951"/> <bbox w="100.0" h="120.0" x="6050.0" y="1685.0"/> <glyph class="macromolecule" id="s1952_sa1223"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:TLR2_4 MAP:DENDRITIC_CELL CASCADE:CCR7 CASCADE:CATENINB PMID:17035340 The secretion of HMGB1 is required for the migration of maturing dendritic cells. myeloid DC, which rapidly secrete upon maturation induction their own HMGB1, remodel their actin-based cytoskeleton, up-regulate the CCR7 and the CXCR4 chemokine receptors, and acquire the ability to migrate in response to chemokine receptor ligands. The events are apparently causally related: DC challenged with LPS in the presence of HMGB1-specific antibodies fail to up-regulate the expression of the CCR7 and CXCR4 receptors and to rearrange actin-rich structures. Moreover, DC matured in the presence of anti-HMGB1 antibodies fail to migrate in response to the CCR7 ligand CCL19 and to the CXCR4 ligand CXCL12 References_end </body> </html> </notes> <label text="CCR7"/> <bbox w="80.0" h="50.0" x="6060.0" y="1740.0"/> <glyph class="unit of information" id="_b92d8a64-1d7c-49c4-940f-abf6bc3ed529"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6077.5" y="1735.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1953_sa1224"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CCL19 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CCR7 CASCADE:IFNAB PMID:17035340 The secretion of HMGB1 is required for the migration of maturing dendritic cells. myeloid DC, which rapidly secrete upon maturation induction their own HMGB1, remodel their actin-based cytoskeleton, up-regulate the CCR7 and the CXCR4 chemokine receptors, and acquire the ability to migrate in response to chemokine receptor ligands. The events are apparently causally related: DC challenged with LPS in the presence of HMGB1-specific antibodies fail to up-regulate the expression of the CCR7 and CXCR4 receptors and to rearrange actin-rich structures. Moreover, DC matured in the presence of anti-HMGB1 antibodies fail to migrate in response to the CCR7 ligand CCL19 and to the CXCR4 ligand CXCL12 References_end </body> </html> </notes> <label text="CCL19"/> <bbox w="80.0" h="40.0" x="6060.0" y="1695.0"/> </glyph> </glyph> <glyph class="complex" id="s2038_csa341" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:E-Cadherin*:_alpha_-Catenin*:_beta_-Catenin* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CATENINB PMID:17936032, PMID:22174153 Disruption of E-cadherin-mediated contacts induce DC maturation. It activates a β-catenin-TCF/LEF signaling pathway independent of TLR signaling References_end </body> </html> </notes> <label text="s2038"/> <bbox w="130.0" h="180.0" x="2515.0" y="3300.0"/> <glyph class="macromolecule" id="s2036_sa2611"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CATENINB PMID:17936032, PMID:22174153 Disruption of E-cadherin-mediated contacts induce DC maturation. It activates a β-catenin-TCF/LEF signaling pathway independent of TLR signaling References_end </body> </html> </notes> <label text="E-Cadherin*"/> <bbox w="80.0" h="40.0" x="2540.0" y="3310.0"/> </glyph> <glyph class="macromolecule" id="s2037_sa2612"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CTNNB1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CATENINB PMID:24023259 β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells PMID:25730849 L-10 Mediates β-Catenin–Dependent Inhibition of Cross-Priming,β-catenin enhanced IL-10 induction through mTOR pathway. β-Catenin up-regulates level of mTOR in DCs and activates mTOR signaling. PMID:20705860 β-catenin signaling in DCs is required to induce Treg cells and suppress TH1/TH17 responses. β-catenin signaling in intestinal DCs promotes the expression of Raldh and suppresses the expression of proinflammatory cytokines (IL6, IL23a,IL12p40) but induces IL10 production. PMID:15001769, PMID:17936032 GSK3B phosphorylates beta-catenin and inhibits its activity. Beta-catenin signaling prevents production of inflammatory cytokines IL6, IL-1α, IL-6, TNF-α, and IL-12 p40, But upregulates CCR7, both at the mRNA level and on the plasma membrane. CCR7 is a chemokine receptor important for the migration of DCs from the periphery to T cell areas of lymph nodes. DCs matured by CD activation of beta-catenin signaling alone failed to prime CD4 T cells to produce IFN-γ but did generate high levels of IL10 (Fig. 6A) together with other cytokines (not shown) consistent with type I regulatory T cells References_end </body> </html> </notes> <label text="β-Catenin*"/> <bbox w="80.0" h="40.0" x="2535.0" y="3410.0"/> <glyph class="state variable" id="_4f290c22-45ac-4670-a33c-bfdd92defa7c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2530.0" y="3425.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2040_sa2613"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CTNNA1 HUGO:CTNNA2 HUGO:CTNNA3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CATENINB PMID:17936032 Disruption of E-cadherin-mediated contacts induce DC maturation. It activates a β-catenin-TCF/LEF signaling pathway independent of TLR signaling References_end </body> </html> </notes> <label text="α-Catenin*"/> <bbox w="80.0" h="40.0" x="2530.0" y="3360.0"/> </glyph> </glyph> <glyph class="complex" id="s2147_csa322" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TICAM1:TLR4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:TLR2_4 PMID:20154735 , PMID:16306937 TICAM1 (TRIF)/TRAF pathway downstream of TLR4 is MYD88 independent. PMID:17114424 Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals. PMID:23508573, PMID:20547845, PMID:15644117 HMGB1 induces secretion of TNFa via TLR4/MyD88 and TRIF (TICAM1) dependent pathway probably via NFkB References_end </body> </html> </notes> <label text="s2147"/> <bbox w="120.0" h="190.0" x="15925.0" y="1665.0"/> <glyph class="macromolecule" id="s2148_sa2463"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TLR4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:MIF CASCADE:IFNG Maps_Modules_end References_begin: PMID:11964313, PMID:11672593, PMID:12032143, PMID:12811837. INFG upregulates mRNA level and surface expression of TLR4 and TLR2. References_end </body> </html> </notes> <label text="TLR4"/> <bbox w="80.0" h="50.0" x="15945.0" y="1715.0"/> <glyph class="unit of information" id="_e1d3befd-841f-49e5-b77d-cacab9dece64"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15962.5" y="1710.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2151_sa2464"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TIKAM1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TLR2_4 PMID:16917499 TIKAM1(TRIF) is an adaptor of TLR signaling, TLR signaling via ARHGEF2 (GEFH1)and RHOB regulates MHCII surface expression PMID:20154735 , PMID:16306937 TICAM1 (TRIF)/TRAF pathway downstream of TLR4 is MYD88 independent. PMID:17114424 Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals. References_end </body> </html> </notes> <label text="TICAM1"/> <bbox w="80.0" h="40.0" x="15945.0" y="1775.0"/> </glyph> </glyph> <glyph class="complex" id="s2176_csa195" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ATP:P2RX7 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE::P2RX7 References_end </body> </html> </notes> <label text="s2176"/> <bbox w="100.0" h="120.0" x="7032.5" y="1700.0"/> <glyph class="macromolecule" id="s2177_sa1463"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:P2RX7 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE::P2RX7 PMID:20086177 ATP was released by tumor cells succumbing to chemotherapy. ATP activates purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflammasome and driving the secretion of interleukin-1beta (IL-1beta). IL-1beta then is required for the adequate polarization of IFNgamma-producing CD8(+) T cells. References_end </body> </html> </notes> <label text="P2RX7"/> <bbox w="80.0" h="50.0" x="7042.5" y="1745.0"/> <glyph class="unit of information" id="_99086013-3c2d-4aa0-a5a2-5384154de751"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7060.0" y="1740.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s2178_sa1464"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE::P2RX7 PMID:20086177 ATP was released by tumor cells succumbing to chemotherapy. ATP activates purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflammasome and driving the secretion of interleukin-1beta (IL-1beta). IL-1beta then is required for the adequate polarization of IFNgamma-producing CD8(+) T cells. </body> </html> </notes> <label text="ATP"/> <bbox w="70.0" h="25.0" x="7047.5" y="1717.5"/> </glyph> </glyph> <glyph class="complex" id="s2184_csa193" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CALR:LRP1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:LRP1 References_end </body> </html> </notes> <label text="s2184"/> <bbox w="100.0" h="120.0" x="7122.5" y="1510.0"/> <glyph class="macromolecule" id="s2186_sa1459"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CALR Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:LRP1 PMID:16181333, PMID:22076556 CALR (CRT or calreticulin) is a lectin specific for monoglucosylated N-linked glycans (17) that binds to the MHC class I molecule via its carbohydrate side chain. It also associates non-covalently with ERp57 in peptide-loading complex. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting PMID:23157435, PMID:16239148, PMID:20958319 CALR (CRT or calreticulin) is released by dying tumor cells and acts as eat-me signal. It acts via CD91 (LRP1) and initiates clearance of viable or apoptotic cells. References_end </body> </html> </notes> <label text="CALR"/> <bbox w="80.0" h="40.0" x="7132.5" y="1570.0"/> </glyph> <glyph class="macromolecule" id="s2185_sa1460"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LRP1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:DENDRITIC_CELL CASCADE:LRP1 PMID:25351513 Bright expression of CD91 identifies highly activated human dendritic cells PMID:23157435, PMID:16239148 CALR (CRT or calreticulin) is released by dying tumor cells and acts as eat-me signal for macrophages and neutrophils. It acts via CD91 (LRP1). References_end </body> </html> </notes> <label text="LRP1"/> <bbox w="80.0" h="50.0" x="7132.5" y="1515.0"/> <glyph class="unit of information" id="_3bf9b875-35a2-40a0-8cd6-c46131246f0e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7150.0" y="1510.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2191_csa191" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME: CX3CR1:CX3CL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CX3CR1 PMID:11766992 Fractalkine via CX3CR1 induces chemotaxis and migration associated actin polymerization in immature as well as in mature DCs. References_end </body> </html> </notes> <label text="s2191"/> <bbox w="100.0" h="140.0" x="6832.5" y="1680.0"/> <glyph class="macromolecule" id="s2190_sa1455"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CX3CL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CX3CR1 PMID:18799722 CX3CL1/fractalkine is released from dying cells PMID:18363071 Fractalkine (CX3CL1) is the only CX3C chemokine that can chemoattract natural killer (NK) cells, CD8+ T cells, monocytes, and dendritic cells. PMID:12455035 CX3CL1 induces chemoattraction and activation of DC via CX3CR1 and induces Tcell activation. Adherence of DC to cells expressed CX3CL1 resulted in phenotypic maturation and upregulated IL-12 secretion of DC, and more strong stimulation of allogeneic T-cell proliferation by DC. References_end </body> </html> </notes> <label text="CX3CL1"/> <bbox w="80.0" h="40.0" x="6842.5" y="1750.0"/> </glyph> <glyph class="macromolecule" id="s2192_sa1456"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CX3CR1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CX3CR1 PMID:12455035 CX3CL1 induces chemoattraction and activation of DC via CX3CR1 and induces Tcell activation. Adherence of DC to cells expressed CX3CL1 resulted in phenotypic maturation and upregulated IL-12 secretion of DC, and more strong stimulation of allogeneic T-cell proliferation by DC PMID:11766992 Fractalkine induces chemotaxis and migration associated actin polymerization in immature as well as in mature DCs References_end </body> </html> </notes> <label text=" CX3CR1"/> <bbox w="80.0" h="50.0" x="6842.5" y="1695.0"/> <glyph class="unit of information" id="_5be35252-2a89-4a8c-9868-644c681fdeb4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6860.0" y="1690.