</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_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="12013.125" y="6792.5"/> <glyph class="unit of information" id="_e3c411e9-981d-4ef5-8fd0-6b19afa6cc27"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12028.125" y="6787.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3392_csa23" 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:CD74:MHC_class_II* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:IL6 Maps_Modules_end References_begin: MAP:DENDRITIC_CELL 16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. 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="12453.125" y="6377.5"/> <glyph class="macromolecule" id="s3393_sa167"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="12463.125" y="6387.5"/> </glyph> <glyph class="macromolecule" id="s3394_sa168"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="12463.125" y="6437.5"/> <glyph class="state variable" id="_611dbcc6-f4d8-4dc6-a791-08346863b00c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12458.125" y="6452.5"/> </glyph> <glyph class="unit of information" id="_5c6f6677-dfa7-49d0-b568-36c8aadc432f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12480.625" y="6432.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3488_csa267" 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 References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="s35"/> <bbox w="110.0" h="150.0" x="12705.0" y="3755.0"/> <glyph class="macromolecule" id="s37_sa2029"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="12715.0" y="3845.0"/> <glyph class="unit of information" id="_ffb3fa6e-4d1b-4de6-b1da-cf1efce0cf73"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12730.0" y="3840.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3506_sa2030"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="12715.0" y="3805.0"/> </glyph> <glyph class="macromolecule" id="s3489_sa2031"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="12715.0" y="3765.0"/> <glyph class="state variable" id="_d5cfe11f-71b5-43b0-8aac-f89082c7111c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12710.0" y="3780.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3493_csa271" 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:CD247:NFKB1_p50*:p100 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL 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="s2447"/> <bbox w="112.69231" h="171.92308" x="12073.654" y="3774.0386"/> <glyph class="macromolecule" id="s3509_sa2040"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="12089.038" y="3785.9614"/> </glyph> <glyph class="macromolecule" id="s66_sa2041"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="CD247"/> <bbox w="80.0" h="40.0" x="12089.038" y="3835.9614"/> </glyph> <glyph class="macromolecule" id="s83_sa2042"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="81.25" h="46.0" x="12088.413" y="3872.9614"/> <glyph class="unit of information" id="_9ed1b31a-ee2b-4d7f-9331-8728f30dbb67"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12104.038" y="3867.9614"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3498_csa276" 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*:cREL* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="s2447"/> <bbox w="100.0" h="120.0" x="12695.0" y="4350.0"/> <glyph class="macromolecule" id="s3515_sa2055"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: 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="12705.0" y="4360.0"/> </glyph> <glyph class="macromolecule" id="s3526_sa2056"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="81.25" h="46.0" x="12705.0" y="4404.0"/> <glyph class="unit of information" id="_8c4e7ebf-6751-44f3-a99b-725c6cf06089"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12720.625" y="4399.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3499_csa277" 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*:RELB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL 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. TLRs activate RelB-p50 via the canonical NFκB pathway IKKB signaling is required for RelB activation. PMID:23394901 dimer RelB/p50 rather than the p50/p50 complex inhibits TNF production in LPS-stimulated DCs and macrophages. This implies that the non-canonical RelB/p50 could modulate the canonical p65/p50 pathway. PMID:19655301 RelB/p50 regulates CCL19 production, but fails to promote human DC maturation References_end </body> </html> </notes> <label text="s2440"/> <bbox w="110.0" h="130.0" x="12960.0" y="4335.0"/> <glyph class="macromolecule" id="s2441_sa2057"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="68.75" h="46.0" x="12975.625" y="4392.0"/> </glyph> <glyph class="macromolecule" id="s2442_sa2058"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="81.25" h="46.0" x="12968.75" y="4345.0"/> <glyph class="unit of information" id="_38b8c424-ebed-43b2-8baf-5afa72ad8609"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12984.375" y="4340.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3501_csa280" 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:RELB:p100 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE References_end </body> </html> </notes> <label text="s2443"/> <bbox w="100.0" h="130.0" x="11910.0" y="3925.0"/> <glyph class="macromolecule" id="s2438_sa2063"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="11920.0" y="3935.0"/> </glyph> <glyph class="macromolecule" id="s3527_sa2064"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="67.5" h="52.0" x="11926.25" y="3979.0"/> </glyph> </glyph> <glyph class="complex" id="s3502_csa281" 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:RELB:p52 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE References_end </body> </html> </notes> <label text="s2445"/> <bbox w="100.0" h="130.0" x="11910.0" y="4185.0"/> <glyph class="macromolecule" id="s3522_sa2065"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 MAP:MACROPHAGE 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="p52"/> <bbox w="80.0" h="40.0" x="11920.0" y="4195.0"/> <glyph class="unit of information" id="_9406e625-baf0-4424-a59f-b239732ce46f"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="11935.0" y="4190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2446_sa2066"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="57.5" h="42.0" x="11921.25" y="4249.0"/> </glyph> </glyph> <glyph class="complex" id="s3503_csa282" 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:CREBBP:IRF3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: CASCADE:TGFB MAP:DENDRITIC_CELL References_end </body> </html> </notes> <label text="s22"/> <bbox w="100.0" h="120.0" x="11005.0" y="4725.0"/> <glyph class="macromolecule" id="s3524_sa2067"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRF3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TGFB CASCADE:STING 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:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages.. References_end </body> </html> </notes> <label text="IRF3"/> <bbox w="80.0" h="40.0" x="11015.0" y="4785.0"/> <glyph class="state variable" id="_b56f9668-165d-4065-bf8d-7345f52ead52"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11007.5" y="4800.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3528_sa2068"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CREBBP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL 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. References_end </body> </html> </notes> <label text="CREBBP"/> <bbox w="80.0" h="40.0" x="11015.0" y="4735.0"/> </glyph> </glyph> <glyph class="complex" id="s3510_csa274" 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*:RELA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MAP:MACROPHAGE MAP:MDSC CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF Maps_Modules_end </body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="13197.5" y="3962.5"/> <glyph class="macromolecule" id="s3512_sa2049"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="80.0" h="40.0" x="13210.0" y="4021.5"/> </glyph> <glyph class="macromolecule" id="s72_sa2050"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 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="13212.5" y="4069.5"/> <glyph class="unit of information" id="_b4375186-d59e-47ef-8422-071493d94a95"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="13227.5" y="4064.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3511_sa2051"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="13211.5" y="3979.5"/> <glyph class="state variable" id="_ed89dfaa-1268-48cc-abb0-cd522f0efce6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13204.0" y="3994.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3551_csa184" 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:MYD88 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL18 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="6306.25" y="1448.75"/> <glyph class="macromolecule" id="s3552_sa1231"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="6313.75" y="1506.25"/> <glyph class="unit of information" id="_46ea82ad-83dc-454a-bde1-0ff50138f244"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6331.25" y="1501.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s3553_sa1232"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="6403.75" y="1506.25"/> <glyph class="unit of information" id="_d5afa323-6c9d-424a-bcb8-5b300cf6c054"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6421.25" y="1501.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s3554_sa1233"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="6313.75" y="1461.25"/> </glyph> <glyph class="macromolecule" id="s3555_sa1234"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="6313.75" y="1561.25"/> </glyph> </glyph> <glyph class="complex" id="s3619_csa287" 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:C5:C5AR* Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:C5 MAP:MDSC PMID:18820683 C5a via C5AR regulates the accumulation and migration of MDSCs in tumor References_end </body> </html> </notes> <label text="s3619"/> <bbox w="100.0" h="120.0" x="5580.0" y="1665.0"/> <glyph class="macromolecule" id="s3620_sa2141"> <notes> <html xmlns="http://www.w3.org/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:C5 MAP:MDSC PMID:25050844, PMID:23028051 Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness PMID:18820683 C5a via C5AR regulates the accumulation and migration of MDSCs in tumor References_end </body> </html> </notes> <label text="C5"/> <bbox w="80.0" h="40.0" x="5590.0" y="1675.0"/> </glyph> <glyph class="macromolecule" id="s3621_sa2142"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C5AR1 HUGO:C5AR2 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:C5 MAP:MDSC PMID:18820683 C5a via C5AR regulates the accumulation and migration of MDSCs in tumor References_end </body> </html> </notes> <label text="C5AR*"/> <bbox w="80.0" h="50.0" x="5590.0" y="1720.0"/> <glyph class="unit of information" id="_171832b7-0936-423c-ac30-d6c9cdf833dd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5607.5" y="1715.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3628_csa288" 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:TUMOR_DNA:cGAS* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING References_end </body> </html> </notes> <label text="s2425"/> <bbox w="150.0" h="110.0" x="6782.5" y="1965.0"/> <glyph class="nucleic acid feature" id="s3632_sa2152"> <notes> <html xmlns="http://www.w3.org/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: MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE:STING Maps_Modules_end References_begin: PMID:25517615, PMID:25517609, PMID:24766893 DNA from dying cells activates cGAS to form a dimeric cGAS-DNA complex which synthesizes 2′3′-cGAMP from ATP and GTP. cGAMP binds to STING and activates two pathways, NfkB activation (via IKK activation) and IRF3 via TBK1 activation. IRF3 induces IFNB expression in DC downsteam of STING signaling PMID:24799564, PMID:15967784, PMID:16237046, PMID:2398653 But at the same time STING signaling induces IDO activation (production) probably via IFN I/STAT1 pathway and suppress local immunity. References_end </body> </html> </notes> <label text="TUMOR_DNA"/> <bbox w="115.0" h="22.5" x="6795.0" y="1973.75"/> </glyph> <glyph class="macromolecule" id="s3639_sa2153"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TMEM173 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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="cGAS*"/> <bbox w="80.0" h="40.0" x="6792.5" y="2005.0"/> </glyph> </glyph> <glyph class="complex" id="s3629_csa289" 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:STING*:cGAMP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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="s2428"/> <bbox w="100.0" h="120.0" x="7117.5" y="2120.0"/> <glyph class="macromolecule" id="s2430_sa2154"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TMEM173 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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: 23986532 STING ablation abolished hallmark TGF-β and IL-10 regulatory cytokine induction (mRNA)by apoptotic cells, and proinflammatory IL-6 mRNA was expressed instead in DCs References_end </body> </html> </notes> <label text="STING*"/> <bbox w="80.0" h="40.0" x="7127.5" y="2170.0"/> </glyph> <glyph class="simple chemical" id="s2429_sa2155"> <notes> <html xmlns="http://www.w3.org/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:STING cyclic-GMP-AMP PMID:24766893 Cytosolic DNA activates cGAS to form a dimeric cGAS-DNA complex which synthesizes 2′3′-cGAMP from ATP and GTP. </body> </html> </notes> <label text="cGAMP"/> <bbox w="70.0" h="25.0" x="7132.5" y="2137.5"/> </glyph> </glyph> <glyph class="complex" id="s3630_csa290" 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:STING*:TBK1:cGAMP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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. As a high-affinity ligand for STING, 2′3′-cGAMP binds and activates STING through a series of structural changes. Activated STING then recruits TBK1 to phosphorylate IRF3 and activate IKK to phosphorylate IκBα, leading to IκBα degradation. References_end </body> </html> </notes> <label text="s2431"/> <bbox w="120.0" h="160.0" x="7147.5" y="2310.0"/> <glyph class="simple chemical" id="s3635_sa2156"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> cyclic-GMP-AMP PMID:24766893 Cytosolic DNA activates cGAS to form a dimeric cGAS-DNA complex which synthesizes 2′3′-cGAMP from ATP and GTP. </body> </html> </notes> <label text="cGAMP"/> <bbox w="70.0" h="25.0" x="7162.5" y="2317.5"/> </glyph> <glyph class="macromolecule" id="s3637_sa2157"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TMEM173 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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: 23986532 STING ablation abolished hallmark TGF-β and IL-10 regulatory cytokine induction (mRNA)by apoptotic cells, and proinflammatory IL-6 mRNA was expressed instead in DCs References_end </body> </html> </notes> <label text="STING*"/> <bbox w="80.0" h="40.0" x="7157.5" y="2350.0"/> </glyph> <glyph class="macromolecule" id="s3640_sa2158"> <notes> <html xmlns="http://www.w3.org/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:DANGER_SIGNAL_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING PMID:25517615, PMID:25517609, PMID:24766893 Activated STING then recruits TBK1 to phosphorylate IRF3 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. References_end </body> </html> </notes> <label text="TBK1"/> <bbox w="80.0" h="40.0" x="7157.5" y="2400.0"/> </glyph> </glyph> <glyph class="complex" id="s3642_csa291" 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:DAG:PRKCQ Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IFNAB MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s3642"/> <bbox w="100.0" h="120.0" x="6320.0" y="3145.0"/> <glyph class="macromolecule" id="s3643_sa2161"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKCQ Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB PMID:25960930 IFNα induces PKC-θ auto-phosphorylation in NK cells via P3K and PLC pathways and improves the degranulation via PKC-θ signaling Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice PMID:19201850 Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression. PRKCQ upregulates granzyme A and B expression in NK cells recruited to the tumor environment. PRKCQ could be activated downstream of IL15 and TLR3 signaling. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. PMID:18784374; PMID:23077238, PMID:17548359 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2. PMID:18784374 PKC-theta–mediated signals activate AP-1 and NFAT1. The capacity of NFAT to bind DNA was reduced in PKC-theta–deﬁcient NK cells. There is a signiﬁcant decrease in AP-1 activation in PKC-theta–deﬁcient NK cells. References_end </body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="6330.0" y="3185.0"/> <glyph class="state variable" id="_e0420907-e298-4fc1-8295-782414fd07c2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6325.0" y="3200.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s3644_sa2162"> <notes> <html xmlns="http://www.w3.org/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:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 </body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="6335.0" y="3152.5"/> </glyph> </glyph> <glyph class="complex" id="s3645_csa292" 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:DAG:PRKCQ 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="s3642"/> <bbox w="100.0" h="120.0" x="6410.0" y="3385.0"/> <glyph class="macromolecule" id="s3647_sa2163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKCQ Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB PMID:25960930 IFNα induces PKC-θ auto-phosphorylation in NK cells via P3K and PLC pathways and improves the degranulation via PKC-θ signaling Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice PMID:19201850 Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression. PRKCQ upregulates granzyme A and B expression in NK cells recruited to the tumor environment. PRKCQ could be activated downstream of IL15 and TLR3 signaling. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. PMID:18784374; PMID:23077238, PMID:17548359 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2. PMID:18784374 PKC-theta–mediated signals activate AP-1 and NFAT1. The capacity of NFAT to bind DNA was reduced in PKC-theta–deﬁcient NK cells. There is a signiﬁcant decrease in AP-1 activation in PKC-theta–deﬁcient NK cells. References_end </body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="6420.0" y="3425.0"/> <glyph class="state variable" id="_d44b5803-9976-42d8-9070-bba54e09a03b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6412.5" y="3440.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s3646_sa2164"> <notes> <html xmlns="http://www.w3.org/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:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 </body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="6425.0" y="3392.5"/> </glyph> </glyph> <glyph class="complex" id="s3684_csa293" 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:PtdSer:STAB2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:STAB2 PMID:17962816 The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-beta. Furthermore, the results of time-lapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. References_end </body> </html> </notes> <label text="s3684"/> <bbox w="100.0" h="120.0" x="7272.5" y="1510.0"/> <glyph class="macromolecule" id="s3693_sa2170"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAB2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:STAB2 PMID:17962816 The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-beta. Furthermore, the results of time-lapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. References_end </body> </html> </notes> <label text="STAB2"/> <bbox w="80.0" h="50.0" x="7282.5" y="1545.0"/> <glyph class="unit of information" id="_abd4fcaa-11c3-40d9-be58-e12659e28780"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7300.0" y="1540.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s3686_sa2171"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE:STAB2 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="7287.5" y="1517.5"/> </glyph> </glyph> <glyph class="complex" id="s3688_csa294" 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:ADGRB1:PtdSer Identifiers_end Maps_Modules_begin: MODULE:DANGER_SIGNAL_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: MAP:MACROPHAGE References_end </body> </html> </notes> <label text="s3688"/> <bbox w="100.0" h="120.0" x="7392.5" y="1510.0"/> <glyph class="macromolecule" id="s3689_sa2173"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ADGRB1 Identifiers_end References_begin: PMID:17960134 ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment. phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells by macrophages. References_end </body> </html> </notes> <label text="ADGRB1"/> <bbox w="80.0" h="50.0" x="7402.5" y="1555.0"/> <glyph class="unit of information" id="_2a459210-3c76-43f6-94b9-edf18a3ba013"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7420.0" y="1550.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s3690_sa2174"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="7407.5" y="1517.5"/> </glyph> </glyph> <glyph class="complex" id="s3695_csa295"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PROS1:PtdSer Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK References_end </body> </html> </notes> <label text="s3695"/> <bbox w="100.0" h="120.0" x="7730.0" y="1070.0"/> <glyph class="macromolecule" id="s3696_sa2177"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PROS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK PMID:12447359 Purified protein S was equivalent to serum in its ability to stimulate macrophage phagocytosis of apoptotic lymphoma cells, and immunodepletion of protein S eliminated the prophagocytic activity of serum. Protein S acted by binding to phosphatidylserine expressed on the apoptotic cell surface. PMID:25695599 Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells downstream of PROS1 and Gas6 References_end </body> </html> </notes> <label text="PROS1"/> <bbox w="80.0" h="40.0" x="7740.0" y="1080.0"/> </glyph> <glyph class="simple chemical" id="s3697_sa2178"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="7745.0" y="1137.5"/> </glyph> </glyph> <glyph class="complex" id="s3698_csa296" 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:HAVCR1:PtdSer Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:HAVCR1 References_end </body> </html> </notes> <label text="s3698"/> <bbox w="100.0" h="120.0" x="7522.5" y="1510.0"/> <glyph class="macromolecule" id="s3699_sa2180"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HAVCR1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:HAVCR1 PMID:18082433 TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1(HAVCR1) specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. References_end </body> </html> </notes> <label text="HAVCR1"/> <bbox w="80.0" h="50.0" x="7532.5" y="1555.0"/> <glyph class="unit of information" id="_676e2098-03cc-439a-992e-c8fd0eb2df03"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7550.0" y="1550.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s3700_sa2183"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE:HAVCR1 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="7537.5" y="1517.5"/> </glyph> </glyph> <glyph class="complex" id="s3701_csa297" 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:PtdSer:TIMD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TIMD4 MAP:DENDRITIC_CELL PMID:18082433 TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. References_end </body> </html> </notes> <label text="s3701"/> <bbox w="100.0" h="120.0" x="7642.5" y="1510.0"/> <glyph class="macromolecule" id="s3702_sa2181"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TIMD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TIMD4 PMID:18082433 TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. References_end </body> </html> </notes> <label text="TIMD4"/> <bbox w="80.0" h="50.0" x="7652.5" y="1545.0"/> <glyph class="unit of information" id="_948bfc23-113d-40b5-adf9-6876b9d17d11"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7670.0" y="1540.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s3703_sa2182"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE:TIMD4 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="7657.5" y="1517.5"/> </glyph> </glyph> <glyph class="complex" id="s3706_csa298" 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:CD36:oxPS Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:CD36 References_end </body> </html> </notes> <label text="s3706"/> <bbox w="100.0" h="120.0" x="7852.5" y="1500.0"/> <glyph class="simple chemical" id="s3707_sa2186"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Oxidized phosphatidylserine </body> </html> </notes> <label text="oxPS"/> <bbox w="70.0" h="25.0" x="7867.5" y="1507.5"/> </glyph> <glyph class="macromolecule" id="s3708_sa2187"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD36 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL13 CASCADE:IL4 CASCADE:THBS1 CASCADE:CD36 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. PMID:17101731 Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. PMID:14568985 The exogenous and endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47 and probably CD36 References_end </body> </html> </notes> <label text="CD36"/> <bbox w="80.0" h="50.0" x="7862.5" y="1535.0"/> <glyph class="unit of information" id="_a52653cf-e796-46ea-a531-154ba5bed85f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7880.0" y="1530.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3711_csa299"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GAS6:PtdSer Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK References_end </body> </html> </notes> <label text="s3711"/> <bbox w="100.0" h="120.0" x="7900.0" y="1070.0"/> <glyph class="simple chemical" id="s3712_sa2191"> <notes> <html xmlns="http://www.w3.org/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: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="7915.0" y="1137.5"/> </glyph> <glyph class="macromolecule" id="s3713_sa2192"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GAS6 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK PMID:19631584 The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. PMID:25695599 Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells downstream of PROS1 and Gas6 References_end </body> </html> </notes> <label text="GAS6"/> <bbox w="80.0" h="40.0" x="7910.0" y="1080.0"/> </glyph> </glyph> <glyph class="complex" id="s3736_csa301" 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:CD11b*:CD18* 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: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 PMID:2060581, PMID:9218574 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity PMID:1358992 Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized cells. PMID:8326130 CR3 (CD11b/CD18) pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+ 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. PMID:2060581 PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:20404138 Inhibition of Mac-1 (CD11b/CD18) reduces myeloid cell recruitment PMID:1679046 INFG upregulates CD18 surface expression. References_end </body> </html> </notes> <label text="s1779"/> <bbox w="100.0" h="130.0" x="9562.5" y="1660.0"/> <glyph class="macromolecule" id="s3737_sa2210"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGAM ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_MACROPHAGE MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MDSC CASCADE:CR3 PMID:18633355 The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="9577.5" y="1675.0"/> <glyph class="unit of information" id="_da7b9322-d037-49be-9e43-ad8e206f6a27"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9595.0" y="1670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3738_sa2211"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="9572.5" y="1715.0"/> <glyph class="unit of information" id="_2f6bfd75-3bc6-42ef-acf7-8d2f05137019"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9590.0" y="1710.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3740_csa302" 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:CD11c*:CD18*:iC3b* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:1358992 Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized cells. References_end </body> </html> </notes> <label text="s3723"/> <bbox w="110.0" h="160.0" x="9672.5" y="1630.0"/> <glyph class="macromolecule" id="s3742_sa2212"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="9682.5" y="1715.0"/> <glyph class="unit of information" id="_fcfb9086-43d5-4d46-bb1d-1f1538f6f80e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9700.0" y="1710.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3741_sa2213"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:CR4 CASCADE:FLT3LG CASCADE:IFNAB PMID:15573129 CD11c is a maker of myeloid DCs. PMID:8920882 FLT3 ligand upregulates surface expression of CD11c 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, CD206, CD23 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="CD11c*"/> <bbox w="80.0" h="50.0" x="9687.5" y="1675.0"/> <glyph class="unit of information" id="_321b948b-6f3d-4d80-a75e-226ef9945a25"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9705.0" y="1670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3743_sa2215"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR1 CASCADE:CR4 CASCADE:CR3 PMID:1358992 Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized cells. References_end </body> </html> </notes> <label text="iC3b*"/> <bbox w="80.0" h="40.0" x="9682.5" y="1630.0"/> <glyph class="unit of information" id="_ea694349-1ebd-45c9-86c4-4e911342d495"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="9697.5" y="1625.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3748_csa304" 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:FCER1G:Fc_gamma_RI*:Immunoglobulins* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:Fc_gamma_RI References_end </body> </html> </notes> <label text="s3748"/> <bbox w="100.0" h="180.0" x="10107.5" y="1590.0"/> <glyph class="macromolecule" id="s3750_sa2219"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCGR1A HUGO:FCGR1B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:Fc_gamma_RI 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 PMID:8064233 Hck, Lyn binds to Fc_gamma_RI (cd64) in monocytes and probably phosphorylate ignal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. PMID:26819959 Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy. References_end </body> </html> </notes> <label text="FcγRI*"/> <bbox w="80.0" h="50.0" x="10117.5" y="1635.0"/> <glyph class="unit of information" id="_06246735-699f-4cdf-a39c-03ef393bae31"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10135.0" y="1630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3752_sa2221"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="10122.5" y="1600.0"/> </glyph> <glyph class="macromolecule" id="s3767_sa2236"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="10117.5" y="1695.0"/> <glyph class="state variable" id="_0abe2a54-c135-45a4-95ce-d98f77726b02"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10110.0" y="1715.0"/> </glyph> <glyph class="unit of information" id="_38fb8c6d-31d6-4d95-b2f8-0a5b283ceaed"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10135.0" y="1690.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3749_csa305" 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:Fc_gamma_RII_activating*:Immunoglobulins* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:Fc_gamma_RII References_end </body> </html> </notes> <label text="s3749"/> <bbox w="100.0" h="120.0" x="10217.5" y="1590.0"/> <glyph class="macromolecule" id="s3751_sa2220"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCGR2A HUGO:FCGR2C Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:Fc_gamma_RII 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. 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:8132624 Hck, Lyn binds to Fc_gamma_RII (CD32) and phosphorylates it in monocytes. References_end </body> </html> </notes> <label text="FcγRII_activating*"/> <bbox w="80.0" h="50.0" x="10222.5" y="1635.0"/> <glyph class="state variable" id="_4b5dbae8-40c8-4420-b566-c5c7946fe5f6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10215.0" y="1655.0"/> </glyph> <glyph class="unit of information" id="_09a46f6c-0a91-4aac-9ed7-5cca9573ac0a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10240.0" y="1630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3753_sa2222"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="10227.5" y="1600.0"/> </glyph> </glyph> <glyph class="complex" id="s3756_csa306" 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:Fc_epsilon_R*:Immunoglobulins* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL CASCADE:FCER References_end </body> </html> </notes> <label text="s3756"/> <bbox w="100.0" h="120.0" x="9887.5" y="1590.0"/> <glyph class="macromolecule" id="s3758_sa2225"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCER1A HUGO:FCER1G HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL CASCADE:FCER PMID:8283051 FCE RI and FcyRlll trigger phagocytosis in mast cells PMID:9000133 Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. PMID:1534410 Two forms of the low-affinity Fc receptor for IgE (Fc epsilon RIIa and Fc epsilon RIIb)differentially mediate endocytosis and phagocytosis PMID:6401249 Fc receptor for IgE provides phagocytosis in macrophages. 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="FcεR*"/> <bbox w="80.0" h="50.0" x="9897.5" y="1645.0"/> <glyph class="state variable" id="_2c6917d5-221c-45e5-8ffa-8601ad645f22"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9890.0" y="1665.0"/> </glyph> <glyph class="unit of information" id="_67f066e2-d3b0-4707-aaaf-24efaf51b2c4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9915.0" y="1640.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3760_sa2227"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="9897.5" y="1600.0"/> </glyph> </glyph> <glyph class="complex" id="s3757_csa307" 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:FCAR:FCER1G:Immunoglobulins* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:FCAR PMID:15081523 FcαRI is dependent on association with the FcRγ chain for signalling and function References_end </body> </html> </notes> <label text="s3757"/> <bbox w="100.0" h="180.0" x="9997.5" y="1590.0"/> <glyph class="macromolecule" id="s3759_sa2226"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCAR Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:FCAR PMID:9952373, PMID:2451784 FcαRI provides phagocytosis in neurophiles. GM-CSF and G-CSF both activates gA-mediated phagocytosis in neutrophiles PMID:7590867 Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation. References_end </body> </html> </notes> <label text="FCAR"/> <bbox w="80.0" h="50.0" x="10007.5" y="1645.0"/> <glyph class="unit of information" id="_f5e9e4ca-8960-48cb-98b4-1d592491e063"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10025.0" y="1640.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3761_sa2228"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="10007.5" y="1600.0"/> </glyph> <glyph class="macromolecule" id="s3769_sa2238"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="10007.5" y="1695.0"/> <glyph class="state variable" id="_3e0ddc9e-b002-4f80-bfce-d0a17d8d4dbe"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10000.0" y="1715.0"/> </glyph> <glyph class="unit of information" id="_3ede9cb0-c324-4b61-8234-fda32f0df834"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10025.0" y="1690.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3778_csa308" 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:ELC_MYOSIN_II*:MYH9:RLC_MYOSIN_II* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:12194823 Rho-Kinase and Myosin-II Control Phagocytic Cup Formation during CR3, but Not FcγR, 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. References_end </body> </html> </notes> <label text="MYOSIN_IIA"/> <bbox w="100.0" h="170.0" x="10671.0" y="6250.0"/> <glyph class="macromolecule multimer" id="s3779_sa2247"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYH9 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end </body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="10678.0" y="6257.0"/> <glyph class="unit of information" id="_be9806c0-53a4-4ccb-a295-d6cab5a0e0ac"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="10711.0" y="6252.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3781_sa2248"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYL6 HUGO:MYL6B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10681.0" y="6310.0"/> </glyph> <glyph class="macromolecule" id="s3780_sa2249"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYL9 HUGO:MYL12A HUGO:MYL12B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10681.0" y="6350.0"/> <glyph class="state variable" id="_407d5e5b-554d-4993-9d94-9fa3d5b0f6d0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10676.0" y="6365.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3782_csa309" 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:ELC_MYOSIN_II*:MYH9:RLC_MYOSIN_II* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:12194823 Rho-Kinase and Myosin-II Control Phagocytic Cup Formation during CR3, but Not FcγR, Phagocytosis References_end </body> </html> </notes> <label text="MYOSIN_IIA"/> <bbox w="100.0" h="170.0" x="10670.0" y="6475.0"/> <glyph class="macromolecule multimer" id="s3783_sa2250"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYH9 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end </body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="10677.0" y="6482.0"/> <glyph class="unit of information" id="_3e6e0dcc-4425-4ae5-a7c9-fff122d4a1a8"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="10710.0" y="6477.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3784_sa2251"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYL6 HUGO:MYL6B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10680.0" y="6530.0"/> </glyph> <glyph class="macromolecule" id="s3785_sa2252"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYL9 HUGO:MYL12A HUGO:MYL12B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10680.0" y="6575.0"/> <glyph class="state variable" id="_afad62e5-54bd-4e7d-a92c-87289217b0e5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10672.5" y="6590.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3787_csa52" 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:ELC_MYOSIN_II*:MYH9:RLC_MYOSIN_II*:WASP*:WIPF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE 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="122.5" h="305.0" x="10338.75" y="6577.5"/> <glyph class="macromolecule" id="s3788_sa326"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="10353.75" y="6762.5"/> <glyph class="state variable" id="_1df47925-d24a-4495-b0c0-ef9493815501"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10348.75" y="6777.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3789_sa327"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="10351.25" y="6807.5"/> <glyph class="state variable" id="_649c3a67-1180-4f2b-a116-59167e0fbe0d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10343.75" y="6822.4683"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s3790_sa2255"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYH9 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end </body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="10348.25" y="6704.5"/> <glyph class="unit of information" id="_57af58c8-1030-4561-bbaa-38fe21c219b2"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="10381.25" y="6699.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3793_sa2256"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYL6 HUGO:MYL6B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10351.25" y="6647.5"/> </glyph> <glyph class="macromolecule" id="s3792_sa2258"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYL9 HUGO:MYL12A HUGO:MYL12B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10351.25" y="6597.5"/> <glyph class="state variable" id="_f65402ea-fac4-4991-adac-e2e047288092"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10343.75" y="6612.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3796_csa310" 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:CRK:DOCK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE 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="s2221"/> <bbox w="200.0" h="150.0" x="7930.0" y="3440.0"/> <glyph class="macromolecule" id="s2223_sa2263"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="8030.0" y="3460.0"/> <glyph class="state variable" id="_c3d7a7c9-7dad-4697-85de-c418ec035bdb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8025.0" y="3475.