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2195_csa188" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:S1PR*:Sphingosine 1-phosphate Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:S1PR PMID:11919175 S1P induces Ca2+ mobilization, actin polymerization, and migration in immature, but not in LPS-differentiated DC. S1P reduces IL-12 and TNF-α production, and augments IL-10 release in maturing DC inhibiting their capacity to induce Th1 immune responses. References_end </body> </html> </notes> <label text="s2195"/> <bbox w="200.0" h="120.0" x="6622.5" y="1610.0"/> <glyph class="macromolecule" id="s2196_sa1448"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S1PR1 HUGO:S1PR2 HUGO:S1PR3 HUGO:S1PR4 HUGO:S1PR5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:S1PR PMID:11919175 Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. Immature and mature DC express the mRNA for different S1P receptors, such as endothelial differentiation gene (EDG)-1, EDG-3, EDG-5, and EDG-6. In immature DC, S1P stimulated pertussis toxin-sensitive Ca2+ increase actin polymerization and chemotaxis. These responses were lost by DC matured with lipopolysaccharide. In maturing DC, however, S1P inhibited the secretion of tumor necrosis References_end </body> </html> </notes> <label text="S1PR*"/> <bbox w="80.0" h="50.0" x="6682.5" y="1655.0"/> <glyph class="unit of information" id="_237cdd27-61bc-46b4-aaad-f8fe576b5f87"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6700.0" y="1650.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s2197_sa1449"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:S1PR PMID:18362204 Apoptotic cells may up-regulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells PMID:11919175 Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. Immature and mature DC express the mRNA for different S1P receptors, such as endothelial differentiation gene (EDG)-1, EDG-3, EDG-5, and EDG-6. In immature DC, S1P stimulated pertussis toxin-sensitive Ca2+ increase actin polymerization and chemotaxis. These responses were lost by DC matured with lipopolysaccharide. In maturing DC, however, S1P inhibited the secretion of tumor necrosis factor α and interleukin (IL)-12, whereas it enhanced secretion of IL-10. As a consequence, mature DC exposed to S1P showed a reduced and increased capacity to generate allogeneic Th1 and Th2 responses, respectively. In summary, our study implicates that S1P might regulate the trafficking of DC and ultimately favor Th2 lymphocyte-dominated immunity. </body> </html> </notes> <label text="Sphingosine 1-phosphate"/> <bbox w="175.0" h="32.5" x="6635.0" y="1623.75"/> </glyph> </glyph> <glyph class="complex" id="s2206_csa197" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB3:MFGE8:PtdSer Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB3 PMID:22035837, PMID:12000961 The ‘bridging’ molecule MFG-E8 (which binds to PtdSer on apoptotic cells and facilitate engulfment by engaging the integrin αvβ3 on phagocytes (directly demonstrated for macrophages only) References_end </body> </html> </notes> <label text="s2206"/> <bbox w="190.0" h="152.5" x="8047.5" y="1483.75"/> <glyph class="macromolecule" id="s2205_sa1469"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAV Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB5 CASCADE:INTEGRIN_AVB3 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGAV"/> <bbox w="80.0" h="50.0" x="8057.5" y="1498.75"/> <glyph class="unit of information" id="_8f10c6b6-1f31-4d60-864f-361c631e8b1f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8075.0" y="1493.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s2207_sa1470"> <notes> <html xmlns="http://www.w3.org/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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB3 CASCADE:INTEGRIN_AVB5 PMID:22035837, PMID:15031725 The ‘bridging’ molecule MFG-E8 (which binds to PtdSer on apoptotic cells and facilitate engulfment by engaging the integrin αvβ3 on phagocytes PMID:14697347, PMID: 11146654 The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells by DCs.. References_end </body> </html> </notes> <label text="MFGE8"/> <bbox w="80.0" h="40.0" x="8147.5" y="1546.25"/> </glyph> <glyph class="simple chemical" id="s2976_sa1471"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS CASCADE:INTEGRIN_AVB3 CASCADE:INTEGRIN_AVB5 MODULE:DANGER_SIGNAL_PATHWAYS PMID:22035837 The ‘bridging’ molecule MFG-E8 (which binds to PtdSer on apoptotic cells and facilitate engulfment by engaging the integrin αvβ3 on phagocytes </body> </html> </notes> <label text="PtdSer"/> <bbox w="70.0" h="25.0" x="8152.5" y="1593.75"/> </glyph> <glyph class="macromolecule" id="s2209_sa1472"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB3 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGB3"/> <bbox w="80.0" h="50.0" x="8057.5" y="1543.75"/> <glyph class="unit of information" id="_810845db-c8da-4b96-b1e2-b3808b7fe85c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8075.0" y="1538.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2212_csa196" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB5:MFGE8 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB5 PMID:14697347, PMID:11146654 Integrin αvβ5 regulates phagocytosis via CRK /DOCK1 (DOCK180) /RAC1 pathway downstream of. Integrin αvβ5 activation results in recruitment of the p130cas–CrkII–Dock180 complex and RAC1 activation. References_end </body> </html> </notes> <label text="s2212"/> <bbox w="187.5" h="157.5" x="8288.75" y="1481.25"/> <glyph class="macromolecule" id="s2213_sa1465"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB3 CASCADE:INTEGRIN_AVB5 PMID:22035837, PMID:15031725 The ‘bridging’ molecule MFG-E8 (which binds to PtdSer on apoptotic cells and facilitate engulfment by engaging the integrin αvβ3 on phagocytes PMID:14697347, PMID: 11146654 The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells by DCs.. References_end </body> </html> </notes> <label text="MFGE8"/> <bbox w="80.0" h="40.0" x="8298.75" y="1546.25"/> </glyph> <glyph class="macromolecule" id="s2215_sa1467"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAV Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:INTEGRIN_AVB5 CASCADE:INTEGRIN_AVB3 PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGAV"/> <bbox w="80.0" h="50.0" x="8386.25" y="1493.75"/> <glyph class="unit of information" id="_12f1cd23-c113-4c13-9652-119cfbdeb6b3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8403.75" y="1488.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s2216_sa1468"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:9295024, PMID:9763615 Dendritic cells phagocytose apoptotic cells via alphavbeta5, alphavbeta3, and CD36. The interaction between apoptotic bodies and dendritic cells elicits a rise in intracellular free calcium concentration ([Ca2+]i) which is essential for the process of engulfment. References_end </body> </html> </notes> <label text="ITGB5"/> <bbox w="80.0" h="50.0" x="8386.25" y="1543.75"/> <glyph class="unit of information" id="_7b7c3b2e-99be-4774-879f-0526f879a97e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8403.75" y="1538.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2225_csa10" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:AP2A1:AP2A2:AP2B1:AP2M1:AP2S1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:15749704, PMID:15911768 AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. References_end </body> </html> </notes> <label text="AP2_adaptor_complex"/> <bbox w="193.28125" h="201.875" x="11963.359" y="7129.0625"/> <glyph class="macromolecule" id="s2226_sa132"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AP2A1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:15749704, PMID:15911768 AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. References_end </body> </html> </notes> <label text="AP2A1"/> <bbox w="80.0" h="40.0" x="11976.641" y="7250.9375"/> </glyph> <glyph class="macromolecule" id="s2227_sa133"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AP2A2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:15749704, PMID:15911768 AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. References_end </body> </html> </notes> <label text="AP2A2"/> <bbox w="80.0" h="40.0" x="11976.641" y="7200.9375"/> </glyph> <glyph class="macromolecule" id="s2228_sa134"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AP2B1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:15749704, PMID:15911768 AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. References_end </body> </html> </notes> <label text="AP2B1"/> <bbox w="80.0" h="40.0" x="11976.641" y="7150.9375"/> </glyph> <glyph class="macromolecule" id="s2229_sa135"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AP2M1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:15749704, PMID:15911768 AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. References_end </body> </html> </notes> <label text="AP2M1"/> <bbox w="80.0" h="40.0" x="12063.672" y="7204.0625"/> </glyph> <glyph class="macromolecule" id="s2230_sa136"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AP2M1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:15749704, PMID:15911768 AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. References_end </body> </html> </notes> <label text="AP2S1"/> <bbox w="80.0" h="40.0" x="12062.422" y="7149.0625"/> </glyph> </glyph> <glyph class="complex" id="s2270_csa5" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RHOB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="RHOB:GDP"/> <bbox w="100.0" h="120.0" x="12440.0" y="7075.0"/> <glyph class="macromolecule" id="s1908_sa114"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RHOB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16917499 TIKAM1(TRIF) is an adaptor of TLR signaling, TLR signaling via ARHGEF2 (GEFH1)and RHOB regulates MHCII surface expression References_end </body> </html> </notes> <label text="RHOB"/> <bbox w="80.0" h="40.0" x="12450.0" y="7085.0"/> </glyph> <glyph class="simple chemical" id="s1907_sa115"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:17552, KEGGCOMPOUND:C00035 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="GDP"/> <bbox w="70.0" h="25.0" x="12455.0" y="7132.5"/> </glyph> </glyph> <glyph class="complex" id="s2271_csa4" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RHOB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="RHOB:GTP"/> <bbox w="100.0" h="120.0" x="12630.0" y="7075.0"/> <glyph class="simple chemical" id="s1910_sa112"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="12645.0" y="7132.5"/> </glyph> <glyph class="macromolecule" id="s2710_sa113"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RHOB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16917499 TIKAM1(TRIF) is an adaptor of TLR signaling, TLR signaling via ARHGEF2 (GEFH1)and RHOB regulates MHCII surface expression References_end </body> </html> </notes> <label text="RHOB"/> <bbox w="80.0" h="40.0" x="12640.0" y="7085.0"/> </glyph> </glyph> <glyph class="complex" id="s2272_csa32" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ORP1L*:RAB7*:RILP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11696325, PMID:21112200 The Rab7‐RILP complex interacts with a second EFFECTOR_ACTIVATION protein—OSBP‐related protein 1L (ORP1L)—to form a tripartite complex on lysosomal membranes. This complex regulate transport vesicules with of MHC class II complex along microtubes. References_end </body> </html> </notes> <label text="RAB7*:RILP:ORP1L*"/> <bbox w="110.0" h="170.0" x="12795.0" y="7210.0"/> <glyph class="macromolecule" id="s2256_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:RAB7A HUGO:RAB7B Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:11696325, PMID:21112200 The Rab7‐RILP complex interacts with a second EFFECTOR_ACTIVATION protein—OSBP‐related protein 1L (ORP1L)—to form a tripartite complex on lysosomal membranes. This complex regulate transport vesicules with of MHC class II complex along microtubes. References_end </body> </html> </notes> <label text="RAB7*"/> <bbox w="80.0" h="40.0" x="12805.0" y="7220.0"/> </glyph> <glyph class="macromolecule" id="s4075_sa187"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RILP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:11696325, PMID:21112200 The Rab7‐RILP complex interacts with a second EFFECTOR_ACTIVATION protein—OSBP‐related protein 1L (ORP1L)—to form a tripartite complex on lysosomal membranes. This complex regulate transport vesicules with of MHC class II complex along microtubes. References_end </body> </html> </notes> <label text="RILP"/> <bbox w="80.0" h="40.0" x="12805.0" y="7260.0"/> </glyph> <glyph class="macromolecule" id="s4076_sa188"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:OSBPL1A Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:11696325, PMID:21112200 The Rab7‐RILP complex interacts with a second EFFECTOR_ACTIVATION protein—OSBP‐related protein 1L (ORP1L)—to form a tripartite complex on lysosomal membranes. This complex regulate transport vesicules with of MHC class II complex along microtubes. References_end </body> </html> </notes> <label text="ORP1L*"/> <bbox w="80.0" h="40.0" x="12805.0" y="7300.0"/> </glyph> </glyph> <glyph class="complex" id="s2275_csa248" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL2RA:IL2RB:IL2RG Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL2 References_end </body> </html> </notes> <label text="s2275"/> <bbox w="103.75" h="210.0" x="16093.125" y="4435.0"/> <glyph class="macromolecule" id="s2354_sa1878"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL2 CASCADE:IL15 CASCADE:IL21 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:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) References_end </body> </html> </notes> <label text="IL2RA"/> <bbox w="80.0" h="50.0" x="16098.125" y="4440.0"/> <glyph class="unit of information" id="_51a1dfbf-778e-4c62-aaf4-9fa87b090fae"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16115.625" y="4435.