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2222_sa2264"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="7940.0" y="3460.0"/> <glyph class="state variable" id="_b4fb912a-4d85-4987-bd60-6b865f4f9e3a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7935.0" y="3475.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2220_sa2265"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:DOC1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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="DOCK1"/> <bbox w="80.0" h="40.0" x="7990.0" y="3520.0"/> </glyph> </glyph> <glyph class="complex" id="s3867_csa250" 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:IL4:IL4R:JAK1:JAK2:JAK3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 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 PMID:20510870 Type I IL-4 receptors is assosiated with Jak1,JAK2 and JAK3. IL-4Ra associates with JAK1, JAK2 and gammaC with JAK3. PMID:23124025 IL4 binding induces Jak1 phosphorylation (but not Jak2, JAK3, or TYK2). References_end </body> </html> </notes> <label text="IL4_receptor_TYPE1"/> <bbox w="190.0" h="175.5" x="15550.0" y="4912.25"/> <glyph class="macromolecule" id="s3868_sa1887"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: 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="15650.0" y="5015.0"/> <glyph class="state variable" id="_aa9d0c55-371f-407f-b324-9830849ac015"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15645.0" y="5030.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3869_sa1888"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: 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="15640.0" y="4975.0"/> <glyph class="state variable" id="_356d5fa8-d322-41ed-9258-b6ce3be18b1e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15632.5" y="4990.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3870_sa1889"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="15646.0" y="4925.75"/> </glyph> <glyph class="macromolecule" id="s3871_sa1890"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="15560.0" y="4927.75"/> </glyph> <glyph class="macromolecule" id="s3872_sa1891"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="15560.0" y="5010.0"/> <glyph class="state variable" id="_c0549b42-09c2-438e-a404-8edbfdf5b236"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15635.0" y="5044.389"/> </glyph> <glyph class="unit of information" id="_68cd6200-bae8-4483-a5b1-632a8314b527"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15577.5" y="5005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3873_sa1892"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15550.0" y="4960.0"/> <glyph class="unit of information" id="_cec8ef47-2d2a-4794-b073-1a1ef03b2d3b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15567.5" y="4955.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3874_csa246" 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:IL13:IL13RA1:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS 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 PMID:14610620, PMID:12223527, PMID:20510870 JAK1 associated with IL4R and JAK2 or TYK associated with IL13RA1 participate in signal transduction; They phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain. PMID:23124025 IL13 signaling aktivates JAK2 and TYK2 not JAK1. References_end </body> </html> </notes> <label text="IL13/Receptor-TYPE_2"/> <bbox w="215.25" h="175.0" x="15567.375" y="4672.5"/> <glyph class="macromolecule" id="s3875_sa1866"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="15682.625" y="4772.5"/> <glyph class="state variable" id="_79d05496-3605-4c78-bad7-e6f70aab6b50"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15675.125" y="4787.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3876_sa1867"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: 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="15682.625" y="4732.5"/> <glyph class="state variable" id="_0bc8a3f5-c3cb-412f-bead-480c695acfb6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15675.125" y="4747.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3877_sa1868"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="15587.375" y="4722.5"/> <glyph class="state variable" id="_6dfeb031-948e-4ec0-9faf-77d1f57ee649"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15659.875" y="4756.889"/> </glyph> <glyph class="unit of information" id="_c25956a2-2bd0-4511-83d8-799df766e78a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15604.875" y="4717.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3878_sa1869"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: 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"/> <bbox w="80.0" h="50.0" x="15587.375" y="4772.5"/> <glyph class="state variable" id="_2b3ee913-83fc-4f4d-9cec-36efbaf2fdf9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15659.875" y="4806.257"/> </glyph> <glyph class="unit of information" id="_19a483a4-1e23-4df7-b4b8-70a96213ff0f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15604.875" y="4767.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3879_sa1870"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <bbox w="80.0" h="40.0" x="15585.0" y="4680.0"/> </glyph> <glyph class="macromolecule" id="s3880_sa1871"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: 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="4675.0"/> <glyph class="state variable" id="_b3f7a2c4-773c-4f84-801f-caf81879a050"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15685.0" y="4690.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3881_csa249" 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:IL4:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 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 PMID:12223527 Type II IL-4 receptors associates with Jak1,JAK2 and TYK2 PMID:23124025 IL4 binding induces Jak1 phosphorylation (but not Jak2, JAK3, or TYK2). References_end </body> </html> </notes> <label text="IL4/Receptor-TYPE_2"/> <bbox w="222.0" h="176.5" x="15544.0" y="5141.75"/> <glyph class="macromolecule" id="s3882_sa1881"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15660.0" y="5155.0"/> <glyph class="state variable" id="_3bea36db-6cc2-4767-b53d-ca89b4b3d515"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15655.0" y="5170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3924_sa1882"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="15670.0" y="5245.0"/> <glyph class="state variable" id="_c79aafd0-a947-4c93-acf9-1b39d6de8e08"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15662.5" y="5260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3884_sa1883"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: 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="15660.0" y="5205.0"/> <glyph class="state variable" id="_574586d5-b742-4b9c-9560-03f1af12d5e2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15655.0" y="5220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3885_sa1884"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="15560.0" y="5145.0"/> </glyph> <glyph class="macromolecule" id="s3886_sa1885"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: 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"/> <bbox w="80.0" h="50.0" x="15570.0" y="5200.0"/> <glyph class="state variable" id="_1aae149a-320d-4c1f-85f9-32c3f7afb7c5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15645.0" y="5233.757"/> </glyph> <glyph class="unit of information" id="_6e52c502-11df-4b9c-864a-ca6b18df9e1e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15587.5" y="5195.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3887_sa1886"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="15564.0" y="5243.25"/> <glyph class="state variable" id="_bceaf5f8-189e-49e4-955a-d8890c5de57b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15639.0" y="5277.639"/> </glyph> <glyph class="unit of information" id="_3ffb8f08-29d0-46ee-9a96-a49786292730"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15581.5" y="5238.25"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4001_csa320" 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:BCL3:HDAC1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:15465827 BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. References_end </body> </html> </notes> <label text="BCL3/HDAC1"/> <bbox w="100.0" h="120.0" x="12826.25" y="5285.0"/> <glyph class="macromolecule" id="s4003_sa2456"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HDAC1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:15465827 BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. References_end </body> </html> </notes> <label text="HDAC1"/> <bbox w="80.0" h="40.0" x="12839.75" y="5341.0"/> </glyph> <glyph class="macromolecule" id="s71_sa2457"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:BCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL10 Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="12836.75" y="5297.0"/> </glyph> </glyph> <glyph class="complex" id="s4004_csa321" 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:BCL3:NFKB1_p50* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:IL10 PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="s4004"/> <bbox w="100.0" h="120.0" x="12606.25" y="5285.0"/> <glyph class="macromolecule" id="s4005_sa2458"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:BCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL10 Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="12616.25" y="5345.0"/> </glyph> <glyph class="macromolecule" id="s4006_sa2459"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="85.75" h="46.5" x="12616.25" y="5295.0"/> <glyph class="unit of information" id="_42ecef00-2ee9-4d4e-ad25-efd5c25454ba"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12634.125" y="5290.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4038_csa335" 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*:cAMP Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 Maps_Modules_end </body> </html> </notes> <label text="s978"/> <bbox w="100.0" h="170.0" x="4350.0" y="3585.0"/> <glyph class="simple chemical" id="s986_sa2566"> <notes> <html xmlns="http://www.w3.org/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 CASCADE:IL13 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="4365.0" y="3592.5"/> </glyph> <glyph class="macromolecule" id="s984_sa2567"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="4360.0" y="3635.0"/> </glyph> <glyph class="macromolecule" id="s985_sa2568"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="4360.0" y="3680.0"/> </glyph> </glyph> <glyph class="complex" id="s4051_csa337" 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:IFNG:MIR15/16* Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="s4051"/> <bbox w="100.0" h="120.0" x="11576.25" y="5285.0"/> <glyph class="nucleic acid feature" id="s4050_sa2583"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="11581.25" y="5302.5"/> <glyph class="unit of information" id="_77bdbfed-11db-452b-96d8-b16c1d5e02cc"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="11611.25" y="5297.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4052_sa2584"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:IL4 CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 CASCADE:Fc_gamma_RIII CASCADE:IL18 PMID:8700208, PMID:9715265, PMID:11449378 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. PMID:12759422 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:18768831, PMID:16713975 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="82.5" h="26.25" x="11585.0" y="5331.875"/> <glyph class="unit of information" id="_e4baa7b7-9075-4289-b6cc-de7ce318ceea"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11616.25" y="5326.875"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4063_csa338" 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:CCL2:CCR2 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CCR2 References_end </body> </html> </notes> <label text="s4063"/> <bbox w="100.0" h="120.0" x="5710.0" y="1655.0"/> <glyph class="macromolecule" id="s4064_sa2591"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TGFB CASCADE:CSF1 CASCADE:CCR2 CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:19915063 Phosphorylated STAT1 is critical for IFN-gamma-induced (CCL2)MCP-1 production PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="80.0" h="40.0" x="5720.0" y="1675.0"/> </glyph> <glyph class="macromolecule" id="s4065_sa2592"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CCR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TNF Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. TNF inhibit CCR2 expression in tumor associated macrophages. PMID:15032599 CCR2 is a recptor for CLL2 References_end </body> </html> </notes> <label text="CCR2"/> <bbox w="80.0" h="50.0" x="5720.0" y="1720.0"/> <glyph class="unit of information" id="_04723cb6-f450-42e6-8fa3-66be691c6b7d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5737.5" y="1715.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4068_csa340" 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:DEPTOR:MLST8:ORP1L*:PRAS40*:RILP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER 16469695, 26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR 22504639, 20805416 Impaired mTORC1 signal resulted in the suppression of IL-10 production in DC. IL-10 expression was impaired at both protein and mRNA levels in RaptorDC−/− mice. 19143636 The signalling function of mTOR complex 1 is activated by Rheb-GTP. 20805416 mTOR pathway plays divergent roles during activation and differentiation of myeloid DCs (MDSC) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in MDSC activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on MDSC and significantly increased the T cell allostimulatory potential of MDSC. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. References_end </body> </html> </notes> <label text="mTORC1*"/> <bbox w="210.0" h="210.0" x="8965.0" y="4615.0"/> <glyph class="macromolecule" id="s2257_sa2600"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR CASCADE:CSF2 CASCADE:IL15 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:18492954 mTOR regulates IL-12 expression through an autocrine action of IL-10 in DC. PMID:24973821, PMID:24795729 mTOR activity in NK cells is mainly under the control of IL-15. mTOR deficiency profoundly impaired the early cytokine-driven activation of NK cells at multiple levels. Inhibition of mTOR abrogates inflammation-induced priming. mTOR controls the maturation and homeostasis of NK cells. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. mTOR has positive influence on GZMA level in the NK cells. and NK cells from rapamycin-treated mice (mTOR-inhibition) had attenuated lytic activities toward target tumor cells. IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end </body> </html> </notes> <label text="RILP"/> <bbox w="80.0" h="40.0" x="8980.0" y="4750.0"/> <glyph class="state variable" id="_c198d8c5-ea72-4147-aa64-b8093a08515b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8975.0" y="4765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2258_sa2601"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RPTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="ORP1L*"/> <bbox w="80.0" h="40.0" x="8980.0" y="4690.0"/> </glyph> <glyph class="macromolecule" id="s1978_sa2602"> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="9070.0" y="4690.0"/> </glyph> <glyph class="macromolecule" id="s1979_sa2603"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:DEPTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="DEPTOR"/> <bbox w="80.0" h="40.0" x="9070.0" y="4740.0"/> </glyph> <glyph class="macromolecule" id="s1980_sa2604"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AKT1S1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="PRAS40*"/> <bbox w="80.0" h="40.0" x="9070.0" y="4630.0"/> </glyph> </glyph> <glyph class="complex" id="s4077_csa339" 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:DEPTOR:MLST8:MTOR:PRAS40*:RPTOR 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 24973821, 24795729 High level of IL15 activates mTOR. mTOR controls production of GZMA and GZMB and IFNG production downstream of IL15 16469695, 26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR 22504639, 20805416 Impaired mTORC1 signal resulted in the suppression of IL-10 production in DC. IL-10 expression was impaired at both protein and mRNA levels in RaptorDC−/− mice. 19143636 The signalling function of mTOR complex 1 is activated by Rheb-GTP. 20805416 mTOR pathway plays divergent roles during activation and differentiation of myeloid DCs (MDSC) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in MDSC activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on MDSC and significantly increased the T cell allostimulatory potential of MDSC. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF And this signaling is needful for DC differentiation. References_end </body> </html> </notes> <label text="mTORC1*"/> <bbox w="210.0" h="210.0" x="8620.0" y="4610.0"/> <glyph class="macromolecule" id="s4082_sa2595"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR CASCADE:CSF2 CASCADE:IL15 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:18492954 mTOR regulates IL-12 expression through an autocrine action of IL-10 in DC. PMID:24973821, PMID:24795729 mTOR activity in NK cells is mainly under the control of IL-15. mTOR deficiency profoundly impaired the early cytokine-driven activation of NK cells at multiple levels. Inhibition of mTOR abrogates inflammation-induced priming. mTOR controls the maturation and homeostasis of NK cells. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. mTOR has positive influence on GZMA level in the NK cells. and NK cells from rapamycin-treated mice (mTOR-inhibition) had attenuated lytic activities toward target tumor cells. IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. References_end </body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="8635.0" y="4745.0"/> <glyph class="state variable" id="_a9858061-903f-4562-b4e6-38988629eb1b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8627.5" y="4760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4078_sa2596"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RPTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="RPTOR"/> <bbox w="80.0" h="40.0" x="8635.0" y="4685.0"/> </glyph> <glyph class="macromolecule" id="s4079_sa2597"> <notes> <html xmlns="http://www.w3.org/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:MLST8 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR </body> </html> </notes> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="8725.0" y="4685.0"/> </glyph> <glyph class="macromolecule" id="s4080_sa2598"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:DEPTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="DEPTOR"/> <bbox w="80.0" h="40.0" x="8725.0" y="4735.0"/> </glyph> <glyph class="macromolecule" id="s4081_sa2599"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AKT1S1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="PRAS40*"/> <bbox w="80.0" h="40.0" x="8725.0" y="4625.0"/> </glyph> </glyph> <glyph class="complex" id="s4084_csa342" 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:CXCL10:CXCR3 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:CXCR3 References_end </body> </html> </notes> <label text="s4084"/> <bbox w="100.0" h="120.0" x="5280.0" y="1655.0"/> <glyph class="macromolecule" id="s4085_sa2616"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCR3 Identifiers_end References_begin: MAP:NATURAL_KILLER CASCADE:CXCR3 PMID:18922917 Significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3−/− mice, and the capacity of adoptively transferred CXCR3−/− NK cells to accumulate in the tumor was severely impaired. Ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell–dependent survival. References_end </body> </html> </notes> <label text="CXCR3"/> <bbox w="80.0" h="50.0" x="5290.0" y="1720.0"/> <glyph class="unit of information" id="_b6645861-1ce1-4a2a-a7c4-666401fdb250"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5307.5" y="1715.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4086_sa2617"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CXCL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MAP:NATURAL_KILLER CASCADE:CXCR3 CASCADE:IFNAB CASCADE:TLR2_4 MAP:DENDRITIC_CELL Maps_Modules_end References_begin: PMID:18922917 Significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3−/− mice, and the capacity of adoptively transferred CXCR3−/− NK cells to accumulate in the tumor was severely impaired. Ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell–dependent survival. References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="80.0" h="40.0" x="5290.0" y="1665.0"/> </glyph> </glyph> <glyph class="complex" id="s4091_csa343" 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:CXCR2:IL8* Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 References_end </body> </html> </notes> <label text="s4091"/> <bbox w="100.0" h="120.0" x="5460.0" y="1405.0"/> <glyph class="macromolecule" id="s4093_sa2622"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCR2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 PMID:18633355 The surface markers of myeloid cells PMID:21328342, PMID:18980965 Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils, downstream of IL8. References_end </body> </html> </notes> <label text="CXCR2"/> <bbox w="80.0" h="50.0" x="5470.0" y="1460.0"/> <glyph class="unit of information" id="_7b6244e2-8f84-4706-899a-8d53d679b6e8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5487.5" y="1455.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4092_sa2625"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MAST_CELL CASCADE:TNF CASCADE:CSF2 MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 MAP:NATURAL_KILLER CASCADE:IL8 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself iDC in ovarian cancer ascites promote angiogenesis in vivo through production of TNF and CXCL8 PMID:18980965 Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="80.0" h="40.0" x="5470.0" y="1415.0"/> </glyph> </glyph> <glyph class="complex" id="s4094_csa344" 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:CXCR1:IL8* Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 References_end </body> </html> </notes> <label text="s4094"/> <bbox w="100.0" h="120.0" x="5360.0" y="1405.0"/> <glyph class="macromolecule" id="s4096_sa2623"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCR1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 PMID:18633355 The surface markers of myeloid cells PMID:21328342, PMID:18980965 Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils, downstream of IL8. References_end </body> </html> </notes> <label text="CXCR1"/> <bbox w="80.0" h="50.0" x="5370.0" y="1460.0"/> <glyph class="unit of information" id="_2063e3f6-eb4f-44fa-9051-60522cc99ac6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5387.5" y="1455.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4095_sa2624"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MAST_CELL CASCADE:TNF CASCADE:CSF2 MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 MAP:NATURAL_KILLER CASCADE:IL8 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself iDC in ovarian cancer ascites promote angiogenesis in vivo through production of TNF and CXCL8 PMID:18980965 Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="80.0" h="40.0" x="5370.0" y="1415.0"/> </glyph> </glyph> <glyph class="complex" id="s4104_csa93" 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:CD11b*:CD18* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:CR3 PMID:2060581, PMID:9218574 The CR3(MAC-1) reactive mAb potentiates NK-mediated cytotoxicity PMID:1358992 Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized cells. PMID:8326130 CR3 (CD11b/CD18) pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+ 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="CR3"/> <bbox w="100.0" h="130.0" x="9552.5" y="1315.0"/> <glyph class="macromolecule" id="s1780_sa675"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_MACROPHAGE MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MDSC CASCADE:CR3 PMID:18633355 The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="9567.5" y="1330.0"/> <glyph class="unit of information" id="_d0d30bf1-da59-4bb4-bddc-5c424c2c7cb9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9585.0" y="1325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1782_sa676"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="9562.5" y="1375.0"/> <glyph class="unit of information" id="_8a56318d-eba5-4549-be7a-0e42fecce1bc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9580.0" y="1370.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4105_csa300" 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:CD11c*:CD18* Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR4 PMID:1358992 Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized cells. References_end </body> </html> </notes> <label text="CR4"/> <bbox w="100.0" h="120.0" x="9692.5" y="1400.0"/> <glyph class="macromolecule" id="s3725_sa2197"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="9702.5" y="1455.0"/> <glyph class="unit of information" id="_580d5896-f518-483e-b0b7-eba1b511cb42"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9720.0" y="1450.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3724_sa2198"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:CR4 CASCADE:FLT3LG CASCADE:IFNAB PMID:15573129 CD11c is a maker of myeloid DCs. PMID:8920882 FLT3 ligand upregulates surface expression of CD11c 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, CD206, CD23 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="CD11c*"/> <bbox w="80.0" h="50.0" x="9707.5" y="1405.0"/> <glyph class="unit of information" id="_00e5b544-69f5-47d5-b5c2-ba4c5bf9a577"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9725.0" y="1400.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4121_csa213" 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:IFNG:IFNGR1:IFNGR2:JAK1:JAK2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: 17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. 19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2. Ligand engagement of the IFNG receptor leads to activation of receptor-associated Jak1 and Jak2 and phosphorylation of a receptor tyrosine residue (Y440) that serves as a docking site for STAT1, which exists in a latent state in the cytoplasm. References_end </body> </html> </notes> <label text="IFNGR"/> <bbox w="205.0" h="170.0" x="15552.5" y="2665.0"/> <glyph class="macromolecule" id="s4122_sa1630"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15665.0" y="2715.0"/> <glyph class="state variable" id="_0cb8b2ad-9bf7-4b47-8e3c-b4629823008a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15657.5" y="2734.9602"/> </glyph> <glyph class="unit of information" id="_4ff44169-790f-4d37-a4f6-b5681fbceefb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15682.5" y="2710.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4123_sa1629"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNGR2 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="IFNGR2"/> <bbox w="80.0" h="50.0" x="15575.0" y="2715.0"/> <glyph class="unit of information" id="_d61bc67e-ab3d-435f-9997-a14eeee5e2d1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15592.5" y="2710.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4124_sa1628"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15572.5" y="2765.0"/> <glyph class="state variable" id="_1b8290fe-6150-49af-b1aa-8f865eea6dbb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15567.5" y="2780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4125_sa1627"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15662.5" y="2765.0"/> <glyph class="state variable" id="_53521671-c677-4a32-aa37-53b29af2c78c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15657.5" y="2780.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s4126_sa1626"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:IL4 CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 CASCADE:KLRG1 CASCADE:KIR2DL2 CASCADE:KIR2DL4 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:Fc_gamma_RIII CASCADE:IL18 CASCADE:IL2 Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID:16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 expression. NK cells stimuletad by IL4 have NK2 subtype PMID:21149606 Nkp80 signaling induces marked IFNG production PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:11489965, PMID:15778339 KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells 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 References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="86.0" h="46.0" x="15612.0" y="2667.0"/> <glyph class="unit of information" id="_68166db6-97fb-4ae1-8e12-8074529de6f5"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="15645.0" y="2662.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4164_csa345" 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 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: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. References_end </body> </html> </notes> <label text="s4164"/> <bbox w="100.0" h="120.0" x="16170.0" y="3885.0"/> <glyph class="macromolecule" id="s4165_sa2686"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="16180.0" y="3940.0"/> <glyph class="unit of information" id="_b05ac350-1d4a-4777-955b-747cac6ff312"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16197.5" y="3935.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4166_sa2687"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="16180.0" y="3895.0"/> </glyph> </glyph> <glyph class="complex" id="s4205_csa349" 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*:CREB1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:16007092 GSK3B inhibits CREB1 interaction with CBP and inhibits CREB1 dependent IL10 expression. CREB1/CBP complex formation prevents binding CBP to RELA (p65) and inhibits downstream NF-kB signaling. References_end </body> </html> </notes> <label text="s903"/> <bbox w="105.0" h="150.0" x="13622.5" y="3885.0"/> <glyph class="macromolecule" id="s907_sa2745"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CREB1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. 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 References_end </body> </html> </notes> <label text="CREB1"/> <bbox w="80.0" h="40.0" x="13637.5" y="3895.0"/> <glyph class="state variable" id="_7b78dacc-c43b-4fd6-b066-7c2aa2cec848"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13630.0" y="3910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4207_sa2746"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="13637.5" y="3945.0"/> </glyph> </glyph> <glyph class="complex" id="s4268_csa350" 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:KIT:KITLG Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:18524989 Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="s4268"/> <bbox w="100.0" h="120.0" x="5590.0" y="1465.0"/> <glyph class="macromolecule" id="s4269_sa2804"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KITLG Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, histamine, which is an immunosuppressant, mitogenic factors, such as platelet-derived growth factor (PDGF), nerve GF (NGF), stem-cell factor (SCF), and proteases, which disrupt the surrounding matrix and facilitate metastases. PMID:18524989 SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="KITLG"/> <bbox w="80.0" h="40.0" x="5600.0" y="1475.0"/> </glyph> <glyph class="macromolecule" id="s4270_sa2805"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIT Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:18633355 The surface markers of myeloid cells PMID:18524989 Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="KIT"/> <bbox w="80.0" h="50.0" x="5600.0" y="1520.0"/> <glyph class="unit of information" id="_ecec7d8b-f240-40e9-9dbf-8fb5f0393b7c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5617.5" y="1515.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4733_csa183" 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:IL18R1:IL18RAP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end </body> </html> </notes> <label text="s1260"/> <clone/> <bbox w="180.0" h="100.0" x="6330.0" y="1265.0"/> <glyph class="macromolecule" id="s4734_sa1229"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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"/> <clone/> <bbox w="80.0" h="50.0" x="6340.0" y="1290.0"/> <glyph class="unit of information" id="_6949cc8e-275b-4ca1-848f-1df2c3eda300"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6357.5" y="1285.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4735_sa1230"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="1290.0"/> <glyph class="unit of information" id="_5bdec4f3-8f46-4e14-b651-b58095cc41ab"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6437.5" y="1285.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4733_csa231" 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:IL18R1:IL18RAP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. References_end </body> </html> </notes> <label text="s1260"/> <clone/> <bbox w="180.0" h="100.0" x="16105.0" y="1960.0"/> <glyph class="macromolecule" id="s4734_sa1702"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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"/> <clone/> <bbox w="80.0" h="50.0" x="16115.0" y="1985.0"/> <glyph class="unit of information" id="_76bac389-7a52-4929-9e09-94cd8f841c79"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16132.5" y="1980.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4735_sa1703"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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"/> <clone/> <bbox w="80.0" h="50.0" x="16195.0" y="1985.0"/> <glyph class="unit of information" id="_79cd7967-de70-4eee-b9a1-174ae58c968d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16212.5" y="1980.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4808_csa220" 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:CSF2:CSF2RA:CSF2RB:JAK2 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="182.5" h="125.0" x="15573.75" y="5417.5"/> <glyph class="macromolecule" id="s4809_sa1651"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15665.0" y="5475.0"/> <glyph class="unit of information" id="_aae1516a-15a9-4dc7-8b16-df4e02bd966e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15682.5" y="5470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4810_sa1652"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15585.0" y="5475.0"/> <glyph class="unit of information" id="_1e4b801c-25a2-4783-9405-d56b59d4432d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15602.5" y="5470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4814_sa2696"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15670.0" y="5435.0"/> <glyph class="state variable" id="_46e0a503-ff6e-4d0f-96ed-d04a2049fc4c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15662.5" y="5450.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4811_sa2875"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:CSF2 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:NKG2D CASCADE:KIR2DS2 CASCADE:Fc_gamma_RIII CASCADE:CSF2 PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway via NKG2D. PMID:11015446 Cross-linking of the KIR2DS2/DAP12 receptor on NKL cells resulted in the dose-dependent secretion of IFNG and GM-CSF PMID:21765015, PMID:22869907 CSF2 signaling can have both positive and negative influence on angiogenesis in tumors. First, CSF2 upregulates angiogenic factor VEGF expression via HIF1a, specific inhibition of PHD2 increases VEGF production. Second, CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. ( PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. 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. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="15590.0" y="5425.0"/> </glyph> </glyph> <glyph class="complex" id="s4895_csa34" 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:TUBGCP2:TUBGCP3:TUBGCP4:TUBGCP5:TUBGCP6:Tubulin-_alpha_*:Tubulin-_beta_*:Tubulin-_gamma_* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:NKG2D MAP:NATURAL_KILLER PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. PMID:16887996 Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. References_end </body> </html> </notes> <label text="MTOC"/> <bbox w="211.25" h="256.25" x="7814.375" y="5321.875"/> <glyph class="macromolecule" id="s4896_sa260"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBG1 HUGO:TUBG2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="Tubulin-γ*"/> <bbox w="80.0" h="40.0" x="7925.625" y="5338.125"/> </glyph> <glyph class="macromolecule" id="s4897_sa261"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP2"/> <bbox w="80.0" h="40.0" x="7835.625" y="5338.125"/> </glyph> <glyph class="macromolecule" id="s4898_sa262"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP3 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP3"/> <bbox w="80.0" h="40.0" x="7835.625" y="5378.125"/> </glyph> <glyph class="macromolecule" id="s4899_sa263"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP4 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP4"/> <bbox w="80.0" h="40.0" x="7835.625" y="5418.125"/> </glyph> <glyph class="macromolecule" id="s4900_sa264"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP5 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP5"/> <bbox w="80.0" h="40.0" x="7925.625" y="5378.125"/> </glyph> <glyph class="macromolecule" id="s4901_sa265"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP6 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP6"/> <bbox w="80.0" h="40.0" x="7925.625" y="5418.125"/> </glyph> <glyph class="macromolecule" id="s4902_sa266"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBA1A HGNC:20766 ENTREZ:7846 UNIPROT:Q71U36 GENECARDS:TUBA1A HUGO:TUBA1B HGNC:18809 ENTREZ:10376 UNIPROT:P68363 GENECARDS:TUBA1B HUGO:TUBA1C HGNC:20768 ENTREZ:84790 UNIPROT:Q9BQE3 GENECARDS:TUBA1C HUGO:TUBA3C HGNC:12408 ENTREZ:7278 UNIPROT:Q13748 GENECARDS:TUBA3C HUGO:TUBA3D HGNC:24071 ENTREZ:113457 GENECARDS:TUBA3D HUGO:TUBA3E HGNC:20765 ENTREZ:112714 UNIPROT:Q6PEY2 GENECARDS:TUBA3E HUGO:TUBA4A HGNC:12407 ENTREZ:7277 UNIPROT:P68366 GENECARDS:TUBA4A HUGO:TUBA8 HGNC:12410 ENTREZ:51807 UNIPROT:Q9NY65 GENECARDS:TUBA8 Identifiers_end References_begin: REACTOME:191692 KEGG:7846 ATLASONC:GC_TUBA1A WIKI:TUBA1A SwissProt:Q71U36 REACTOME:191693 KEGG:10376 ATLASONC:GC_TUBA1B WIKI:TUBA1B SwissProt:P68363 REACTOME:65667 KEGG:84790 ATLASONC:GC_TUBA1C WIKI:TUBA1C SwissProt:Q9BQE3 tubulin, alpha 3c REACTOME:154750 KEGG:7278 WIKI:TUBA3C SwissProt: Q13748 REACTOME:154750 KEGG:113457 WIKI:TUBA3D tubulin, alpha 3e WIKI:TUBA3E SwissProt:Q6PEY2 REACTOME:191690 KEGG:7277 ATLASONC:GC_TUBA4A WIKI:TUBA4A SwissProt: P68366 KEGG:51807 WIKI:TUBA8 SwissProt:Q9NY65 MAP:NATURAL_KILLER PMID:18287025 References_end </body> </html> </notes> <label text="Tubulin-α*"/> <bbox w="80.0" h="40.0" x="7831.875" y="5498.125"/> </glyph> <glyph class="macromolecule" id="s4903_sa267"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBB HUGO:TUBB1 HUGO:TUBB2A HUGO:TUBB2B HUGO:TUBB2C HUGO:TUBB3 HUGO:TUBB4 HUGO:TUBB4Q HUGO:TUBB6 Identifiers_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="Tubulin-β*"/> <bbox w="80.0" h="40.0" x="7915.625" y="5498.125"/> </glyph> </glyph> <glyph class="complex" id="s4910_csa179" 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:S100A8:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A References_end </body> </html> </notes> <label text="s1007"/> <bbox w="100.0" h="120.0" x="4880.0" y="1945.0"/> <glyph class="macromolecule" id="s4911_sa1191"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S100A8 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. References_end </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="4890.0" y="2005.0"/> </glyph> <glyph class="macromolecule" id="s4912_sa1192"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. References_end </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="4890.0" y="1955.0"/> </glyph> </glyph> <glyph class="complex" id="s4969_csa84" 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:ITGA4:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:INTEGRIN_A4B1 PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. References_end </body> </html> </notes> <label text="s1407"/> <clone/> <bbox w="116.25" h="142.5" x="8634.375" y="1688.75"/> <glyph class="macromolecule" id="s4970_sa655"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end </body> </html> </notes> <label text="ITGA4"/> <clone/> <bbox w="80.0" h="50.0" x="8654.375" y="1748.75"/> <glyph class="unit of information" id="_cdee712e-2aac-4adf-bf44-0bcfe39f766b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8671.875" y="1743.