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2355_sa1879"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL2 PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. PMID:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) References_end </body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="16106.875" y="4560.0"/> <glyph class="state variable" id="_61513888-c08f-495f-92d7-5db09b5943c5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16101.875" y="4580.0"/> </glyph> <glyph class="unit of information" id="_53bdb998-5f46-47c9-84a2-6fbd3e0a4df6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16124.375" y="4555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3312_sa1880"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <bbox w="80.0" h="50.0" x="16100.625" y="4490.0"/> <glyph class="unit of information" id="_bf103768-022e-4dd9-8dc9-0aaad05e6c5e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16118.125" y="4485.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2280_csa30" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MHC_class_II*:Tumor_antigen_fragment Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_II*:Tumor_antigen_fragment"/> <bbox w="120.0" h="140.0" x="12800.0" y="7740.0"/> <glyph class="macromolecule" id="s2211_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:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL6 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12391186 Maturation of monocyte-derived DCs was induced by TNF-α The surface levels of MHC class II increased markedly after TNF-α stimulation on CD83+ DC PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:22076556, PMID:22076556, PMID:25720354 Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. MHC class II molecules present antigen peptides to CD4+ T cells PMID:22076556, PMID:21220452 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:11702064 IL15 signaling upregulates surface expression of MHC class II PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="40.0" x="12810.0" y="7820.0"/> <glyph class="state variable" id="_e5d6fc49-a407-461d-aab4-e0ed2386ee5c"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="12800.0" y="7835.0"/> </glyph> <glyph class="unit of information" id="_d6b5e543-2d8a-4a50-9066-f8c166d771a0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12827.5" y="7815.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2210_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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11154916, PMID:11509172, PMID:22076556 Processed antigen peptide in lysosomes forms complex with MHC-class-II. formation and transport to the cell surface of MHC-class-II–peptide complexes is induced by maturation. Immature DCs in culture can take up antigen but do not present it efficiently to T cells. After detecting microbial products or proinflammatory cytokines, immature DCs transform into mature DCs, cells with a reduced capacity for antigen uptake but now with an exceptional capacity for T cell stimulation. PMID:22790179, PMID:14508489 The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome4, 5, 6. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex “loading machinery” (which includes tapasin, calreticulin and Erp57) References_end </body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="12820.0" y="7760.0"/> <glyph class="unit of information" id="_e2bb50bc-9b6d-4452-aab1-2b60c60f2473"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12835.0" y="7755.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2281_csa27" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD40:CD40LG Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:8760829 Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. PMID:23002440 CD40/CD154 Blockade Inhibits Dendritic Cell Expression of Inflammatory Cytokines IL-1β (C) and IL-12p35 transcripts and IL6, TNF secretion. References_end </body> </html> </notes> <label text="CD40:CD40LG"/> <bbox w="100.0" h="130.0" x="14420.0" y="8000.0"/> <glyph class="macromolecule" id="s2083_sa176"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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:CD40 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:MARKERS_DC MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION CASCADE:IL3 CASCADE:TLR2_4 CASCADE:TNF CASCADE:IFNAB Maps_Modules_end References_begin: PMID:15197224, PMID:7523569, PMID:9359474 The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation. PMID:11964292, PMID:14764699 IFNAR signaling upregulates surface expression of CD80, CD86, CD40.Probably via STAT1 PMID:8760829 Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. PMID: 15034038 IL3 induces CD80, CD86, CD40 surface expression in pDC PMID: 11207245 I IFN receptor signaling regulates antigen cross-presentation to CD8(+) T cells. (), probably via upregulation of CD80, CD86, CD40, CD83 and MHC class II and CD11c, PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="CD40"/> <bbox w="80.0" h="40.0" x="14430.0" y="8010.0"/> <glyph class="unit of information" id="_daad5a22-6085-4c88-9954-5233a2d5070e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14447.5" y="8005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2084_sa177"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD40LG Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11581322 CD40LG induce maturation of DC. PMID:8760829 Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce production ICOS-L and expression of OX40L.. References_end </body> </html> </notes> <label text="CD40LG"/> <bbox w="80.0" h="40.0" x="14430.0" y="8060.0"/> </glyph> </glyph> <glyph class="complex" id="s2285_csa16" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ARL14:ARL14EP:GTP:MYO1E Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MYO1E:ARL14EP:ARL14:GTP"/> <bbox w="180.0" h="140.0" x="13220.0" y="7320.0"/> <glyph class="macromolecule" id="s1873_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:ARL14EP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 MHC-II transport was controlled by the GTPase ARL14/ARF7, which recruits the motor myosin 1E via an EFFECTOR_ACTIVATION protein ARF7EP. This complex controls movement of MHC-II vesicles along the actin cytoskeleton in human dendritic cells (DCs). References_end </body> </html> </notes> <label text="ARL14EP"/> <bbox w="80.0" h="40.0" x="13230.0" y="7380.0"/> </glyph> <glyph class="simple chemical" id="s1890_sa150"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 </body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="13315.0" y="7347.5"/> </glyph> <glyph class="macromolecule" id="s1889_sa151"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ARL14 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 MHC-II transport was controlled by the GTPase ARL14/ARF7, which recruits the motor myosin 1E via an EFFECTOR_ACTIVATION protein ARF7EP. This complex controls movement of MHC-II vesicles along the actin cytoskeleton in human dendritic cells (DCs). References_end </body> </html> </notes> <label text="ARL14"/> <bbox w="80.0" h="40.0" x="13310.0" y="7380.0"/> </glyph> <glyph class="macromolecule" id="s1891_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:MYO1E Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 MHC-II transport was controlled by the GTPase ARL14/ARF7, which recruits the motor myosin 1E via an EFFECTOR_ACTIVATION protein ARF7EP. This complex controls movement of MHC-II vesicles along the actin cytoskeleton in human dendritic cells (DCs). References_end </body> </html> </notes> <label text="MYO1E"/> <bbox w="80.0" h="40.0" x="13230.0" y="7330.0"/> </glyph> </glyph> <glyph class="complex" id="s2286_csa29" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ARL14:GTP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 PSD4 is selectively expressed in the immune system and promotes GTP loading of ARL14/ARF7. References_end </body> </html> </notes> <label text="ARL14:GTP"/> <bbox w="100.0" h="120.0" x="13370.0" y="7120.0"/> <glyph class="macromolecule" id="s1884_sa180"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ARL14 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 MHC-II transport was controlled by the GTPase ARL14/ARF7, which recruits the motor myosin 1E via an EFFECTOR_ACTIVATION protein ARF7EP. This complex controls movement of MHC-II vesicles along the actin cytoskeleton in human dendritic cells (DCs). References_end </body> </html> </notes> <label text="ARL14"/> <bbox w="80.0" h="40.0" x="13380.0" y="7170.0"/> </glyph> <glyph class="simple chemical" id="s2477_sa181"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="13385.0" y="7127.5"/> </glyph> </glyph> <glyph class="complex" id="s2287_csa12" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ARL14:GDP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 PSD4 is selectively expressed in the immune system and promotes GTP loading of ARL14/ARF7. References_end </body> </html> </notes> <label text="ARL14:GDP"/> <bbox w="100.0" h="120.0" x="13540.0" y="7120.0"/> <glyph class="macromolecule" id="s1881_sa139"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ARL14 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21458045 MHC-II transport was controlled by the GTPase ARL14/ARF7, which recruits the motor myosin 1E via an EFFECTOR_ACTIVATION protein ARF7EP. This complex controls movement of MHC-II vesicles along the actin cytoskeleton in human dendritic cells (DCs). References_end </body> </html> </notes> <label text="ARL14"/> <bbox w="80.0" h="40.0" x="13550.0" y="7170.0"/> </glyph> <glyph class="simple chemical" id="s2476_sa140"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="GDP"/> <bbox w="70.0" h="25.0" x="13555.0" y="7127.5"/> </glyph> </glyph> <glyph class="complex" id="s2288_csa7" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MHC_class_II*:Tumor_antigen_fragment Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL10 References_end </body> </html> </notes> <label text="MHC_class_II*:Tumor_antigen_fragment"/> <bbox w="120.0" h="140.0" x="12820.0" y="7970.0"/> <glyph class="macromolecule" id="s3_sa119"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL6 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12391186 Maturation of monocyte-derived DCs was induced by TNF-α The surface levels of MHC class II increased markedly after TNF-α stimulation on CD83+ DC PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:22076556, PMID:22076556, PMID:25720354 Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. MHC class II molecules present antigen peptides to CD4+ T cells PMID:22076556, PMID:21220452 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:11702064 IL15 signaling upregulates surface expression of MHC class II PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="40.0" x="12840.0" y="8040.0"/> <glyph class="state variable" id="_82115c47-c41b-4bbb-9414-38c8f2392227"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12835.0" y="8055.0"/> </glyph> <glyph class="unit of information" id="_8fd28ae9-349b-432e-81d4-e7c0a2bd8ee8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12857.5" y="8035.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s6_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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11154916, PMID:11509172, PMID:22076556 Processed antigen peptide in lysosomes forms complex with MHC-class-II. formation and transport to the cell surface of MHC-class-II–peptide complexes is induced by maturation. Immature DCs in culture can take up antigen but do not present it efficiently to T cells. After detecting microbial products or proinflammatory cytokines, immature DCs transform into mature DCs, cells with a reduced capacity for antigen uptake but now with an exceptional capacity for T cell stimulation. PMID:22790179, PMID:14508489 The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome4, 5, 6. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex “loading machinery” (which includes tapasin, calreticulin and Erp57) References_end </body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="12840.0" y="7990.0"/> <glyph class="unit of information" id="_f2ddc9e1-d13e-4eea-8783-eaab57a33105"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12855.0" y="7985.