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s4971_sa656"> <notes> <html xmlns="http://www.w3.org/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 Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="50.0" x="8654.375" y="1698.75"/> <glyph class="unit of information" id="_03d9ebeb-207c-4b4e-ade5-13d2e301d7de"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8671.875" y="1693.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4969_csa80" 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:ITGA4:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:INTEGRIN_A4B1 PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. References_end </body> </html> </notes> <label text="s1407"/> <clone/> <bbox w="110.0" h="140.0" x="8627.5" y="1340.0"/> <glyph class="macromolecule" id="s4971_sa645"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="50.0" x="8642.5" y="1345.0"/> <glyph class="unit of information" id="_d34f726e-12e0-4ff5-84d6-8477da8668bb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8660.0" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4970_sa646"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end </body> </html> </notes> <label text="ITGA4"/> <clone/> <bbox w="80.0" h="50.0" x="8642.5" y="1395.0"/> <glyph class="unit of information" id="_79f3a362-a08d-40c6-acdd-67c81e308b91"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8660.0" y="1390.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5051_csa36" 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:GZMB:MIR223 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR223:GZMB"/> <bbox w="100.0" h="120.0" x="7270.0" y="6010.0"/> <glyph class="nucleic acid feature" id="s1620_sa277"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="7275.0" y="6017.5"/> <glyph class="unit of information" id="_e0bf4481-c26b-4bb2-8403-0d9f62376d81"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7305.0" y="6012.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1621_sa278"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="7275.0" y="6047.5"/> <glyph class="unit of information" id="_e7b10fca-f8ca-4eed-8f67-3391f76441bb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7310.0" y="6042.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5052_csa37" 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:GZMB:MIR27A* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR27A*:GZMB"/> <bbox w="100.0" h="120.0" x="7430.0" y="6010.0"/> <glyph class="nucleic acid feature" id="s1594_sa279"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="7435.0" y="6057.5"/> <glyph class="unit of information" id="_d9dbb2c2-090a-4f70-b7a0-9cb2561fe9e1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7470.0" y="6052.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1595_sa280"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="7435.0" y="6027.5"/> <glyph class="unit of information" id="_2b26fe23-1f0f-4cfc-9f65-c4271ff61a35"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7465.0" y="6022.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5054_csa41" 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:MIR150:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR150:PRF1"/> <bbox w="100.0" h="120.0" x="7680.0" y="6010.0"/> <glyph class="nucleic acid feature" id="s1605_sa297"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 CASCADE:IFNAB PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="7685.0" y="6057.5"/> <glyph class="unit of information" id="_ddf75236-eddf-40c4-bc5d-8232fe9f5525"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7720.0" y="6052.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1604_sa298"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="7685.0" y="6027.5"/> <glyph class="unit of information" id="_7700567b-b611-4a50-92d2-e88731972469"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7715.0" y="6022.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5058_csa45" 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:GZMB:MIR378 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR378:GZMB"/> <bbox w="100.0" h="120.0" x="7830.0" y="6010.0"/> <glyph class="nucleic acid feature" id="s4908_sa305"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="7835.0" y="6047.5"/> <glyph class="unit of information" id="_01d539c7-4380-4b9d-bf68-d72eca210bb2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7870.0" y="6042.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4909_sa306"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="7835.0" y="6017.5"/> <glyph class="unit of information" id="_5d1ab79f-d619-43f4-b020-e047dbe1eb66"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7865.0" y="6012.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5059_csa351" 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:GZMB:MIR30E Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR30E:GZMB"/> <bbox w="100.0" h="120.0" x="7510.0" y="5780.0"/> <glyph class="nucleic acid feature" id="s5056_sa2876"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="7515.0" y="5787.5"/> <glyph class="unit of information" id="_11226b44-f42b-4319-abc7-3e31bf35d9ce"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7545.0" y="5782.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5057_sa2877"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="7515.0" y="5817.5"/> <glyph class="unit of information" id="_a893c842-d28d-49b0-af85-7ba4e0b0db7a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7550.0" y="5812.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5060_csa54" 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:MIR30E:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR30E:PRF1"/> <bbox w="100.0" h="120.0" x="7640.0" y="5780.0"/> <glyph class="nucleic acid feature" id="s2481_sa337"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="7645.0" y="5787.5"/> <glyph class="unit of information" id="_2a6cc5e8-82b0-460b-b89c-5a05ec090b31"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7675.0" y="5782.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2482_sa338"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 CASCADE:IFNAB PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="7645.0" y="5817.5"/> <glyph class="unit of information" id="_a1f704e1-5a74-473a-8b89-45cf39b1140b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7680.0" y="5812.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5061_csa40" 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:MIR27A*:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR27A*:PRF1"/> <bbox w="100.0" h="120.0" x="7560.0" y="6010.0"/> <glyph class="nucleic acid feature" id="s1596_sa293"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 CASCADE:IFNAB PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="7565.0" y="6057.5"/> <glyph class="unit of information" id="_eb9d5d8a-f6a3-45a7-a0dd-33608c1194c2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7600.0" y="6052.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1597_sa294"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="7565.0" y="6027.5"/> <glyph class="unit of information" id="_43161447-1f14-471f-b25e-635cd3f41ff0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="7595.0" y="6022.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5062_csa35" 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:PXN:TUBGCP2:TUBGCP3:TUBGCP4:TUBGCP5:TUBGCP6:Tubulin-_alpha_*:Tubulin-_beta_*:Tubulin-_gamma_* Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:NKG2D MAP:NATURAL_KILLER PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. PMID:16887996 Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. References_end </body> </html> </notes> <label text="MTOC:PXN"/> <bbox w="200.0" h="293.125" x="8260.0" y="5583.4375"/> <glyph class="macromolecule" id="s850_sa268"> <notes> <html xmlns="http://www.w3.org/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: CASCADE:NKG2D PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. References_end </body> </html> </notes> <label text="PXN"/> <bbox w="80.0" h="40.0" x="8320.0" y="5816.5625"/> </glyph> <glyph class="macromolecule" id="s4214_sa2756"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBB HUGO:TUBB1 HUGO:TUBB2A HUGO:TUBB2B HUGO:TUBB2C HUGO:TUBB3 HUGO:TUBB4 HUGO:TUBB4Q HUGO:TUBB6 Identifiers_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="Tubulin-β*"/> <bbox w="80.0" h="40.0" x="8360.0" y="5756.5625"/> </glyph> <glyph class="macromolecule" id="s4215_sa2757"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBA1A HGNC:20766 ENTREZ:7846 UNIPROT:Q71U36 GENECARDS:TUBA1A HUGO:TUBA1B HGNC:18809 ENTREZ:10376 UNIPROT:P68363 GENECARDS:TUBA1B HUGO:TUBA1C HGNC:20768 ENTREZ:84790 UNIPROT:Q9BQE3 GENECARDS:TUBA1C HUGO:TUBA3C HGNC:12408 ENTREZ:7278 UNIPROT:Q13748 GENECARDS:TUBA3C HUGO:TUBA3D HGNC:24071 ENTREZ:113457 GENECARDS:TUBA3D HUGO:TUBA3E HGNC:20765 ENTREZ:112714 UNIPROT:Q6PEY2 GENECARDS:TUBA3E HUGO:TUBA4A HGNC:12407 ENTREZ:7277 UNIPROT:P68366 GENECARDS:TUBA4A HUGO:TUBA8 HGNC:12410 ENTREZ:51807 UNIPROT:Q9NY65 GENECARDS:TUBA8 Identifiers_end References_begin: REACTOME:191692 KEGG:7846 ATLASONC:GC_TUBA1A WIKI:TUBA1A SwissProt:Q71U36 REACTOME:191693 KEGG:10376 ATLASONC:GC_TUBA1B WIKI:TUBA1B SwissProt:P68363 REACTOME:65667 KEGG:84790 ATLASONC:GC_TUBA1C WIKI:TUBA1C SwissProt:Q9BQE3 tubulin, alpha 3c REACTOME:154750 KEGG:7278 WIKI:TUBA3C SwissProt: Q13748 REACTOME:154750 KEGG:113457 WIKI:TUBA3D tubulin, alpha 3e WIKI:TUBA3E SwissProt:Q6PEY2 REACTOME:191690 KEGG:7277 ATLASONC:GC_TUBA4A WIKI:TUBA4A SwissProt: P68366 KEGG:51807 WIKI:TUBA8 SwissProt:Q9NY65 MAP:NATURAL_KILLER PMID:18287025 References_end </body> </html> </notes> <label text="Tubulin-α*"/> <bbox w="80.0" h="40.0" x="8276.25" y="5756.5625"/> </glyph> <glyph class="macromolecule" id="s4216_sa2758"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP6 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP6"/> <bbox w="80.0" h="40.0" x="8370.0" y="5676.5625"/> </glyph> <glyph class="macromolecule" id="s4217_sa2759"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP4 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP4"/> <bbox w="80.0" h="40.0" x="8280.0" y="5676.5625"/> </glyph> <glyph class="macromolecule" id="s4218_sa2760"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP3 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP3"/> <bbox w="80.0" h="40.0" x="8280.0" y="5636.5625"/> </glyph> <glyph class="macromolecule" id="s4219_sa2761"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP2"/> <bbox w="80.0" h="40.0" x="8280.0" y="5596.5625"/> </glyph> <glyph class="macromolecule" id="s4220_sa2762"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBG1 HUGO:TUBG2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="Tubulin-γ*"/> <bbox w="80.0" h="40.0" x="8370.0" y="5596.5625"/> </glyph> <glyph class="macromolecule" id="s4221_sa2763"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TUBGCP5 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end </body> </html> </notes> <label text="TUBGCP5"/> <bbox w="80.0" h="40.0" x="8370.0" y="5636.5625"/> </glyph> </glyph> <glyph class="complex" id="s5063_csa312" 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:FLT1:VEGFA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="FLT1:VEGFA"/> <bbox w="100.0" h="130.0" x="1070.0" y="6035.0"/> <glyph class="macromolecule" id="s3915_sa2330"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MODULE:MARKERS_MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MDSC CASCADE:VEGFA PMID:16002046, PMID:9570538 Inhibitory function of VEGF on DC function is most likely mediated by Flt-1. PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="FLT1"/> <bbox w="80.0" h="50.0" x="1080.0" y="6095.0"/> <glyph class="unit of information" id="_26cfc16c-d88d-4a7d-8455-9afadd63bcd8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1097.5" y="6090.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4495_sa2331"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1080.0" y="6040.0"/> </glyph> </glyph> <glyph class="complex" id="s5064_csa311" 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:KDR:VEGFA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:17086423 Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2 (KDR) References_end </body> </html> </notes> <label text="KDR:VEGFA"/> <bbox w="100.0" h="120.0" x="980.0" y="5890.0"/> <glyph class="macromolecule" id="s3910_sa2324"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KDR Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:17086423 Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2 (KDR) VEGF treatment enhanced the phospho-Erk 1 and 2 via KDR. References_end </body> </html> </notes> <label text="KDR"/> <bbox w="80.0" h="50.0" x="990.0" y="5945.0"/> <glyph class="unit of information" id="_b2f19305-200a-4995-a2fa-99e42173af39"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1007.5" y="5940.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3911_sa2325"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="990.0" y="5900.0"/> </glyph> </glyph> <glyph class="complex" id="s5065_csa199" 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:CD47:THBS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:THBS1 PMID:10657674 CD47 engagement by Thrombospondin-1 peptide inhibits cytokine production and maturation of human dendritic cells. References_end </body> </html> </notes> <label text="THBS1:CD47"/> <bbox w="100.0" h="130.0" x="1120.0" y="5515.0"/> <glyph class="macromolecule" id="s2239_sa1475"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD47 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: CASCADE:CD47 MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:SIRPA PMID:11509594 CD47 binds SIRP-α on DC. SIRP-α engagement down-regulates DC function CD47-Fc potently suppressed IL-12 and TNF-α release by monocyte-derived DC stimulated by SAC. The inhibitory effect was dose dependent, and significant suppression was seen with as little as 10 ng/ml CD47-Fc (Fig. 5⇓B). Other cytokines, including IL-6 and IL-10, were also suppressed, CD47-Fc not only suppressed cytokine release by maturing DC, but also largely prevented DC phenotypic maturation. As indicated in Fig. 6⇓, CD83 and CD86 up-regulation were strongly reduced regardless of the stimulus used. For CD80, the inhibition was almost complete in response to CD40 signaling, moderate in response to SAC, and modest, but significant in response to LPS. CD40 expression was weakly up-regulated during DC maturation. In all three conditions, SIRP-α ligation by CD47-Fc abrogated the CD40 increase. Note only a slight reduction in HLA-DR expression. All together, these results demonstrate that engagement of SIRP-α largely inhibits DC maturation. PMID:10657674, PMID:10657674 CD47 is expresed on dendritic cells PMID:10657674, PMID:14568985 CD47 engagement by Thrombospondin-1 inhibits cytokine production and maturation of human dendritic cells. PMID:22310103 CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s [20]. Since then, CD47 has been found to be expressed on multiple human tumor types CD47 functions as an inhibitor of phagocytosis through ligation of SIRPα expressed on phagocytes, leading to tyrosine phosphatase activation and inhibition of myosin accumulation at the submembrane assembly site of the phagocytic synapse [14]. In this way, CD47 serves as a ‘don’t eat me signal’ and a marker of self, as loss of CD47 leads to homeostatic phagocytosis of aged or damaged cells References_end </body> </html> </notes> <label text="CD47"/> <bbox w="80.0" h="50.0" x="1130.0" y="5570.0"/> <glyph class="unit of information" id="_abf68b00-5843-43f1-a6b8-53400c20aa71"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1147.5" y="5565.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2237_sa1476"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:THBS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:IL10 CASCADE:TGFB CASCADE:PGE2 PMID:14996710 Thrombospondin-1 is associated with tumor microenvironment. PMID:10657674 CD47 engagement by Thrombospondin-1 peptide inhibits cytokine production and maturation of human dendritic cells. PMID:14568985 Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47. IL-10, TGF-β, and PGE2 enhance TSP secretion by Dcs References_end </body> </html> </notes> <label text="THBS1"/> <bbox w="80.0" h="40.0" x="1130.0" y="5525.0"/> </glyph> </glyph> <glyph class="complex" id="s5066_csa316" 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:CD36:THBS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:THBS1 PMID:14568985 The exogenous and endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47 and probably CD36 References_end </body> </html> </notes> <label text="THBS1:CD36"/> <bbox w="100.0" h="130.0" x="1120.0" y="5335.0"/> <glyph class="macromolecule" id="s3947_sa2363"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:THBS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:IL10 CASCADE:TGFB CASCADE:PGE2 PMID:14996710 Thrombospondin-1 is associated with tumor microenvironment. PMID:10657674 CD47 engagement by Thrombospondin-1 peptide inhibits cytokine production and maturation of human dendritic cells. PMID:14568985 Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47. IL-10, TGF-β, and PGE2 enhance TSP secretion by Dcs References_end </body> </html> </notes> <label text="THBS1"/> <bbox w="80.0" h="40.0" x="1130.0" y="5345.0"/> </glyph> <glyph class="macromolecule" id="s3948_sa2364"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD36 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL13 CASCADE:IL4 CASCADE:THBS1 CASCADE:CD36 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. PMID:17101731 Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. PMID:14568985 The exogenous and endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47 and probably CD36 References_end </body> </html> </notes> <label text="CD36"/> <bbox w="80.0" h="50.0" x="1130.0" y="5390.0"/> <glyph class="unit of information" id="_2b5880c5-60ca-47af-9d85-e39199673afe"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1147.5" y="5385.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5067_csa150" 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:IL4:IL4R:JAK1:JAK2:JAK3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:IL4 References_end </body> </html> </notes> <label text="IL4_receptor_TYPE1:IL4:JAK1:JAK2:JAK3"/> <bbox w="214.5" h="155.5" x="942.75" y="5027.25"/> <glyph class="macromolecule" id="s5068_sa1018"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="1060.0" y="5125.0"/> <glyph class="state variable" id="_0db73514-8e3a-4178-ba33-93a35a9cebde"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1055.0" y="5140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5069_sa1019"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="1059.75" y="5079.75"/> <glyph class="state variable" id="_c2404848-da1f-4b58-ba43-c43115956103"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1052.25" y="5094.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s5070_sa1020"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="1062.75" y="5042.75"/> </glyph> <glyph class="macromolecule" id="s5071_sa1021"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="962.75" y="5042.75"/> </glyph> <glyph class="macromolecule" id="s5072_sa1022"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="962.75" y="5117.75"/> <glyph class="state variable" id="_fc1ea15f-d534-4ffa-a97f-8c77fda374f2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1037.75" y="5152.139"/> </glyph> <glyph class="unit of information" id="_0c847c1c-4226-40b9-88e1-be3af4ff1a68"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="980.25" y="5112.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s5073_sa1023"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="962.75" y="5077.75"/> <glyph class="unit of information" id="_3d7cce4c-d5ba-4cbb-b33c-33186e59cba9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="980.25" y="5072.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5074_csa313" 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:IL4:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 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:IL4"/> <bbox w="92.0" h="186.5" x="794.0" y="4941.75"/> <glyph class="macromolecule" id="s4460_sa2344"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="800.0" y="5050.0"/> <glyph class="state variable" id="_316b0611-9a5a-4be4-a570-8b9ee19ef9cf"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="875.0" y="5084.389"/> </glyph> <glyph class="unit of information" id="_22879001-e27b-4513-85d2-ad35455b2725"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="817.5" y="5045.