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2296_csa8" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CYBA:CYBB:FAD:GTP:NCF1:NCF2:NCF4:RAC1_2*:heme Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. The regulation of phagosomal pH exerted by NOX2, and thereby of the efficacy of antigen cross-presentation in DCs, represents a clear illustration of how NOX2 can influence CD8(+) T lymphocyte responses. PMID:22157818 Phagosomal proteolysis in dendritic cells is modulated by NADPH oxidase in a pH-independent manner. PMID:22157818, PMID:22827577 CTSS (cathepsin S), CTSB (cathepsin B) and CTSL (cathepsin L) are active in DC phagosomes. Phagosomal NOX2 activity via ROS inhibits the activities of local cysteine (B/S/L ), but not aspartic (D/E), cathepsins. References_end </body> </html> </notes> <label text="NADPH_oxidase"/> <bbox w="215.0" h="235.0" x="11424.375" y="6150.0"/> <glyph class="macromolecule" id="s2821_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:CYBB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. References_end </body> </html> </notes> <label text="CYBB"/> <bbox w="80.0" h="40.0" x="11439.375" y="6155.0"/> </glyph> <glyph class="macromolecule" id="s2822_sa122"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CYBA Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="CYBA"/> <bbox w="80.0" h="40.0" x="11439.375" y="6205.0"/> </glyph> <glyph class="macromolecule" id="s2823_sa123"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCF1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. References_end </body> </html> </notes> <label text="NCF1"/> <bbox w="80.0" h="40.0" x="11539.375" y="6155.0"/> </glyph> <glyph class="macromolecule" id="s2824_sa124"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="NCF4"/> <bbox w="80.0" h="40.0" x="11539.375" y="6205.0"/> </glyph> <glyph class="macromolecule" id="s2825_sa125"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCF2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="NCF2"/> <bbox w="80.0" h="40.0" x="11539.375" y="6255.0"/> </glyph> <glyph class="macromolecule" id="s2826_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:RAC1 HUGO:RAC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. 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. PMID:14697347, PMID: 11146654 Integrin αvβ5 regulates phagocytosis via CRK /DOCK1 (DOCK180) /RAC1 pathway downstream of. Integrin αvβ5 activation results in recruitment of the p130cas–CrkII–Dock180 complex and RAC1 activation. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="11439.375" y="6255.0"/> </glyph> <glyph class="simple chemical" id="s2827_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> CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="11444.375" y="6302.5"/> </glyph> <glyph class="simple chemical" id="s2828_sa128"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:30413 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="heme"/> <bbox w="70.0" h="25.0" x="11494.375" y="6332.5"/> </glyph> <glyph class="simple chemical" id="s2475_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> CHEBI:16238 KEGGCOMPOUND:C00016 CAS:146-14-5 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION </body> </html> </notes> <label text="FAD"/> <bbox w="70.0" h="25.0" x="11544.375" y="6302.5"/> </glyph> </glyph> <glyph class="complex" id="s2297_csa284" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GATA1:SPI1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:10753833 GATA-1 interacts with the myeloid PU.1 transcription factor and represses PU.1-dependent transcription References_end </body> </html> </notes> <label text="s2297"/> <bbox w="100.0" h="120.0" x="9515.0" y="4725.0"/> <glyph class="macromolecule" id="s2298_sa2076"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GATA1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:FLT3LG PMID:10753833 GATA-1 interacts with the myeloid PU.1 transcription factor and represses PU.1-dependent transcription PMID:16418395 FLT3L induces PU.1 and STAT3 mRNA expression in DC progenitors and downregulates GATA1 mRNA expression. References_end </body> </html> </notes> <label text="GATA1"/> <bbox w="80.0" h="40.0" x="9525.0" y="4735.0"/> </glyph> <glyph class="macromolecule" id="s3566_sa2077"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SPI1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:FLT3LG PMID:20510871 SPI1 (PU.1) is a critical regulator of both conventional and plasmacytoid DC development. It is directly upregulates Flt3 gene activation. PMID:16418395 FLT3L induces PU.1 and STAT3 mRNA expression in DC progenitors and downregulates GATA1 mRNA expression. PMID:16283355, PMID:12803886 MIF upregulates expression of TLR4 in macrothages via PU.1 (SPI1) activation PMID:10734131 PU.1 (SPI1) together with IRF8 relulates TLR4 expression in myeloid cells () References_end </body> </html> </notes> <label text="SPI1"/> <bbox w="80.0" h="40.0" x="9525.0" y="4775.0"/> </glyph> </glyph> <glyph class="complex" id="s2299_csa18" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CLIP*:MHC_class_II* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22076556 The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II's export from the ER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed, degraded proteins. It is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP which blocks peptide binding until HLA-DM binds to MHC II, releasing CLIP and allowing other peptides to bind. The stable MHC class-II is then presented on the cell surface. References_end </body> </html> </notes> <label text="MHC_class_II*:CLIP*"/> <bbox w="100.0" h="120.0" x="12313.125" y="6597.5"/> <glyph class="macromolecule" id="s26_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: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL6 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12391186 Maturation of monocyte-derived DCs was induced by TNF-α The surface levels of MHC class II increased markedly after TNF-α stimulation on CD83+ DC PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:22076556, PMID:22076556, PMID:25720354 Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. MHC class II molecules present antigen peptides to CD4+ T cells PMID:22076556, PMID:21220452 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:11702064 IL15 signaling upregulates surface expression of MHC class II PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="40.0" x="12323.125" y="6657.5"/> <glyph class="state variable" id="_ce5e41db-ef43-4cb3-8c2c-2695ae94a383"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12318.125" y="6672.5"/> </glyph> <glyph class="unit of information" id="_3bc8b008-e40f-431a-8179-5a2c3b155305"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12340.625" y="6652.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5246_sa2904"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD74 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181339 Processing of CD74 includes its initial cleavage by Legumain, followed by late stage cleavage by Cathepsin S and Cathepsin L References_end </body> </html> </notes> <label text="CLIP*"/> <bbox w="80.0" h="40.0" x="12320.0" y="6610.0"/> <glyph class="unit of information" id="_e69358ef-c368-4588-8898-1ae73029754f"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12335.0" y="6605.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2300_csa2" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:B2M:CD1*:Lipid_antigen Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin References_end </body> </html> </notes> <label text="CD1*:B2M:Lipid_antigen"/> <bbox w="190.0" h="130.0" x="12205.0" y="7975.0"/> <glyph class="simple chemical" id="s3530_sa107"> <label text="Lipid_antigen"/> <bbox w="115.0" h="42.5" x="12207.5" y="7983.75"/> </glyph> <glyph class="macromolecule" id="s14_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:CD1A HUGO:CD1B HUGO:CD1C HUGO:CD1D Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL10 CASCADE:TLR2_4 CASCADE:TNF PMID:10837075, PMID:10358761, PMID:12391186 CD1 family as nonclassical, Ag-presenting molecules involved in regulation of T cell responses to microbial lipids and glycolipids-containing Ag. Both endogenous and exogenous lipids can be presented, and this pathway may contribute not only to microbial immunity but to autoimmunity and antitumor responses. In humans, four CD1 proteins (CD1a–d) are expressed by myeloid DCs, whereas in mice only CD1d has been identified. CD1 proteins are functionally heterogeneous, and two subgroups can be identified. Subgroup I, including human CD1b–c, can present glycolipids to a large repertoire of T cells. Indeed, mycobacteria-specific, CD1b-restricted CD8+α/β TCR T cells have been demonstrated. Binding of the lipids to these CD1 molecules requires endosomal acidification. Subgroup II includes mouse and human CD1d and binds a limited set of Ags (α-galactosyloceramide) and activates a restricted set of T cells as well as NK T cells PMID:10190903 Alpha-galactosylceramide (alpha-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12-mediated antitumor activities. Production of IFN-gamma by NKT cells in response to alpha-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, alpha-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1(-/-) or Valpha14(-/-) mice. PMID:15579430 Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) Molecules on Dendritic Cells in Metastatic Tumor Lesions. PMID:25582338 CD1a, which is involved in lipid Ag presentation, was significantly lower on imIL-15 DCs and mIL-15 DCs than on IL-4 DCs PMID:11238627 SB203580, an inhibitor of the p38 MAPK, but not the extracellular signal-regulated kinase l/2 pathway blocker PD98059, inhibited the up-regulation of CD1a, CD40, CD80, CD86, HLA-DR, and the DC maturation marker CD83 induced by LPS and TNF-α. Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) protein Molecules on Dendritic Cells in Metastatic Tumor Lesions PMID:11306493 IL4 signaling upregulates CD1a on cell surface of DC cells. References_end </body> </html> </notes> <label text="CD1*"/> <bbox w="80.0" h="40.0" x="12220.0" y="8030.0"/> <glyph class="unit of information" id="_af58fb16-9386-450e-8db8-b33b5992898e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12237.5" y="8025.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s16_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:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="12310.0" y="8030.0"/> </glyph> </glyph> <glyph class="complex" id="s2301_csa13" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CANX:MHC_class_I* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_I*:CANX"/> <bbox w="100.0" h="120.0" x="14860.176" y="6658.972"/> <glyph class="macromolecule" id="s2800_sa141"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CANX Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation. References_end </body> </html> </notes> <label text="CANX"/> <bbox w="80.0" h="40.0" x="14868.125" y="6667.5"/> </glyph> <glyph class="macromolecule" id="s3531_sa142"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNG PMID:16181333, PMID:22076556, PMID:10559964 MHC class I molecules is heterodimers that consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The MHC class I heavy chain, a transmembrane glycoprotein of approximately 44 kDa, binds upon synthesis to the membrane-associated endoplasmic reticulum (ER) chaperone, calnexin (CNX). Upon dissociation from CNX, the heavy chain binds β2 microglobulin (β2m) and is incorporated into the peptide-loading complex. The other constituents of the complex are the two subunits of the transporter associated with antigen processing (TAP1 and TAP2), the transmembrane glycoprotein tapasin, the soluble ER chaperone calreticulin (CRT), and the soluble thiol oxidoreductase ERp57. Peptides are transported into the ER from the cytosol via TAP, and, if necessary, they are trimmed by an ER-associated aminopeptidase (ERAAP or ERAP1) to 8–10 amino acids, the length that is generally required for association with class I molecules. If the peptide has the appropriate sequence, it binds to the MHC class I-β2m heterodimer, which is released from the peptide-loading complex. The fully assembled class I molecule then leaves the ER and travels via the Golgi apparatus to the plasma membrane, where it is accessible to CD8+ T cells. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="14870.176" y="6713.972"/> <glyph class="unit of information" id="_1815cc21-f839-42d3-8bc3-a0a339e0bd0e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14887.676" y="6708.972"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2303_csa21" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CALR:PDIA3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="PDIA3:CALR1"/> <bbox w="100.0" h="120.0" x="14553.125" y="6807.5"/> <glyph class="macromolecule" id="s1923_sa163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PDIA3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 PDIA3(ERp57) is a disulfide isomerase it is a non-covalently associated component of the peptide-loading complex. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting References_end </body> </html> </notes> <label text="PDIA3"/> <bbox w="80.0" h="40.0" x="14563.125" y="6817.5"/> </glyph> <glyph class="macromolecule" id="s1924_sa164"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CALR Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:LRP1 PMID:16181333, PMID:22076556 CALR (CRT or calreticulin) is a lectin specific for monoglucosylated N-linked glycans (17) that binds to the MHC class I molecule via its carbohydrate side chain. It also associates non-covalently with ERp57 in peptide-loading complex. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting PMID:23157435, PMID:16239148, PMID:20958319 CALR (CRT or calreticulin) is released by dying tumor cells and acts as eat-me signal. It acts via CD91 (LRP1) and initiates clearance of viable or apoptotic cells. References_end </body> </html> </notes> <label text="CALR"/> <bbox w="80.0" h="40.0" x="14563.125" y="6867.5"/> </glyph> </glyph> <glyph class="complex" id="s2308_csa26" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CALR:PDIA3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="PDIA3:CALR"/> <bbox w="100.0" h="120.0" x="12050.0" y="5820.0"/> <glyph class="macromolecule" id="s18_sa174"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PDIA3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 PDIA3(ERp57) is a disulfide isomerase it is a non-covalently associated component of the peptide-loading complex. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting References_end </body> </html> </notes> <label text="PDIA3"/> <bbox w="80.0" h="40.0" x="12060.0" y="5830.0"/> </glyph> <glyph class="macromolecule" id="s19_sa175"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CALR Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:LRP1 PMID:16181333, PMID:22076556 CALR (CRT or calreticulin) is a lectin specific for monoglucosylated N-linked glycans (17) that binds to the MHC class I molecule via its carbohydrate side chain. It also associates non-covalently with ERp57 in peptide-loading complex. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting PMID:23157435, PMID:16239148, PMID:20958319 CALR (CRT or calreticulin) is released by dying tumor cells and acts as eat-me signal. It acts via CD91 (LRP1) and initiates clearance of viable or apoptotic cells. References_end </body> </html> </notes> <label text="CALR"/> <bbox w="80.0" h="40.0" x="12060.0" y="5880.0"/> </glyph> </glyph> <glyph class="complex" id="s2356_csa31" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD74:MHC_class_II* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:TLR2_4 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB PMID:22076556 The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II's export from the ER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed, degraded proteins. It is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP which blocks peptide binding until HLA-DM binds to MHC II, releasing CLIP and allowing other peptides to bind. The stable MHC class-II is then presented on the cell surface. PMID:15644117 HMGB1 upregulates the expression of MHC class II molecules on the surface of macrophages and increases intigen presentation PMID:10477595, PMID:8920882, PMID:25215878 FLT3L induces Ag-presenting ability of Dcs. Probably via induction of surface expression of class II MHC and CD86 () References_end </body> </html> </notes> <label text="CD74:MHC_class_II*"/> <bbox w="100.0" h="120.0" x="11930.0" y="7980.0"/> <glyph class="macromolecule" id="s2357_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:CD74 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:MIF PMID:16181339 Processing of CD74 includes its initial cleavage by Legumain, followed by late stage cleavage by Cathepsin S and Cathepsin L PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation. References_end </body> </html> </notes> <label text="CD74"/> <bbox w="80.0" h="40.0" x="11940.0" y="7990.0"/> </glyph> <glyph class="macromolecule" id="s2358_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: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL6 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12391186 Maturation of monocyte-derived DCs was induced by TNF-α The surface levels of MHC class II increased markedly after TNF-α stimulation on CD83+ DC PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:22076556, PMID:22076556, PMID:25720354 Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. MHC class II molecules present antigen peptides to CD4+ T cells PMID:22076556, PMID:21220452 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:11702064 IL15 signaling upregulates surface expression of MHC class II PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="40.0" x="11940.0" y="8040.0"/> <glyph class="state variable" id="_fe16c463-390c-4437-a5e1-c58938a7eb4f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11935.0" y="8055.0"/> </glyph> <glyph class="unit of information" id="_80956499-5cb3-48b2-b540-59fd3e55bda8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11957.5" y="8035.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2372_csa6" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:B2M:MHC_class_I*:Tumor_antigen_fragment Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_I*:B2M:Tumor_antigen_fragment"/> <bbox w="230.0" h="135.0" x="13105.0" y="7982.5"/> <glyph class="macromolecule" id="s2374_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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11154916, PMID:11509172, PMID:22076556 Processed antigen peptide in lysosomes forms complex with MHC-class-II. formation and transport to the cell surface of MHC-class-II–peptide complexes is induced by maturation. Immature DCs in culture can take up antigen but do not present it efficiently to T cells. After detecting microbial products or proinflammatory cytokines, immature DCs transform into mature DCs, cells with a reduced capacity for antigen uptake but now with an exceptional capacity for T cell stimulation. PMID:22790179, PMID:14508489 The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome4, 5, 6. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex “loading machinery” (which includes tapasin, calreticulin and Erp57) References_end </body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="13180.0" y="7990.0"/> <glyph class="unit of information" id="_41c5eaec-7cea-43b4-962c-85f350ad5c08"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="13195.0" y="7985.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2373_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:HLA-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNG PMID:16181333, PMID:22076556, PMID:10559964 MHC class I molecules is heterodimers that consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The MHC class I heavy chain, a transmembrane glycoprotein of approximately 44 kDa, binds upon synthesis to the membrane-associated endoplasmic reticulum (ER) chaperone, calnexin (CNX). Upon dissociation from CNX, the heavy chain binds β2 microglobulin (β2m) and is incorporated into the peptide-loading complex. The other constituents of the complex are the two subunits of the transporter associated with antigen processing (TAP1 and TAP2), the transmembrane glycoprotein tapasin, the soluble ER chaperone calreticulin (CRT), and the soluble thiol oxidoreductase ERp57. Peptides are transported into the ER from the cytosol via TAP, and, if necessary, they are trimmed by an ER-associated aminopeptidase (ERAAP or ERAP1) to 8–10 amino acids, the length that is generally required for association with class I molecules. If the peptide has the appropriate sequence, it binds to the MHC class I-β2m heterodimer, which is released from the peptide-loading complex. The fully assembled class I molecule then leaves the ER and travels via the Golgi apparatus to the plasma membrane, where it is accessible to CD8+ T cells. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="13125.0" y="8037.5"/> <glyph class="unit of information" id="_9aa788f7-2777-4d67-97ab-7d766886ed1f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13142.5" y="8032.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2375_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:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="13215.0" y="8037.5"/> </glyph> </glyph> <glyph class="complex" id="s2460_csa92" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:HRAS Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="9455.0" y="3559.0"/> <glyph class="macromolecule" id="s2461_sa673"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HRAS Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="HRAS"/> <bbox w="80.0" h="40.0" x="9465.0" y="3569.0"/> </glyph> <glyph class="simple chemical" id="s2485_sa674"> <label text="GDP"/> <bbox w="70.0" h="25.0" x="9470.0" y="3616.5"/> </glyph> </glyph> <glyph class="complex" id="s2463_csa101" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ARF6:GTP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1864"/> <bbox w="100.0" h="120.0" x="8525.0" y="2970.0"/> <glyph class="macromolecule" id="s1857_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:ARF6 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII 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="8535.0" y="2980.0"/> </glyph> <glyph class="simple chemical" id="s2486_sa693"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="8540.0" y="3027.5"/> </glyph> </glyph> <glyph class="complex" id="s2503_csa124" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAP12*:HLA-E:KLRC3:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRC3 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s1490"/> <bbox w="210.0" h="190.0" x="12080.0" y="1415.0"/> <glyph class="macromolecule" id="s2517_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:KLRC3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRC3 MAP:NATURAL_KILLER PMID:15728498 NKG2E/CD94 receptors bind HLA-E 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="12090.0" y="1480.0"/> <glyph class="unit of information" id="_20da736d-0784-4657-8edf-c47bbf1c59df"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12107.5" y="1475.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2518_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:KLRD1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER CASCADE:KLRC2 CASCADE:KLRC3 References_end </body> </html> </notes> <label text="KLRD1"/> <bbox w="80.0" h="50.0" x="12090.0" y="1530.0"/> <glyph class="unit of information" id="_ed9cf465-90b8-4510-a67a-baee98ee79f6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12107.5" y="1525.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4009_sa762"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER CASCADE:KLRC2 CASCADE:KLRC3 PMID:2731048 HLA-E is a ligand of inhibitory receptor NKG2A. PMID:9486650, 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="12105.0" y="1430.0"/> </glyph> <glyph class="macromolecule" id="s2520_sa763"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TYROBP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:KLRC2 CASCADE:KLRC3 CASCADE:NKP44 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="12185.0" y="1525.0"/> <glyph class="state variable" id="_cfc3df5e-7e1e-407a-a59f-5f1cdfc5f93d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12177.5" y="1545.0"/> </glyph> <glyph class="unit of information" id="_8b7685cf-4fad-440a-9a1d-b7540345581a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12202.5" y="1520.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2816_csa169" compartmentRef="c12_ca12"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CYBA:CYBB:FAD:GTP:NCF1:NCF2:NCF4:RAC1_2*:heme Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:S100A PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. PMID:18809714 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. References_end </body> </html> </notes> <label text="NADPH oxidase"/> <bbox w="263.75" h="228.75" x="5841.7188" y="6631.5625"/> <glyph class="simple chemical" id="s1047_sa1130"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION </body> </html> </notes> <label text="FAD"/> <bbox w="70.0" h="25.0" x="5940.4688" y="6806.5625"/> </glyph> <glyph class="simple chemical" id="s1046_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> CHEBI:30413 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION </body> </html> </notes> <label text="heme"/> <bbox w="70.0" h="25.0" x="5870.4688" y="6806.5625"/> </glyph> <glyph class="simple chemical" id="s2880_sa1132"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION </body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="6016.7188" y="6807.8125"/> </glyph> <glyph class="macromolecule" id="s1043_sa1133"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 HUGO:RAC2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:15169870 Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. 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. PMID:14697347, PMID: 11146654 Integrin αvβ5 regulates phagocytosis via CRK /DOCK1 (DOCK180) /RAC1 pathway downstream of. Integrin αvβ5 activation results in recruitment of the p130cas–CrkII–Dock180 complex and RAC1 activation. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="5865.4688" y="6739.0625"/> </glyph> <glyph class="macromolecule" id="s1042_sa1134"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCF2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="NCF2"/> <bbox w="80.0" h="40.0" x="5983.5938" y="6735.9375"/> </glyph> <glyph class="macromolecule" id="s1041_sa1135"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="NCF4"/> <bbox w="80.0" h="40.0" x="5983.5938" y="6695.9375"/> </glyph> <glyph class="macromolecule" id="s1040_sa1136"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCF1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. References_end </body> </html> </notes> <label text="NCF1"/> <bbox w="80.0" h="40.0" x="5983.5938" y="6655.9375"/> </glyph> <glyph class="macromolecule" id="s1039_sa1137"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CYBA Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="CYBA"/> <bbox w="80.0" h="40.0" x="5862.9688" y="6696.5625"/> </glyph> <glyph class="macromolecule" id="s1038_sa1138"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CYBB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:TUMOR_KILLING MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. References_end </body> </html> </notes> <label text="CYBB"/> <bbox w="80.0" h="40.0" x="5862.9688" y="6656.5625"/> </glyph> </glyph> <glyph class="complex" id="s2841_csa172" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SLC3A2:SLC7A11 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:20414655, PMID:2880923, PMID:3115975 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. References_end </body> </html> </notes> <label text="s1118"/> <bbox w="105.0" h="145.0" x="15017.5" y="7957.5"/> <glyph class="macromolecule" id="s1121_sa1153"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:SLC3A2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION CASCADE:LGALS3 Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98). References_end </body> </html> </notes> <label text="SLC3A2"/> <bbox w="80.0" h="50.0" x="15030.0" y="8015.0"/> <glyph class="unit of information" id="_6b91f83d-3669-4fd6-8e2f-2124fcfae2ad"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15047.5" y="8010.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2819_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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC PMID:20414655, PMID:2880923, PMID:3115975, PMID:20028852 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. PMID:20028852 MDSCs express the cystine transporter but lack cystathionase and the ASC neutral amino acid transporter Therefore, macrophages, DCs, and MDSCs can import cystine; however, unlike macrophages and DCs, MDSCs are unable to export cysteine. MDSC sequester cystine and prevent T cells from obtaining cysteine which is important for Tcell activation. References_end </body> </html> </notes> <label text="SLC7A11"/> <bbox w="80.0" h="40.0" x="15030.0" y="7980.0"/> </glyph> </glyph> <glyph class="complex" id="s2842_csa173" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SLC3A2:SLC7A10 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:20414655, PMID:2880923, PMID:3115975 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. References_end </body> </html> </notes> <label text="s1123"/> <bbox w="100.0" h="130.0" x="15340.0" y="7965.0"/> <glyph class="macromolecule" id="s1124_sa1155"> <notes> <html xmlns="http://www.w3.org/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:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC PMID:20414655, PMID:2880923, PMID:3115975, PMID:20028852 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. PMID:20028852 MDSCs express the cystine transporter but lack cystathionase and the ASC neutral amino acid transporter Therefore, macrophages, DCs, and MDSCs can import cystine; however, unlike macrophages and DCs, MDSCs are unable to export cysteine. MDSC sequester cystine and prevent T cells from obtaining cysteine which is important for Tcell activation. References_end </body> </html> </notes> <label text="SLC7A10"/> <bbox w="80.0" h="40.0" x="15350.0" y="7975.0"/> </glyph> <glyph class="macromolecule" id="s1125_sa1156"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:SLC3A2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION CASCADE:LGALS3 Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98). References_end </body> </html> </notes> <label text="SLC3A2"/> <bbox w="80.0" h="50.0" x="15350.0" y="8020.0"/> <glyph class="unit of information" id="_60ce2573-e258-4ee4-8f41-cad3e85ed661"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15367.5" y="8015.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2886_csa177" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PGE2:PTGER2 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:PGE2 PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. References_end </body> </html> </notes> <label text="s1092"/> <bbox w="100.0" h="120.0" x="4910.0" y="1705.0"/> <glyph class="macromolecule" id="s2887_sa1187"> <notes> <html xmlns="http://www.w3.org/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:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:PGE2 PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. References_end </body> </html> </notes> <label text="PTGER2"/> <bbox w="80.0" h="50.0" x="4920.0" y="1750.0"/> <glyph class="unit of information" id="_3fc400a4-a87a-4c3c-8ed0-f03f0d381b42"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4937.5" y="1745.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s1093_sa1188"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CASCADE:PGE2 CASCADE:MIF MAP:MDSC PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="4925.0" y="1722.5"/> </glyph> </glyph> <glyph class="complex" id="s2888_csa178" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PGE2:PTGER4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:PGE2 PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. References_end </body> </html> </notes> <label text="s1095"/> <bbox w="100.0" h="120.0" x="5030.0" y="1695.0"/> <glyph class="macromolecule" id="s1096_sa1189"> <notes> <html xmlns="http://www.w3.org/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:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:PGE2 PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. PMID:16186186 PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. References_end </body> </html> </notes> <label text="PTGER4"/> <bbox w="80.0" h="50.0" x="5040.0" y="1740.0"/> <glyph class="unit of information" id="_add73e22-227b-4b6e-bd15-c2c94cb06061"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5057.5" y="1735.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s1091_sa1190"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CASCADE:PGE2 CASCADE:MIF MAP:MDSC PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="5045.0" y="1712.5"/> </glyph> </glyph> <glyph class="complex" id="s3112_csa211" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:FADD:RIPK1:TNF:TNFR1*:TRADD:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modified RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. References_end </body> </html> </notes> <label text="TNFR1"/> <bbox w="210.0" h="180.0" x="15580.0" y="3230.0"/> <glyph class="macromolecule" id="s832_sa1618"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RIPK1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IFNG CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="15590.0" y="3290.0"/> <glyph class="state variable" id="_4a9ec407-65e1-4410-a435-18585f9c2f17"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="15660.0" y="3305.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s831_sa1619"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRADD Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:14730360 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="15695.0" y="3340.0"/> </glyph> <glyph class="macromolecule" id="s833_sa1620"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2  induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="15600.0" y="3340.0"/> <glyph class="state variable" id="_07b5c79c-5baa-4318-bdcd-bc2072863bf4"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="15670.0" y="3353.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s830_sa1621"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MAP:MAST_CELL MAP:MDSC MAP:NEUTROPHIL MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:MIF CASCADE:IL10 CASCADE:KLRG1 CASCADE:FCAR CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 CASCADE:IL15 CASCADE:CSF2 CASCADE:CSF1 CASCADE:TNF CASCADE:IFNG PMID:19732719  Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, 14625680 TNF and IFNG cooperate in the activation of macrophages. PMID:18633355 TNF is pro-angiogenic facror. PMID:23510023, PMID:23170255 TRAIL, FASL and TNF provides Dendritic cell tumor killing activity.()  L10 stimulates HO1 expression via MAPK p38 stimulation. HO-1 mediates IL-10-induced suppression of TNF- production and IL-10-induced suppression of MMP9 and INOS expression PMID:22955274 SHIP inhibit MAPKp38 activation and prevent MNK1 phosphorylation by inhibiting the p38 MAPK pathway downstream of IL10. MNK1 regulates TNFa mRNA polysome assembly and upregulates TNFa translation.IL-10 Inhibits TNF Translation through SHIP1-mediated Inhibition of Mnk1 PMID:15699106, PMID:12646658 Phosphorylated STAT1 binds to TNF promoter end induces TNF expression downstream of IFNG. PMID:15099563 Mast cells produce cytokines TNF-a, TGF-b, IFN-a, IL-1a, IL-1b, IL-5, IL-6, IL-13, IL-16, IL-18 PMID:24092389 TANs from early tumors are more cytotoxic toward tumor cells and produce higher levels of TNF-α, NO, and H2O2 and, in established tumors, these functions are downregulated and TAN acquire a more protumorigenic phenotype PMID:21826665 TANs produce TNF and IL1B, probably downstream of TLR4 References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="15700.0" y="3240.0"/> </glyph> <glyph class="macromolecule" id="s829_sa1622"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IFNG CASCADE:TNF Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="15695.0" y="3285.0"/> <glyph class="unit of information" id="_2c06e39f-81b7-4650-8eaf-c95bd403cefc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15712.5" y="3280.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s828_sa1623"> <label text="FADD"/> <bbox w="80.0" h="40.0" x="15595.0" y="3240.0"/> </glyph> </glyph> <glyph class="complex" id="s3308_csa253" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL2:IL2RA:IL2RB:IL2RG:JAK1:JAK3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL2 PMID:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) PMID:12095053, PMID:8683106 IL2 receptor in DC acts probably via JAK1 and JAK3 (demonstrated for NK and T-cells only) References_end </body> </html> </notes> <label text="s2275"/> <bbox w="200.0" h="200.0" x="15585.0" y="4420.0"/> <glyph class="macromolecule" id="s2362_sa1898"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL2 CASCADE:IL15 CASCADE:IL21 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:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) References_end </body> </html> </notes> <label text="IL2RA"/> <bbox w="80.0" h="50.0" x="15593.75" y="4475.0"/> <glyph class="unit of information" id="_6eeb3a8f-96b6-4844-98f1-962fb7f72baa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15611.25" y="4470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2363_sa1899"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL2 PMID:16212621 IL-2- and IL-15-induced phosphorylation of the IL-2RB chain in T cells. PMID:10820393, PMID:24829413 IL2 receptor is expressed in dendritic cells. The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) References_end </body> </html> </notes> <label text="IL2RB"/> <bbox w="80.0" h="50.0" x="15683.75" y="4485.0"/> <glyph class="state variable" id="_89285dcb-a883-41b1-b0ed-da5a7052e2d1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15678.75" y="4505.0"/> </glyph> <glyph class="unit of information" id="_831230d9-9c96-4206-83c2-10925b2c2e15"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15701.25" y="4480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2364_sa1900"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL21 CASCADE:IL2 Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, 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="IL2RG"/> <bbox w="80.0" h="50.0" x="15685.75" y="4425.0"/> <glyph class="unit of information" id="_b997d077-cf58-4094-bebe-716d625ee885"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15703.25" y="4420.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3314_sa1901"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII CASCADE:IL15 CASCADE:CD40LG CASCADE:NKp30 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: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.  