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4459_sa2345"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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: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="800.0" y="5010.0"/> <glyph class="unit of information" id="_5e55b5ad-02b1-4300-b7e6-82026d260f26"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="817.5" y="5005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3929_sa2350"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="806.0" y="4961.75"/> </glyph> </glyph> <glyph class="complex" id="s5075_csa315" 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:IL4:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 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:IL4"/> <bbox w="110.0" h="189.5625" x="775.0" y="4710.2188"/> <glyph class="macromolecule" id="s3931_sa2348"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="790.0" y="4773.9062"/> <glyph class="state variable" id="_e6f3909c-2b17-419d-bc9b-68751838839a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="865.0" y="4808.2954"/> </glyph> <glyph class="unit of information" id="_823cadc8-61fd-4d7f-841b-11fb31e75055"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="807.5" y="4768.9062"/> </glyph> </glyph> <glyph class="macromolecule" id="s3932_sa2349"> <notes> <html xmlns="http://www.w3.org/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"/> <bbox w="80.0" h="50.0" x="790.0" y="4823.9062"/> <glyph class="state variable" id="_0d051706-0320-4368-bf5a-9cc31435ea56"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="865.0" y="4857.663"/> </glyph> <glyph class="unit of information" id="_97849d0c-2117-4cbf-b790-9bc7759920f9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="807.5" y="4818.9062"/> </glyph> </glyph> <glyph class="macromolecule" id="s3933_sa2351"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="785.0" y="4730.2188"/> </glyph> </glyph> <glyph class="complex" id="s5083_csa314" 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:IL13:IL13RA1:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS 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="IL4/IL13_receptor- TYPE 2:IL13"/> <bbox w="100.0" h="179.5625" x="790.0" y="4485.2188"/> <glyph class="macromolecule" id="s3936_sa2346"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="795.0" y="4538.9062"/> <glyph class="state variable" id="_0ae638f8-65bb-4960-8d06-71424054bf10"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="870.0" y="4573.2954"/> </glyph> <glyph class="unit of information" id="_7b1c29fc-cf59-45a4-a20d-0800cb6e2a94"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="812.5" y="4533.9062"/> </glyph> </glyph> <glyph class="macromolecule" id="s3937_sa2347"> <notes> <html xmlns="http://www.w3.org/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"/> <bbox w="80.0" h="50.0" x="795.0" y="4588.9062"/> <glyph class="state variable" id="_e00cf98e-c8e6-467b-ae74-2ea29a9c67a9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="870.0" y="4622.663"/> </glyph> <glyph class="unit of information" id="_c2bb022b-30aa-403c-ac7b-260bf0cef9de"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="812.5" y="4583.9062"/> </glyph> </glyph> <glyph class="macromolecule" id="s3934_sa2352"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <bbox w="80.0" h="40.0" x="800.0" y="4495.0"/> </glyph> </glyph> <glyph class="complex" id="s5084_csa154" 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:IL4:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:IL4 References_end </body> </html> </notes> <label text="IL4/Receptor-TYPE_2:IL4:JAK1:TYK2:JAK2"/> <bbox w="211.0" h="163.25" x="994.5" y="4773.375"/> <glyph class="macromolecule" id="s5077_sa1033"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1105.5" y="4833.375"/> <glyph class="state variable" id="_59ded864-b896-417c-ad96-21860e97b955"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1100.5" y="4848.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s5078_sa1035"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1105.5" y="4873.375"/> <glyph class="state variable" id="_047ee168-f61a-44b5-a7cb-dc87cbab48e9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1100.5" y="4888.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s5079_sa1036"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="1014.5" y="4786.625"/> </glyph> <glyph class="macromolecule" id="s5080_sa1037"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: 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"/> <bbox w="80.0" h="50.0" x="1014.5" y="4871.625"/> <glyph class="state variable" id="_ef3ef08f-767c-4a32-b3d3-3b96efbb3c60"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1089.5" y="4905.382"/> </glyph> <glyph class="unit of information" id="_7bba6d14-9b9b-4662-a97f-03e89de2ca21"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1032.0" y="4866.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s5081_sa1038"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="1014.5" y="4831.625"/> <glyph class="state variable" id="_2791fc91-3911-460a-baf0-7e9015bdd377"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1089.5" y="4866.014"/> </glyph> <glyph class="unit of information" id="_79e69657-5540-41e1-b74e-e511cd6ef41f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1032.0" y="4826.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s5082_sa2343"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1105.5" y="4783.375"/> <glyph class="state variable" id="_7d373a54-bed8-4492-a49f-1adb844c1124"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1098.0" y="4798.375"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5085_csa158" 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:IL13:IL13RA1:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:IL13 References_end </body> </html> </notes> <label text="IL13/Receptor-TYPE_2:IL113:JAK1:TYK2:JAK2"/> <bbox w="215.25" h="165.0" x="982.375" y="4482.5"/> <glyph class="macromolecule" id="s5086_sa1045"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1097.625" y="4582.5"/> <glyph class="state variable" id="_6bbdef4c-fc04-48c0-935d-6a31984f9b7c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1090.125" y="4597.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5087_sa1046"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1097.625" y="4542.5"/> <glyph class="state variable" id="_9555e06d-7fc1-4871-b455-998418b37ab7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1090.125" y="4557.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5088_sa1047"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="1002.375" y="4532.5"/> <glyph class="state variable" id="_340efd8d-a580-45d6-a424-18cbbea986b3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1074.875" y="4566.889"/> </glyph> <glyph class="unit of information" id="_4eb5ac78-0c6d-4dfb-b107-12e0f4d78944"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1019.875" y="4527.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5089_sa1048"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: 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"/> <bbox w="80.0" h="50.0" x="1002.375" y="4582.5"/> <glyph class="state variable" id="_a0090846-7d60-4f29-972c-f9777dcde8a3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1074.875" y="4616.257"/> </glyph> <glyph class="unit of information" id="_b19a6b02-f8ec-4101-9931-66b069822607"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1019.875" y="4577.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5090_sa1049"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <bbox w="80.0" h="40.0" x="992.375" y="4487.5"/> </glyph> <glyph class="macromolecule" id="s5091_sa1050"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1097.625" y="4502.5"/> <glyph class="state variable" id="_2c75c590-3221-47e8-8ac1-d5aca8e8a2df"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1092.625" y="4517.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5092_csa160" 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:IL13:IL13RA2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 References_end </body> </html> </notes> <label text="IL13:IL13RA2"/> <bbox w="100.0" h="120.0" x="880.0" y="4335.0"/> <glyph class="macromolecule" id="s313_sa1053"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175 IL13 signaling via IL13RA2 induces TGFB production in MDSC. References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="80.0" h="50.0" x="889.64703" y="4387.1177"/> <glyph class="unit of information" id="_50a6d093-faa9-4cbd-b8ca-e0d26422e1e9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="907.14703" y="4382.1177"/> </glyph> </glyph> <glyph class="macromolecule" id="s314_sa1054"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <bbox w="80.0" h="40.0" x="888.64703" y="4344.1177"/> </glyph> </glyph> <glyph class="complex" id="s5093_csa151" 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:IL10:IL10RA:IL10RB:JAK1:TYK2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 References_end </body> </html> </notes> <label text="IL10R*:IL10:JAK1:TYK2"/> <bbox w="179.0" h="177.0" x="1020.5" y="4086.5"/> <glyph class="macromolecule" id="s290_sa1025"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL10 CASCADE:TGFB CASCADE:MIF CASCADE:CSF1 CASCADE:IL12 CASCADE:STING CASCADE:TLR2_4 CASCADE:IFNAB CASCADE:FLT3LG CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. 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:16713974 Production of IL10 is partially ERK dependent. PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. At the same tyme IL10 siglaning also participates in ID3 upregulation via PI3K/AKT pathway PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages PMID:9834059 NK cells stimulated by IL12 induces IL10 production. PMID:11207245 IFNA induces IL10 production in Dcs (negative loop) PMID:21220452 that IL-10 increased March1 mRNA by approximately six fold PMID:15579430 Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) protein Molecules on Dendritic Cells in Metastatic Tumor Lesions ( PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="1033.5" y="4091.0"/> </glyph> <glyph class="macromolecule" id="s289_sa1026"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="1110.5" y="4138.5"/> <glyph class="unit of information" id="_d1a0db15-dae2-42ae-875b-9f1e24fae397"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1128.0" y="4133.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s64_sa1027"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="1034.5" y="4138.5"/> <glyph class="state variable" id="_ef5b113f-b5d3-4988-a4bf-516188aa216f"> <state value="P" variable="Y496"/> <bbox w="35.0" h="10.0" x="1017.0" y="4140.3364"/> </glyph> <glyph class="state variable" id="_d1a8f262-d5a2-46f8-8eee-3cb396cbcf20"> <state value="P" variable="Y446"/> <bbox w="35.0" h="10.0" x="1059.1581" y="4183.5"/> </glyph> <glyph class="unit of information" id="_3a08b855-48c9-4fed-8349-92906f1282b4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1052.0" y="4133.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2761_sa1028"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1110.0" y="4205.0"/> <glyph class="state variable" id="_dad132d0-34ea-40f3-92a7-77a6a3854972"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1102.5" y="4220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s288_sa1024"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1030.0" y="4205.0"/> <glyph class="state variable" id="_e0d95c39-11aa-474b-9c74-405a6ca687f6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1022.5" y="4220.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5094_csa149" 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:IL10RA:IL10RB Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10R contains two subunits IL1ORA and IL10RB PMID:‭15833879 ‭Anti IL-10 receptor–specific antibody switched TAMs from an M2 to an M1 macrophage–like phenotype. References_end </body> </html> </notes> <label text="IL10R*"/> <bbox w="179.5" h="93.5" x="800.25" y="4138.25"/> <glyph class="macromolecule" id="s2760_sa1016"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="880.0" y="4155.0"/> <glyph class="unit of information" id="_a41c53f8-3a62-4a4b-8d9e-296b8e628534"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="897.5" y="4150.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3537_sa1017"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="809.25" y="4157.75"/> <glyph class="state variable" id="_a52a98b5-8bb5-442a-98fd-b0d10e737226"> <state value="" variable="Y496"/> <bbox w="30.0" h="10.0" x="794.25" y="4159.5864"/> </glyph> <glyph class="state variable" id="_a1725735-1960-4cf2-8808-f0d779a968af"> <state value="" variable="Y446"/> <bbox w="30.0" h="10.0" x="836.4081" y="4202.75"/> </glyph> <glyph class="unit of information" id="_104f37b8-7b95-41ae-bec0-ac8e9603a714"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="826.75" y="4152.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5095_csa147" 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:IL10:IL10RA:IL10RB Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. PMID:‭15833879 ‭Anti IL-10 receptor–specific antibody switched TAMs from an M2 to an M1 macrophage–like phenotype. References_end </body> </html> </notes> <label text="IL10R*:IL10"/> <bbox w="180.0" h="131.0" x="800.0" y="3924.5"/> <glyph class="macromolecule" id="s50_sa1008"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL10 CASCADE:TGFB CASCADE:MIF CASCADE:CSF1 CASCADE:IL12 CASCADE:STING CASCADE:TLR2_4 CASCADE:IFNAB CASCADE:FLT3LG CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. 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:16713974 Production of IL10 is partially ERK dependent. PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. At the same tyme IL10 siglaning also participates in ID3 upregulation via PI3K/AKT pathway PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages PMID:9834059 NK cells stimulated by IL12 induces IL10 production. PMID:11207245 IFNA induces IL10 production in Dcs (negative loop) PMID:21220452 that IL-10 increased March1 mRNA by approximately six fold PMID:15579430 Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) protein Molecules on Dendritic Cells in Metastatic Tumor Lesions ( PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="810.0" y="3936.0"/> </glyph> <glyph class="macromolecule" id="s49_sa1009"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="891.0" y="3976.5"/> <glyph class="unit of information" id="_f4c357b3-1ff9-47e9-b4f5-d7695d2580e6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="908.5" y="3971.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s48_sa1010"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="810.0" y="3980.0"/> <glyph class="state variable" id="_ac440afd-f1a7-47de-bc31-d859acce53a7"> <state value="" variable="Y496"/> <bbox w="30.0" h="10.0" x="795.0" y="3981.8364"/> </glyph> <glyph class="state variable" id="_69115559-0a07-4189-9ce1-a1dc98df789e"> <state value="" variable="Y446"/> <bbox w="30.0" h="10.0" x="837.1581" y="4025.0"/> </glyph> <glyph class="unit of information" id="_f508d9f1-6d3a-4e69-87c1-c3dd4d91483c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="827.5" y="3975.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5096_csa152" 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:MIR20A:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR20A:STAT3"/> <bbox w="100.0" h="120.0" x="1760.0" y="4055.0"/> <glyph class="nucleic acid feature" id="s1033_sa1029"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MAP:DENDRITIC_CELL CASCADE:IL10 CASCADE:FLT3LG CASCADE:IFNAB PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="90.0" h="25.0" x="1765.0" y="4102.5"/> <glyph class="unit of information" id="_e40de4f9-deb9-4cc7-99f5-812c1f711586"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1800.0" y="4097.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1032_sa1030"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1765.0" y="4072.5"/> <glyph class="unit of information" id="_3425c866-3a11-4b66-9a7c-1e92295baa81"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1795.0" y="4067.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5097_csa155" 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:MIR17:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="MIR17:STAT3"/> <bbox w="100.0" h="120.0" x="1880.0" y="4055.0"/> <glyph class="nucleic acid feature" id="s1030_sa1039"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="1885.0" y="4082.5"/> <glyph class="unit of information" id="_ad0dd7bc-1b9f-493c-9c32-fc83a89253c7"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1915.0" y="4077.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1029_sa1040"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MAP:DENDRITIC_CELL CASCADE:IL10 CASCADE:FLT3LG CASCADE:IFNAB PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="90.0" h="25.0" x="1885.0" y="4112.5"/> <glyph class="unit of information" id="_16714b5a-1e1c-4802-aa48-9590add7f1d2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1920.0" y="4107.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5098_csa285" 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:MIF Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:MIF MAP:DENDRITIC_CELL 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="MIF:CD74"/> <bbox w="110.0" h="140.0" x="1045.0" y="3815.0"/> <glyph class="macromolecule" id="s3583_sa2094"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:MIF CASCADE:TNF CASCADE:IFNG CASCADE:IL4 CASCADE:IL13 CASCADE:TLR2_4 PMID:9637476, PMID:10878343 MIF prevented the release of perforin granules by NK cells but not CTLs. Tumor cells produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells. PMID:18490733 MIF inhibits NK cell activity through a transcriptional down-regulation of NKG2D PMID:16283355, PMID:12803886 MIF upregulates expression of TLR4 in macrothages via PU.1 (SPI1) activation PMID:12782713 MIF signal transduction initiated by binding to CD74. PMID:23390297 MIF deficiency or small-molecule inhibition reduces splenic MDSC immune suppression in tumor-bearing mice PMID:8195715 TNF and INFG induce MIF secretion in macrophages, TLR4 signaling induces MIF expression. 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 References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="1060.0" y="3825.0"/> </glyph> <glyph class="macromolecule" id="s3582_sa2095"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1060.0" y="3875.0"/> </glyph> </glyph> <glyph class="complex" id="s5099_csa161" 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:LGALS3:SLC3A2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS 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:LGALS3"/> <bbox w="100.0" h="150.0" x="1070.0" y="3620.0"/> <glyph class="macromolecule" id="s998_sa1057"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:LGALS3 CASCADE:TGFB CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. 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 CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="1080.0" y="3640.0"/> </glyph> <glyph class="macromolecule" id="s997_sa1058"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="1080.0" y="3690.0"/> <glyph class="unit of information" id="_e45ff5dc-e595-443b-ba58-ace66568d54e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1097.5" y="3685.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5100_csa159" 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:IL13RA1:MIR155 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: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 References_end </body> </html> </notes> <label text="IL13RA1:MIR155"/> <bbox w="114.0" h="102.0" x="1603.0" y="3504.0"/> <glyph class="nucleic acid feature" id="s350_sa1051"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1619.375" y="3523.25"/> <glyph class="unit of information" id="_c93cc0de-1fee-4d5e-a293-12b03b63886a"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1649.375" y="3518.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s349_sa1052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE: Maps_Modules_end References_begin: 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 References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="90.0" h="25.0" x="1619.375" y="3547.25"/> <glyph class="unit of information" id="_dae77325-bac0-4c42-8e17-d4c58686e734"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1654.375" y="3542.25"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5101_csa164" 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:IL6:IL6R:gp130* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: 1439146 IL6 signaling acts through IL6 receptor and receptor-associated signal transducer, gp130 9716487 IL6 signaling acts through jak/stat pathway, probably via Jak1, Jak2 and Tyk2 References_end </body> </html> </notes> <label text="IL6R*:IL6"/> <bbox w="110.0" h="185.70312" x="690.0" y="3017.1484"/> <glyph class="macromolecule" id="s3892_sa1072"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="700.0" y="3123.5547"/> <glyph class="state variable" id="_ebf9f105-009c-4ec3-b92f-ad7586daa1a2"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="762.5" y="3121.0957"/> </glyph> <glyph class="unit of information" id="_391e1b26-c1a4-473d-a8c9-861f1b66c668"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="717.5" y="3118.5547"/> </glyph> </glyph> <glyph class="macromolecule" id="s3893_sa1073"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="700.0" y="3073.5547"/> <glyph class="unit of information" id="_06bbfc7e-51b6-446e-944e-e37f297f2eca"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="717.5" y="3068.5547"/> </glyph> </glyph> <glyph class="macromolecule" id="s3894_sa1074"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IL6 CASCADE:TLR2_4 CASCADE:STING CASCADE:FCAR CASCADE:IL15 PMID:7590867 Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation PMID:15573129, PMID:8837607, PMID:9845545 Macrophage colony-stimulating factor (M-CSF) and IL-6 have also been reported to be involved in the tumour-mediated regulation of DC differentiation. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation PMID:11306493 The presence of high (>400 pg/ml) concentrations of IL-6 and M-CSF in tumor cell supernatant was strongly correlated with the inhibitory capacity of tumor cell medium on MO-DC differentiation 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. The IFN-γ, TNFα and IL-6 transcripts were consistently expressed at higher levels at 330-, 14- and 20-folds, respectively, in donor-matched mIL-15 DCs than mIL-4 DCs 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo 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="IL6"/> <bbox w="80.0" h="40.0" x="700.0" y="3028.5547"/> </glyph> </glyph> <glyph class="complex" id="s5102_csa165" 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:IL6R:gp130* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: 1439146 IL6 sirnaling acts through IL6 receptor and receptor-associated signal transducer, gp130. References_end </body> </html> </notes> <label text="IL6R*"/> <bbox w="123.25" h="133.625" x="833.375" y="2883.1875"/> <glyph class="macromolecule" id="s3896_sa1075"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="855.0" y="2945.0"/> <glyph class="state variable" id="_7123e0b4-8d28-44c7-b24e-488c100f8203"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="917.5" y="2942.541"/> </glyph> <glyph class="unit of information" id="_873d1705-884e-45dc-b952-d7fa77f17760"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="872.5" y="2940.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3897_sa1076"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="856.625" y="2898.1875"/> <glyph class="unit of information" id="_a17a94d2-2bfe-4bbb-9a71-eb1f0c3f1e8d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="874.125" y="2893.1875"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5103_csa319" 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:IL6R:SOCS3:gp130* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling in macrophages. References_end </body> </html> </notes> <label text="IL6R*:SOCS3"/> <bbox w="182.0" h="137.5" x="1339.0" y="2946.25"/> <glyph class="macromolecule" id="s127_sa2448"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="1351.0" y="2958.75"/> <glyph class="state variable" id="_8680f086-5b76-47f1-a5eb-cb85ecdcd787"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="1413.5" y="2956.291"/> </glyph> <glyph class="unit of information" id="_4b524c6b-09ea-498e-91c5-b2e09ba1dd45"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1368.5" y="2953.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s126_sa2449"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="1351.0" y="3008.75"/> <glyph class="unit of information" id="_20cd8b70-2e64-41f1-9082-01e8f2e705dd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1368.5" y="3003.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s132_sa2450"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SOCS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:TLR2_4 CASCADE:IL6 CASCADE:TNF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12754507 IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="80.0" h="40.0" x="1430.0" y="2985.0"/> </glyph> </glyph> <glyph class="complex" id="s5104_csa317" 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:IL6:IL6R:JAK1:JAK2:TYK2:gp130* Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: 1439146 IL6 signaling acts through IL6 receptor and receptor-associated signal transducer, gp130 9716487 IL6 signaling acts through jak/stat pathway, probably via Jak1, Jak2 and Tyk2 12754507 IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling. References_end </body> </html> </notes> <label text="IL6R*:IL6:JAK1:JAK2:TYK2"/> <bbox w="185.0" h="182.85156" x="982.5" y="2988.5742"/> <glyph class="macromolecule" id="s3969_sa2418"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="992.5" y="3092.129"/> <glyph class="state variable" id="_76ddaa78-61ea-4c31-846d-3092873f3024"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="1055.0" y="3089.67"/> </glyph> <glyph class="unit of information" id="_bc97ee15-aef3-4bb3-87f3-698932b8ad26"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1010.0" y="3087.129"/> </glyph> </glyph> <glyph class="macromolecule" id="s3970_sa2419"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="992.5" y="3042.129"/> <glyph class="unit of information" id="_6988c5dd-23c4-48bc-ab60-0afb28388646"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1010.0" y="3037.129"/> </glyph> </glyph> <glyph class="macromolecule" id="s3971_sa2420"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IL6 CASCADE:TLR2_4 CASCADE:STING CASCADE:FCAR CASCADE:IL15 PMID:7590867 Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation PMID:15573129, PMID:8837607, PMID:9845545 Macrophage colony-stimulating factor (M-CSF) and IL-6 have also been reported to be involved in the tumour-mediated regulation of DC differentiation. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation PMID:11306493 The presence of high (>400 pg/ml) concentrations of IL-6 and M-CSF in tumor cell supernatant was strongly correlated with the inhibitory capacity of tumor cell medium on MO-DC differentiation 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. The IFN-γ, TNFα and IL-6 transcripts were consistently expressed at higher levels at 330-, 14- and 20-folds, respectively, in donor-matched mIL-15 DCs than mIL-4 DCs 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo 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="IL6"/> <bbox w="80.0" h="40.0" x="992.5" y="2997.129"/> </glyph> <glyph class="macromolecule" id="s3972_sa2421"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1077.5" y="2998.5742"/> <glyph class="state variable" id="_4bd3c5d3-ea02-4bab-982a-4411a6dc98cf"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1070.0" y="3013.5742"/> </glyph> </glyph> <glyph class="macromolecule" id="s3973_sa2422"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="1077.5" y="3048.5742"/> <glyph class="state variable" id="_433442b1-738a-42ea-b6ec-0f176f3a25ae"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1070.0" y="3063.5742"/> </glyph> </glyph> <glyph class="macromolecule" id="s3974_sa2423"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1077.5" y="3098.5742"/> <glyph class="state variable" id="_15c83f0b-f8a0-4f59-99cd-60c0bf08044e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1070.0" y="3113.5742"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5105_csa162" 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:CSF3R:GSF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MDSC CASCADE:GSF3 PMID:20237318, PMID:18400509 GSF3R is a receptor for GSF3 in myeloid cells. The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. References_end </body> </html> </notes> <label text="CSF3R:CSF3"/> <bbox w="100.0" h="120.0" x="695.0" y="2650.0"/> <glyph class="macromolecule" id="s1068_sa1064"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF3R Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:20237318 GSF3R is a receptor for GSF3 in myeloid cells. The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. References_end </body> </html> </notes> <label text="CSF3R"/> <bbox w="80.0" h="50.0" x="705.0" y="2705.0"/> <glyph class="unit of information" id="_ff3709f5-5ecc-4587-8506-c7db7c3ec3a6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="722.5" y="2700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1069_sa1065"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GSF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter PMID:24091328 G-CSF–induced IRF-8 downregulation via STAT3 in MDSC References_end </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="705.0" y="2660.0"/> </glyph> </glyph> <glyph class="complex" id="s5106_csa318" 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:CSF3R:GSF3:JAK1:JAK2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MDSC CASCADE:GSF3 References_end </body> </html> </notes> <label text="CSF3R:CSF3:JAK1:JAK2"/> <bbox w="190.0" h="140.0" x="990.0" y="2560.0"/> <glyph class="macromolecule" id="s3982_sa2431"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF3R Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:20237318 GSF3R is a receptor for GSF3 in myeloid cells. The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. References_end </body> </html> </notes> <label text="CSF3R"/> <bbox w="80.0" h="50.0" x="995.0" y="2625.0"/> <glyph class="unit of information" id="_9a9f56a8-6f0d-46ba-b508-ee05168e9916"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1012.5" y="2620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3983_sa2432"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GSF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter PMID:24091328 G-CSF–induced IRF-8 downregulation via STAT3 in MDSC References_end </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="1000.0" y="2570.0"/> </glyph> <glyph class="macromolecule" id="s3985_sa2434"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1085.0" y="2620.0"/> <glyph class="state variable" id="_60c92928-25c6-4a4e-96f6-dc6565706860"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1077.5" y="2635.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3986_sa2435"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1085.0" y="2570.0"/> <glyph class="state variable" id="_94f0b84c-dec6-4941-9437-e6377d1e4499"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1077.5" y="2585.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5107_csa145" 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:SMAD2:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB MAP:MACROPHAGE MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="SMAD2:SMAD4"/> <bbox w="100.0" h="120.0" x="1700.0" y="2405.0"/> <glyph class="macromolecule" id="s1361_sa955"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="1710.0" y="2455.0"/> </glyph> <glyph class="macromolecule" id="s1362_sa956"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL12 CASCADE:IL18 PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. 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. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="1710.0" y="2415.0"/> <glyph class="state variable" id="_252cb709-6f10-433f-a74c-e9880502e654"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1702.5" y="2429.9683"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5108_csa146" 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:SMAD3:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB 11792802, 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocatio References_end </body> </html> </notes> <label text="SMAD3:SMAD4"/> <bbox w="100.0" h="120.0" x="1860.0" y="2405.0"/> <glyph class="macromolecule" id="s1334_sa957"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:16713975 TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. 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. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="1870.0" y="2415.0"/> <glyph class="state variable" id="_49a7502e-b0b8-482b-ba81-83da9a6f7fae"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1862.5" y="2430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1333_sa958"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="1870.0" y="2465.0"/> </glyph> </glyph> <glyph class="complex" id="s5109_csa163" 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:CSF1:CSF1R Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:GSF1 Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R References_end </body> </html> </notes> <label text="CSF1R:CSF1"/> <bbox w="100.0" h="120.0" x="860.0" y="2290.0"/> <glyph class="macromolecule" id="s593_sa1066"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:GSF1 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling blocks CSF (M-CSF) production in DC induced by tumor cells. PMID:24669294 SCF1 (M-CSF) is assosiated with M2 phenotype of macrophages References_end </body> </html> </notes> <label text="CSF1"/> <bbox w="80.0" h="40.0" x="870.0" y="2300.0"/> </glyph> <glyph class="macromolecule" id="s592_sa1067"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF1R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:GSF1 CASCADE:IL4 Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="80.0" h="50.0" x="870.0" y="2345.0"/> <glyph class="unit of information" id="_0fbb9a6f-c075-4cbd-ba4d-bce862837023"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="887.5" y="2340.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5110_csa166" 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:CSF2RB:IL3RA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IL3 PMID:18633355 (CD123)The surface markers of myeloid cells PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3R*"/> <bbox w="170.0" h="90.0" x="885.0" y="1735.0"/> <glyph class="macromolecule" id="s2377_sa1081"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL3RA Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:MARKERS_DC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL PMID:18633355 (CD123)The surface markers of myeloid cells CASCADE:IL3 PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3RA"/> <bbox w="80.0" h="50.0" x="970.0" y="1745.0"/> <glyph class="unit of information" id="_83780371-8c5a-482c-95ef-87523ecce1c8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="987.5" y="1740.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2378_sa1082"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="900.0" y="1745.0"/> <glyph class="unit of information" id="_9d9a660d-0ea9-4663-9758-921e249be635"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="917.5" y="1740.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5111_csa167" 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:CSF2RB:IL3:IL3RA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IL3 PMID:18633355 (CD123)The surface markers of myeloid cells PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3R*:IL3"/> <bbox w="117.5" h="202.5" x="1101.25" y="1883.75"/> <glyph class="macromolecule" id="s4287_sa1083"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL3RA Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:MARKERS_DC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL PMID:18633355 (CD123)The surface markers of myeloid cells CASCADE:IL3 PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3RA"/> <bbox w="80.0" h="50.0" x="1111.25" y="2011.25"/> <glyph class="unit of information" id="_e0ee5357-7507-4ba8-a518-312ec7b200a7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1128.75" y="2006.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4288_sa1084"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="1111.25" y="1951.25"/> <glyph class="unit of information" id="_65c9514e-b49c-4f1b-a9c4-e171e5035406"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1128.75" y="1946.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4289_sa1085"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL3 PMID:15549123 IL3 signaling is important for plasmacytoid DC which are expressing IL3RA. PMID:23762788 Tumor-infiltrating plasmacytoid dendritic cells (pDCs) have been associated with poor patient prognosis. PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce expression ICOS-L and OX40L. PMID:24778133, PMID:23026134 Expression ot ICOS-L and OX40L ligands by pDC promotes tumor progression by Promoting Th2 and Regulatory Immunity. References_end </body> </html> </notes> <label text="IL3"/> <bbox w="80.0" h="40.0" x="1111.25" y="1896.25"/> </glyph> </glyph> <glyph class="complex" id="s5112_csa144" 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:TGFB*:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB 11792802, 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation References_end </body> </html> </notes> <label text="TGFBR*:TGFB*"/> <bbox w="120.0" h="170.0" x="1680.0" y="1650.0"/> <glyph class="macromolecule" id="s1322_sa952"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFBR1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end </body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="1690.0" y="1700.0"/> <glyph class="unit of information" id="_b9d31b6e-c5fc-426f-8499-0daa453b210e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1707.5" y="1695.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1321_sa953"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="1690.0" y="1745.0"/> <glyph class="unit of information" id="_a53ceebc-44bc-43f9-88df-de4c559c584a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1707.5" y="1740.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1339_sa954"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MAST_CELL MAP:NEUTROPHIL CASCADE:TGFB CASCADE:STING CASCADE:STAB2 CASCADE:TLR2_4 CASCADE:IFNG PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:17070508, PMID:18490733 TGFB downregulates NKG2D expression. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-β in NK cells via the c-Jun N-terminal kinase (JNK) pathway PMID:2871107 Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. PMID:20538542 TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. The roles of TGFβ in the tumour microenvironment. PMID:20616810 The polarization of immune cells in the tumour environment by TGFbeta. PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. PMID:21372296 HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms. PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC 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:26966341 tudies have shown that, analogously to the M1 and M2 dichotomy, TANs develop a protumorigenic (N2) phenotype in untreated tumors, largely driven by the presence of TGF-β References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="1690.0" y="1660.0"/> </glyph> </glyph> <glyph class="complex" id="s5114_csa303" 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:Fc_gamma_RII_inhibiting*:Immunoglobulins* Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: MAP:MACROPHAGE References_end </body> </html> </notes> <label text="FcγRII_inhibiting*:Immunoglobulins*"/> <bbox w="100.0" h="120.0" x="2255.0" y="1590.0"/> <glyph class="macromolecule" id="s3745_sa2217"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="2265.0" y="1600.0"/> </glyph> <glyph class="macromolecule" id="s3747_sa2218"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCGR2B Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL CASCADE:FCGR2B PMID:24445665 The activation of macrophages by immune complexes is determined by the balance between the triggering of activating ITAM-bearing FcγRs and the triggering of inhibitory ITIM-bearing FcγRIIB. PMID:18759918, PMID:8805703, PMID:1238444 Inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors. 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:12176909, PMID:12773515 In macrophages SHP-1 inhibits Fcgamma receptor-mediated phagocytosis and the activation of RAC. Probably downstream of FcgammaRII(b) and other receptors. References_end </body> </html> </notes> <label text="FcγRII_inhibiting*"/> <bbox w="80.0" h="50.0" x="2265.0" y="1645.0"/> <glyph class="unit of information" id="_181555f8-0613-40b3-84f8-016f10ba1ac2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2282.5" y="1640.