15353479 Human and mouse DCs produce IL-2 downstream of IL15+CD40L signaling References_end </body> </html> </notes> <label text="IL2"/> <bbox w="80.0" h="40.0" x="15595.0" y="4430.0"/> </glyph> <glyph class="macromolecule" id="s2388_sa1903"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:JAK1 Identifiers_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 CASCADE:IFNAB ‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:7512720, PMID:7521688 Jak1 and Jak2 are activated by the G-CSFR References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="15690.0" y="4555.0"/> <glyph class="state variable" id="_2bec4e1b-f779-43dd-b6d7-33238cf8098f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15685.0" y="4570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5207_sa2886"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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 ------ Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IL4 MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 Maps_Modules_end </body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="15600.0" y="4550.0"/> </glyph> </glyph> <glyph class="complex" id="s3330_csa255" compartmentRef="c13_ca13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:FLT3:FLT3LG Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:DC References_end </body> </html> </notes> <label text="s2281"/> <bbox w="100.0" h="140.0" x="15755.0" y="5600.0"/> <glyph class="macromolecule" id="s3332_sa1911"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FLT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:FLT3LG PMID:15253381 It was found that the following signal transduction molecules were all activated by the stimulated FLT3 receptor: phospholipase g-1, RAS GTPase-activating protein GAP, p85 subunit of phosphatidylinositol 3-kinase (PI3 K), SH2-containing sequence proteins (SHCS), SH2-domain-containing inositol phosphatase (SHIP), GRB2, VAV, FYN and SRC. Of these, various molecules were shown to directly physically asssociate with the FLT3 cytoplasmic domain. These proteins are involved in different signal transduction pathways, including the RAS-RAF-MEK-ERK pathway References_end </body> </html> </notes> <label text="FLT3"/> <bbox w="80.0" h="50.0" x="15765.0" y="5665.0"/> <glyph class="unit of information" id="_2c67d8e8-e856-4526-9b99-f2a4116a98ae"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15782.5" y="5660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3334_sa1912"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FLT3LG Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:FLT3LG PMID:10477595, PMID:9268501, PMID:8920882 The cytokine FLT3 ligand (FL) enhances dendritic cell (DC) generation and differentiation. PMID:10477595 FL induces Ag-presenting ability of DCs. FL induced a high level of NF-κB nuclear translocation and specific DNA binding VEGF inhibited FL-inducible activation of transcription factor NF-κB. PMID:14670306 STAT3 is required for Flt3L-dependent dendritic cell differentiation. 9176488  Flt3L treatment not only induced complete tumor regression in a significant proportion of mice, but also decreased tumor growth rate in the remaining mice. Probabli via DC activation. PMID:16418395 Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development. PMID:8920882 Daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. FLT3L induces PU.1 and STAT3 mRNA expression in DC progenitors and downregulates GATA1 mRNA expression. PMID:25215878 FLT3L partially antagonized IL-10-mediated inhibition on DCs function and downregulates IL10 mRNA expression in DCs PMID:10477595, PMID:8920882,  PMID:25215878 FLT3L induces Ag-presenting ability of Dcs. Probably via induction of surface expression of class II MHC and CD86 and also expression of CD83, a and CD80 and was significantly enhanced by the FLT3L Daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers CD11c, DEC205. References_end </body> </html> </notes> <label text="FLT3LG"/> <bbox w="80.0" h="40.0" x="15765.0" y="5620.0"/> </glyph> </glyph> <glyph class="complex" id="s3355_csa19" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:TAP1:TAP2:TAPASIN* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="TAPASIN:TAP1:TAP2"/> <bbox w="100.0" h="180.0" x="12580.0" y="6060.0"/> <glyph class="macromolecule" id="s3356_sa157"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAP1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Antigen peptides are transported into the ER from the cytosol via TAPs PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting. TAP-mediates peptide transport and loading on MHC class I in purified phagosomes. References_end </body> </html> </notes> <label text="TAP1"/> <bbox w="80.0" h="40.0" x="12590.0" y="6120.0"/> </glyph> <glyph class="macromolecule" id="s3357_sa158"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAP2 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:16181333, PMID:22076556 Antigen peptides are transported into the ER from the cytosol via TAPs, tapasin stabilizes the TAP1/TAP2 heterodimer. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. TAP-mediates peptide transport and loading on MHC class I in purified phagosomes. References_end </body> </html> </notes> <label text="TAP2"/> <bbox w="80.0" h="40.0" x="12590.0" y="6170.0"/> </glyph> <glyph class="macromolecule" id="s3358_sa159"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAPBP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333 Tapasin stabilizes the TAP1/TAP2 heterodimer PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation. PMID:10973281 Tapasin may have a quantitative effect on the peptide loading process as suggested by the impaired antigen presentation by DCs from Tpn-/- mice. dendritic cells of tapasin-deficient mice do not cross-present protein antigen via the MHC class I pathway. PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="TAPASIN*"/> <bbox w="80.0" h="40.0" x="12590.0" y="6070.0"/> </glyph> </glyph> <glyph class="complex" id="s3359_csa22" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:B2M:MHC_class_I* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_I*:B2M"/> <bbox w="180.0" h="70.0" x="11850.0" y="5855.0"/> <glyph class="macromolecule" id="s3360_sa165"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNG PMID:16181333, PMID:22076556, PMID:10559964 MHC class I molecules is heterodimers that consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The MHC class I heavy chain, a transmembrane glycoprotein of approximately 44 kDa, binds upon synthesis to the membrane-associated endoplasmic reticulum (ER) chaperone, calnexin (CNX). Upon dissociation from CNX, the heavy chain binds β2 microglobulin (β2m) and is incorporated into the peptide-loading complex. The other constituents of the complex are the two subunits of the transporter associated with antigen processing (TAP1 and TAP2), the transmembrane glycoprotein tapasin, the soluble ER chaperone calreticulin (CRT), and the soluble thiol oxidoreductase ERp57. Peptides are transported into the ER from the cytosol via TAP, and, if necessary, they are trimmed by an ER-associated aminopeptidase (ERAAP or ERAP1) to 8–10 amino acids, the length that is generally required for association with class I molecules. If the peptide has the appropriate sequence, it binds to the MHC class I-β2m heterodimer, which is released from the peptide-loading complex. The fully assembled class I molecule then leaves the ER and travels via the Golgi apparatus to the plasma membrane, where it is accessible to CD8+ T cells. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="11860.0" y="5865.0"/> <glyph class="unit of information" id="_6fd7b6aa-bfe5-4bde-a66d-d3a8e05e7704"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11877.5" y="5860.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3361_sa166"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="11942.949" y="5866.028"/> </glyph> </glyph> <glyph class="complex" id="s3362_csa11" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CD74:MHC_class_II* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22076556 The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II's export from the ER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed, degraded proteins. It is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP which blocks peptide binding until HLA-DM binds to MHC II, releasing CLIP and allowing other peptides to bind. The stable MHC class-II is then presented on the cell surface. References_end </body> </html> </notes> <label text="CD74:MHC_class_II*"/> <bbox w="100.0" h="120.0" x="13748.125" y="6725.0"/> <glyph class="macromolecule" id="s3363_sa137"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD74 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:MIF PMID:16181339 Processing of CD74 includes its initial cleavage by Legumain, followed by late stage cleavage by Cathepsin S and Cathepsin L PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation. References_end </body> </html> </notes> <label text="CD74"/> <bbox w="80.0" h="40.0" x="13761.074" y="6729.778"/> </glyph> <glyph class="macromolecule" id="s3364_sa138"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL6 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12391186 Maturation of monocyte-derived DCs was induced by TNF-α The surface levels of MHC class II increased markedly after TNF-α stimulation on CD83+ DC PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:22076556, PMID:22076556, PMID:25720354 Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. MHC class II molecules present antigen peptides to CD4+ T cells PMID:22076556, PMID:21220452 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:11702064 IL15 signaling upregulates surface expression of MHC class II PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="40.0" x="13758.125" y="6780.0"/> <glyph class="state variable" id="_696d713a-068f-4cf2-9a0c-ecd1fd6edf55"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13753.125" y="6795.0"/> </glyph> <glyph class="unit of information" id="_44e6645d-f0b7-4124-a251-77a910cfec68"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13775.625" y="6775.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3365_csa14" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:B2M:MHC_class_I*:Tumor_antigen_fragment Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_I*:B2M:Tumor_antigen_fragment"/> <bbox w="200.0" h="125.0" x="14323.125" y="6905.0"/> <glyph class="macromolecule" id="s3366_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:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="14433.125" y="6960.0"/> </glyph> <glyph class="macromolecule" id="s3367_sa189"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HLA-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNG PMID:16181333, PMID:22076556, PMID:10559964 MHC class I molecules is heterodimers that consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The MHC class I heavy chain, a transmembrane glycoprotein of approximately 44 kDa, binds upon synthesis to the membrane-associated endoplasmic reticulum (ER) chaperone, calnexin (CNX). Upon dissociation from CNX, the heavy chain binds β2 microglobulin (β2m) and is incorporated into the peptide-loading complex. The other constituents of the complex are the two subunits of the transporter associated with antigen processing (TAP1 and TAP2), the transmembrane glycoprotein tapasin, the soluble ER chaperone calreticulin (CRT), and the soluble thiol oxidoreductase ERp57. Peptides are transported into the ER from the cytosol via TAP, and, if necessary, they are trimmed by an ER-associated aminopeptidase (ERAAP or ERAP1) to 8–10 amino acids, the length that is generally required for association with class I molecules. If the peptide has the appropriate sequence, it binds to the MHC class I-β2m heterodimer, which is released from the peptide-loading complex. The fully assembled class I molecule then leaves the ER and travels via the Golgi apparatus to the plasma membrane, where it is accessible to CD8+ T cells. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="14338.125" y="6962.5"/> <glyph class="unit of information" id="_c8ed23ea-dc3b-4ecf-ab68-8bf8da1935bf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14355.625" y="6957.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3368_sa190"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11154916, PMID:11509172, PMID:22076556 Processed antigen peptide in lysosomes forms complex with MHC-class-II. formation and transport to the cell surface of MHC-class-II–peptide complexes is induced by maturation. Immature DCs in culture can take up antigen but do not present it efficiently to T cells. After detecting microbial products or proinflammatory cytokines, immature DCs transform into mature DCs, cells with a reduced capacity for antigen uptake but now with an exceptional capacity for T cell stimulation. PMID:22790179, PMID:14508489 The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome4, 5, 6. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex “loading machinery” (which includes tapasin, calreticulin and Erp57) References_end </body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="14348.125" y="6907.5"/> <glyph class="unit of information" id="_9684c43a-db90-458b-a3e2-3ab2eeabda88"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="14363.125" y="6902.