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5115_csa139" 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:CLEC2D:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="KLRB1:CLEC2D "/> <bbox w="100.0" h="120.0" x="2395.0" y="1510.0"/> <glyph class="macromolecule" id="s1518_sa878"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KLRB1 CASCADE:IL12 PMID:18159636 Transcription of the KLRB1 gene is suppressed in human cancer tissues PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:22378844, PMID:24227772 miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. IL15 and KLRB1 (NK1.1) ligation also induce MIR155 expression. References_end </body> </html> </notes> <label text="KLRB1"/> <bbox w="80.0" h="50.0" x="2405.0" y="1565.0"/> <glyph class="unit of information" id="_a456bae7-4a3e-4102-962a-a2f248d275e4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2422.5" y="1560.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1514_sa879"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CLEC2D Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KLRB1 PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end </body> </html> </notes> <label text="CLEC2D"/> <bbox w="80.0" h="40.0" x="2405.0" y="1520.0"/> </glyph> </glyph> <glyph class="complex" id="s5116_csa137" 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:CDH1:CDH2:CDH4:KLRG1* Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:17307799 References_end </body> </html> </notes> <label text="KLRG1*:CDH1:CDH2:CDH4"/> <bbox w="120.0" h="220.0" x="2525.0" y="1500.0"/> <glyph class="macromolecule" id="s1500_sa872"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:MARKERS_NK Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end </body> </html> </notes> <label text="KLRG1*"/> <bbox w="80.0" h="50.0" x="2545.0" y="1635.0"/> <glyph class="state variable" id="_54d3b252-f390-4b2b-aa51-a7adca528f02"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2537.5" y="1655.0"/> </glyph> <glyph class="unit of information" id="_a999e44b-21a1-4740-a7aa-bc778694fc3f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2562.5" y="1630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1501_sa873"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. References_end </body> </html> </notes> <label text="CDH1"/> <bbox w="80.0" h="40.0" x="2545.0" y="1590.0"/> </glyph> <glyph class="macromolecule" id="s1502_sa874"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CDH2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. References_end </body> </html> </notes> <label text="CDH2"/> <bbox w="80.0" h="40.0" x="2545.0" y="1550.0"/> </glyph> <glyph class="macromolecule" id="s1503_sa875"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CDH4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. References_end </body> </html> </notes> <label text="CDH4"/> <bbox w="80.0" h="40.0" x="2545.0" y="1510.0"/> </glyph> </glyph> <glyph class="complex" id="s5118_csa133" 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:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KIR2DL3 References_end </body> </html> </notes> <label text="KIR2DL3:HLA-C"/> <bbox w="100.0" h="120.0" x="2735.0" y="1620.0"/> <glyph class="macromolecule" id="s1463_sa864"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL3 MAP:NATURAL_KILLER PMID:11513144, PMID:8574854 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. KIR2DL3 inhibits NK cells downstream of HLA-C via SHP-1 binding and activation. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end </body> </html> </notes> <label text="KIR2DL3"/> <bbox w="80.0" h="50.0" x="2745.0" y="1675.0"/> <glyph class="state variable" id="_57476c64-f32e-4ad2-a52e-628fb6bdaa87"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2737.5" y="1695.0"/> </glyph> <glyph class="unit of information" id="_c80db9aa-0713-4f7d-9311-47a747e736ae"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2762.5" y="1670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1462_sa865"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="2745.0" y="1630.0"/> </glyph> </glyph> <glyph class="complex" id="s5119_csa136" 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:KIR2DL2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL2 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="KIR2DL2:HLA-C"/> <bbox w="100.0" h="130.0" x="2915.0" y="1605.0"/> <glyph class="macromolecule" id="s1436_sa870"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO::KIR2DL2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL2 MAP:NATURAL_KILLER PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:21339333 KIR2DL2 signaling blocks the initiation of activating responses downstream of HLA-C via SHP-1,SHP-2. KIR2DL2 signaling inhibits IFNG secretion and Ca2+ mobilization, probably via inhibition of NKG2D-DAP10 signaling. PMID:9605119 Interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3) with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor cell lysis. References_end </body> </html> </notes> <label text="KIR2DL2"/> <bbox w="80.0" h="50.0" x="2925.0" y="1660.0"/> <glyph class="unit of information" id="_f9e34f12-94c5-4b0b-9e7c-dee3578ffff3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2942.5" y="1655.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1441_sa871"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="2925.0" y="1615.0"/> </glyph> </glyph> <glyph class="complex" id="s5120_csa134" 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:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL1 MAP:NATURAL_KILLER PMID:12917349, PMID:18835194 KIR2DL1 signaling provides Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 and inhibits NK cytotoxicity. PMID:9751747 Potentially KIR2DL1 can acts also via SHP-2 PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream activating signaling . References_end </body> </html> </notes> <label text="KIR2DL1:HLA-C"/> <bbox w="100.0" h="120.0" x="3145.0" y="1590.0"/> <glyph class="macromolecule" id="s1469_sa866"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL1 MAP:NATURAL_KILLER PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor PMID:12917349, PMID:18835194 Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end </body> </html> </notes> <label text="KIR2DL1"/> <bbox w="80.0" h="50.0" x="3155.0" y="1645.0"/> <glyph class="state variable" id="_fa90bda5-9d89-441a-85b2-726c1fdaba1a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3147.5" y="1665.0"/> </glyph> <glyph class="unit of information" id="_7befeb62-fb29-4560-be93-6ca25b54c38e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3172.5" y="1640.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1468_sa867"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="3160.0" y="1600.0"/> </glyph> </glyph> <glyph class="complex" id="s5121_csa129" 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:KLRD1:NKG2A* Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. References_end </body> </html> </notes> <label text="NKG2A*:KLRD1"/> <bbox w="110.0" h="140.0" x="3150.0" y="1340.0"/> <glyph class="macromolecule" id="s3536_sa855"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRC1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. CD3 zeta (associated with NKp46 and NKp30) and KARAP/DAP12 (associated with NKp44). PMID:22464172 NKG2A induces CRK phosphorylation downstream of HLA-E. PMID:9485206 NKG2A inhibits NK cells via direct association with SHP-1 and SHP-2 PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. PMID:15120186 2B4 and LFA1 signalings upregulates FasL mRNA and surface expression in NK cells. FasL transcription is inhibited by NKG2A/CD94 References_end </body> </html> </notes> <label text="NKG2A*"/> <bbox w="80.0" h="50.0" x="3160.0" y="1345.0"/> <glyph class="unit of information" id="_3b8132e9-d59c-4dfe-bc31-fc2b98610d2a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3177.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1389_sa856"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="3160.0" y="1405.0"/> <glyph class="unit of information" id="_0c4fb3a0-f03c-47cb-aa8e-39c3370269ca"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3177.5" y="1400.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5122_csa130" 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-E:KLRD1:NKG2A* Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. References_end </body> </html> </notes> <label text="NKG2A*:KLRD1:HLA-E"/> <bbox w="110.0" h="210.0" x="3360.0" y="1555.0"/> <glyph class="macromolecule" id="s1426_sa857"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRC1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:NKG2A MAP:NATURAL_KILLER PMID:12731048 Engagement of CD94/NKG2A inhibits the tyrosine phosphorylation of NCR-associated ITAM-containing polypeptides. CD3 zeta (associated with NKp46 and NKp30) and KARAP/DAP12 (associated with NKp44). PMID:22464172 NKG2A induces CRK phosphorylation downstream of HLA-E. PMID:9485206 NKG2A inhibits NK cells via direct association with SHP-1 and SHP-2 PMID:10358164 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. PMID:15120186 2B4 and LFA1 signalings upregulates FasL mRNA and surface expression in NK cells. FasL transcription is inhibited by NKG2A/CD94 References_end </body> </html> </notes> <label text="NKG2A*"/> <bbox w="80.0" h="50.0" x="3365.0" y="1565.0"/> <glyph class="unit of information" id="_dc6da8fd-380f-4338-80b9-bd0f854d0d08"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3382.5" y="1560.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1427_sa858"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="3365.0" y="1625.0"/> <glyph class="unit of information" id="_51a2921c-f88b-48ee-bbd3-ebd16a130069"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3382.5" y="1620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1428_sa859"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="3365.0" y="1680.0"/> </glyph> </glyph> <glyph class="complex" id="s5124_csa131" 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-B:KIR3DL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR3DL1 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="KIR3DL1:HLA-B"/> <bbox w="100.0" h="120.0" x="3585.0" y="1630.0"/> <glyph class="macromolecule" id="s1450_sa860"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR3DL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: KIR3DL1 MAP:NATURAL_KILLER PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. Recognition of Inhibitory HLA-B Allotypes (Bw4+) by the KIR NKB1 Alters Stimulatory Signal Transduction Pathways in NK Cells via inhibition of PI3K pathway and Ca2+ mobilization. Probably it acts via LAT inhibition.KIR recognition of inhibitory class I molecules disrupted the ability of pp36 (LAT) to associate with Grb2 in vitro. PTP-1C (SHP-1) activated by KIR3DL1 binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2. PMID:11994457 Tyrosine-phosphorylated KIR3DL1 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2, SHP-1.3DL1-mediated inhibition of cytotoxicity was abolished upon overexpression of SHP-1. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end </body> </html> </notes> <label text="KIR3DL1"/> <bbox w="80.0" h="50.0" x="3595.0" y="1685.0"/> <glyph class="state variable" id="_7ebb6c68-e9b3-4a11-8af9-704b8983029f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3587.5" y="1705.0"/> </glyph> <glyph class="unit of information" id="_845583b2-af56-42f3-9a77-20ed671c1243"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3612.5" y="1680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1451_sa861"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HLA-B Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR3DL1 MAP:NATURAL_KILLER PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end </body> </html> </notes> <label text="HLA-B"/> <bbox w="80.0" h="40.0" x="3595.0" y="1640.0"/> </glyph> </glyph> <glyph class="complex" id="s5126_csa128" 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:FCER1G:HLA-G:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. References_end </body> </html> </notes> <label text="KIR2DL4:FCER1G"/> <bbox w="190.0" h="120.0" x="3780.0" y="1640.0"/> <glyph class="macromolecule" id="s3545_sa853"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:IL2 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 PMID:17100877 KIR2DL4 both contains a cytoplasmic ITIM and encodes a transmembrane arginine residue, through which it can associate with the FcɛRγ-chain KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells References_end </body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="3790.0" y="1695.0"/> <glyph class="state variable" id="_4978cc13-0c6a-4c62-b098-2f4adba3e5cd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3782.5" y="1715.0"/> </glyph> <glyph class="unit of information" id="_9b872663-9fae-4100-989d-6bf35cff884e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3807.5" y="1690.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3546_sa854"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:LILRB1 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end </body> </html> </notes> <label text="HLA-G"/> <bbox w="80.0" h="40.0" x="3790.0" y="1650.0"/> </glyph> <glyph class="macromolecule" id="s4058_sa2587"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="3880.0" y="1695.0"/> <glyph class="state variable" id="_e6e8b8d1-80fb-4307-9559-9157a9c47dc4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3875.0" y="1715.0"/> </glyph> <glyph class="unit of information" id="_65e1899c-df0f-41f7-b595-742371fa2bae"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3897.5" y="1690.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5127_csa126" 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-G:LILRB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:LILRB1 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="LILRB1:HLA-G"/> <bbox w="100.0" h="120.0" x="3995.0" y="1560.0"/> <glyph class="macromolecule" id="s1520_sa849"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LILRB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:LILRB1 MAP:NATURAL_KILLER PMID:15771571, PMID:10591185, PMID:9933109 LILRB1 binds with low afﬁnity to a conserved region in the α3 domain of essentially all HLA class I glycoproteins, including HLA-A, -B, -C, -E, -F, and -G. LILRB1 receptors on NK cells can suppress their activation (cytotoxicity) upon encountering HLA classI–bearing targets (demonstrated for HLA-G, only). References_end </body> </html> </notes> <label text="LILRB1"/> <bbox w="80.0" h="50.0" x="4005.0" y="1615.0"/> <glyph class="unit of information" id="_51dc7cec-eb70-43f2-a855-5bb757fc55f6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4022.5" y="1610.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1521_sa850"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:LILRB1 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end </body> </html> </notes> <label text="HLA-G"/> <bbox w="80.0" h="40.0" x="4005.0" y="1570.0"/> </glyph> </glyph> <glyph class="complex" id="s5128_csa140" 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:ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SLAMF7 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="SLAMF7"/> <bbox w="100.0" h="120.0" x="4315.0" y="1770.0"/> <glyph class="macromolecule multimer" id="s2711_sa880"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="4322.0" y="1802.0"/> <glyph class="unit of information" id="_62662f02-8db9-44f2-88ce-e626d6e6e4ea"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="4355.0" y="1797.0"/> </glyph> <glyph class="state variable" id="_40376bf0-725d-4d72-842b-67ee993a0a5b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4314.5" y="1825.0"/> </glyph> <glyph class="unit of information" id="_e58a69fb-ff59-46d4-9e3c-c8b65916f324"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4342.5" y="1797.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5129_csa200" 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:CD47:SIRPA Identifiers_end Maps_Modules_begin: MODULE:ACTIVATING_RECEPTORS MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:CD47 MAP:NATURAL_KILLER References_end </body> </html> </notes> <label text="SIRPA:CD47"/> <bbox w="110.0" h="150.0" x="4400.0" y="1430.0"/> <glyph class="macromolecule" id="s2235_sa1477"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SIRPA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SIRPA MAP:NATURAL_KILLER PMID:11509594 CD47 binds SIRP-α on DC. SIRP-α engagement down-regulates DC function CD47-Fc potently suppressed IL-12 and TNF-α release by monocyte-derived DC stimulated by SAC. The inhibitory effect was dose dependent, and significant suppression was seen with as little as 10 ng/ml CD47-Fc (Fig. 5⇓B). Other cytokines, including IL-6 and IL-10, were also suppressed, CD47-Fc not only suppressed cytokine release by maturing DC, but also largely prevented DC phenotypic maturation. As indicated in Fig. 6⇓, CD83 and CD86 up-regulation were strongly reduced regardless of the stimulus used. For CD80, the inhibition was almost complete in response to CD40 signaling, moderate in response to SAC, and modest, but significant in response to LPS. CD40 expression was weakly up-regulated during DC maturation. In all three conditions, SIRP-α ligation by CD47-Fc abrogated the CD40 increase. Note only a slight reduction in HLA-DR expression. All together, these results demonstrate that engagement of SIRP-α largely inhibits DC maturation References_end </body> </html> </notes> <label text="SIRPA"/> <bbox w="80.0" h="50.0" x="4415.0" y="1445.0"/> <glyph class="unit of information" id="_a0c17c67-01dc-4e11-af1d-269d006e99ee"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4432.5" y="1440.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2236_sa1478"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD47 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: CASCADE:CD47 MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:SIRPA PMID:11509594 CD47 binds SIRP-α on DC. SIRP-α engagement down-regulates DC function CD47-Fc potently suppressed IL-12 and TNF-α release by monocyte-derived DC stimulated by SAC. The inhibitory effect was dose dependent, and significant suppression was seen with as little as 10 ng/ml CD47-Fc (Fig. 5⇓B). Other cytokines, including IL-6 and IL-10, were also suppressed, CD47-Fc not only suppressed cytokine release by maturing DC, but also largely prevented DC phenotypic maturation. As indicated in Fig. 6⇓, CD83 and CD86 up-regulation were strongly reduced regardless of the stimulus used. For CD80, the inhibition was almost complete in response to CD40 signaling, moderate in response to SAC, and modest, but significant in response to LPS. CD40 expression was weakly up-regulated during DC maturation. In all three conditions, SIRP-α ligation by CD47-Fc abrogated the CD40 increase. Note only a slight reduction in HLA-DR expression. All together, these results demonstrate that engagement of SIRP-α largely inhibits DC maturation. PMID:10657674, PMID:10657674 CD47 is expresed on dendritic cells PMID:10657674, PMID:14568985 CD47 engagement by Thrombospondin-1 inhibits cytokine production and maturation of human dendritic cells. PMID:22310103 CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s [20]. Since then, CD47 has been found to be expressed on multiple human tumor types CD47 functions as an inhibitor of phagocytosis through ligation of SIRPα expressed on phagocytes, leading to tyrosine phosphatase activation and inhibition of myosin accumulation at the submembrane assembly site of the phagocytic synapse [14]. In this way, CD47 serves as a ‘don’t eat me signal’ and a marker of self, as loss of CD47 leads to homeostatic phagocytosis of aged or damaged cells References_end </body> </html> </notes> <label text="CD47"/> <bbox w="80.0" h="50.0" x="4415.0" y="1505.0"/> <glyph class="unit of information" id="_37f30c76-0b8b-47e7-8ae2-bb0851c4f84a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4432.5" y="1500.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5130_csa174"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:S100A8:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A References_end </body> </html> </notes> <label text="S100A8:S100A9"/> <bbox w="100.0" h="120.0" x="4700.0" y="1100.0"/> <glyph class="macromolecule" id="s3008_sa1180"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S100A8 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. References_end </