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3369_csa15" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:TAP1:TAP2:TAPASIN* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="TAPASIN:TAP1:TAP2"/> <bbox w="183.125" h="112.5" x="13750.0" y="6447.5"/> <glyph class="macromolecule" id="s3370_sa146"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAP1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Antigen peptides are transported into the ER from the cytosol via TAPs PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. PMID:14508489 Together with TAP, tapasin, calreticulin, ERp57 and the heavy chain of MHC class I were all detected in purified early phagosomes by western blotting. TAP-mediates peptide transport and loading on MHC class I in purified phagosomes. References_end </body> </html> </notes> <label text="TAP1"/> <bbox w="80.0" h="40.0" x="13753.125" y="6457.5"/> </glyph> <glyph class="macromolecule" id="s3371_sa147"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAP2 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: PMID:16181333, PMID:22076556 Antigen peptides are transported into the ER from the cytosol via TAPs, tapasin stabilizes the TAP1/TAP2 heterodimer. PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. TAP-mediates peptide transport and loading on MHC class I in purified phagosomes. References_end </body> </html> </notes> <label text="TAP2"/> <bbox w="80.0" h="40.0" x="13750.0" y="6500.0"/> </glyph> <glyph class="macromolecule" id="s3372_sa148"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAPBP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333 Tapasin stabilizes the TAP1/TAP2 heterodimer PMID:17204652 DCs, which are biased for MHCI cross-presentation, were enriched in Tap1, Tap2, calreticulin, calnexin, Sec61, ERp57, ERAAP, as well as cystatin B and C, all of which are involved in MHCI presentation or inhibition of enzymes that process peptides for MHCII presentation. PMID:10973281 Tapasin may have a quantitative effect on the peptide loading process as suggested by the impaired antigen presentation by DCs from Tpn-/- mice. dendritic cells of tapasin-deficient mice do not cross-present protein antigen via the MHC class I pathway. PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="TAPASIN*"/> <bbox w="80.0" h="40.0" x="13843.125" y="6497.5"/> </glyph> </glyph> <glyph class="complex" id="s3373_csa9" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:B2M:MHC_class_I* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_I*:B2M"/> <bbox w="180.0" h="70.0" x="14330.176" y="6693.972"/> <glyph class="macromolecule" id="s3374_sa130"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNG PMID:16181333, PMID:22076556, PMID:10559964 MHC class I molecules is heterodimers that consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The MHC class I heavy chain, a transmembrane glycoprotein of approximately 44 kDa, binds upon synthesis to the membrane-associated endoplasmic reticulum (ER) chaperone, calnexin (CNX). Upon dissociation from CNX, the heavy chain binds β2 microglobulin (β2m) and is incorporated into the peptide-loading complex. The other constituents of the complex are the two subunits of the transporter associated with antigen processing (TAP1 and TAP2), the transmembrane glycoprotein tapasin, the soluble ER chaperone calreticulin (CRT), and the soluble thiol oxidoreductase ERp57. Peptides are transported into the ER from the cytosol via TAP, and, if necessary, they are trimmed by an ER-associated aminopeptidase (ERAAP or ERAP1) to 8–10 amino acids, the length that is generally required for association with class I molecules. If the peptide has the appropriate sequence, it binds to the MHC class I-β2m heterodimer, which is released from the peptide-loading complex. The fully assembled class I molecule then leaves the ER and travels via the Golgi apparatus to the plasma membrane, where it is accessible to CD8+ T cells. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="14340.176" y="6703.972"/> <glyph class="unit of information" id="_df735201-a13e-427f-a00c-decdd6553a52"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14357.676" y="6698.972"/> </glyph> </glyph> <glyph class="macromolecule" id="s3375_sa131"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="14420.176" y="6703.972"/> </glyph> </glyph> <glyph class="complex" id="s3381_csa24" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:B2M:MHC_class_I*:Tumor_antigen_fragment Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_I*:B2M:Tumor_antigen_fragment"/> <bbox w="200.0" h="125.0" x="12150.0" y="5947.5"/> <glyph class="macromolecule" id="s3382_sa169"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNG PMID:16181333, PMID:22076556, PMID:10559964 MHC class I molecules is heterodimers that consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The MHC class I heavy chain, a transmembrane glycoprotein of approximately 44 kDa, binds upon synthesis to the membrane-associated endoplasmic reticulum (ER) chaperone, calnexin (CNX). Upon dissociation from CNX, the heavy chain binds β2 microglobulin (β2m) and is incorporated into the peptide-loading complex. The other constituents of the complex are the two subunits of the transporter associated with antigen processing (TAP1 and TAP2), the transmembrane glycoprotein tapasin, the soluble ER chaperone calreticulin (CRT), and the soluble thiol oxidoreductase ERp57. Peptides are transported into the ER from the cytosol via TAP, and, if necessary, they are trimmed by an ER-associated aminopeptidase (ERAAP or ERAP1) to 8–10 amino acids, the length that is generally required for association with class I molecules. If the peptide has the appropriate sequence, it binds to the MHC class I-β2m heterodimer, which is released from the peptide-loading complex. The fully assembled class I molecule then leaves the ER and travels via the Golgi apparatus to the plasma membrane, where it is accessible to CD8+ T cells. References_end </body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="12170.0" y="6002.5"/> <glyph class="unit of information" id="_fdf09b91-9a88-4381-92dc-4de1048d9f95"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12187.5" y="5997.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3383_sa170"> <notes> <html xmlns="http://www.w3.org/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:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11154916, PMID:11509172, PMID:22076556 Processed antigen peptide in lysosomes forms complex with MHC-class-II. formation and transport to the cell surface of MHC-class-II–peptide complexes is induced by maturation. Immature DCs in culture can take up antigen but do not present it efficiently to T cells. After detecting microbial products or proinflammatory cytokines, immature DCs transform into mature DCs, cells with a reduced capacity for antigen uptake but now with an exceptional capacity for T cell stimulation. PMID:22790179, PMID:14508489 The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome4, 5, 6. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex “loading machinery” (which includes tapasin, calreticulin and Erp57) References_end </body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="12170.0" y="5957.5"/> <glyph class="unit of information" id="_21a2ae1d-2bd2-4d98-82be-82deccebf777"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12185.0" y="5952.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3384_sa171"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="12260.0" y="6002.5"/> </glyph> </glyph> <glyph class="complex" id="s3385_csa20" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:B2M:CD1*:Lipid_antigen Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin References_end </body> </html> </notes> <label text="CD1*:B2M:Lipid_antigen"/> <bbox w="190.0" h="130.0" x="11655.0" y="6745.0"/> <glyph class="simple chemical" id="s3386_sa160"> <label text="Lipid_antigen"/> <bbox w="115.0" h="42.5" x="11657.5" y="6753.75"/> </glyph> <glyph class="macromolecule" id="s3387_sa161"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD1A HUGO:CD1B HUGO:CD1C HUGO:CD1D Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL10 CASCADE:TLR2_4 CASCADE:TNF PMID:10837075, PMID:10358761, PMID:12391186 CD1 family as nonclassical, Ag-presenting molecules involved in regulation of T cell responses to microbial lipids and glycolipids-containing Ag. Both endogenous and exogenous lipids can be presented, and this pathway may contribute not only to microbial immunity but to autoimmunity and antitumor responses. In humans, four CD1 proteins (CD1a–d) are expressed by myeloid DCs, whereas in mice only CD1d has been identified. CD1 proteins are functionally heterogeneous, and two subgroups can be identified. Subgroup I, including human CD1b–c, can present glycolipids to a large repertoire of T cells. Indeed, mycobacteria-specific, CD1b-restricted CD8+α/β TCR T cells have been demonstrated. Binding of the lipids to these CD1 molecules requires endosomal acidification. Subgroup II includes mouse and human CD1d and binds a limited set of Ags (α-galactosyloceramide) and activates a restricted set of T cells as well as NK T cells PMID:10190903 Alpha-galactosylceramide (alpha-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12-mediated antitumor activities. Production of IFN-gamma by NKT cells in response to alpha-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, alpha-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1(-/-) or Valpha14(-/-) mice. PMID:15579430 Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) Molecules on Dendritic Cells in Metastatic Tumor Lesions. PMID:25582338 CD1a, which is involved in lipid Ag presentation, was significantly lower on imIL-15 DCs and mIL-15 DCs than on IL-4 DCs PMID:11238627 SB203580, an inhibitor of the p38 MAPK, but not the extracellular signal-regulated kinase l/2 pathway blocker PD98059, inhibited the up-regulation of CD1a, CD40, CD80, CD86, HLA-DR, and the DC maturation marker CD83 induced by LPS and TNF-α. Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) protein Molecules on Dendritic Cells in Metastatic Tumor Lesions PMID:11306493 IL4 signaling upregulates CD1a on cell surface of DC cells. References_end </body> </html> </notes> <label text="CD1*"/> <bbox w="80.0" h="40.0" x="11665.0" y="6805.0"/> <glyph class="unit of information" id="_f119172a-467b-49ca-b830-48fbf4aef988"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11682.5" y="6800.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3388_sa162"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:B2M Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181333, PMID:22076556 Upon dissociation from CNX, the heavy chain of (MHC) class I binds β2 microglobulin (b2m) and is incorporated into the peptide-loading complex. PMID:10358761 All CD1 proteins studied to date are expressed on the surface of cells as type I transmembrane proteins that associate noncovalently with β2-microglobulin PMID:11717192 The gene expression of TAP1, TAP2, tapasin, β2m and HLA-α HC is up-regulated in mature DC. References_end </body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="11755.0" y="6805.0"/> </glyph> </glyph> <glyph class="complex" id="s3389_csa17" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:MHC_class_II*:Tumor_antigen_fragment Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="MHC_class_II*:Tumor_antigen_fragment"/> <bbox w="100.0" h="130.0" x="12003.125" y="6782.5"/> <glyph class="macromolecule" id="s3390_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: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION CASCADE:MIF CASCADE:IL6 CASCADE:IL10 CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:FLT3LG CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12391186 Maturation of monocyte-derived DCs was induced by TNF-α The surface levels of MHC class II increased markedly after TNF-α stimulation on CD83+ DC PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86 and MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:22076556, PMID:22076556, PMID:25720354 Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. MHC class II molecules present antigen peptides to CD4+ T cells PMID:22076556, PMID:21220452 CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. PMID:11702064 IL15 signaling upregulates surface expression of MHC class II PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II  ) References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="40.0" x="12013.125" y="6842.5"/> <glyph class="state variable" id="_895aad8d-6263-472f-84b4-a956b756a023"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12008.125" y="6857.5"/> </glyph> <glyph class="unit of information" id="_ef64513d-82de-47b2-933c-46d3165fdd7b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12030.625" y="6837.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3391_sa154"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRES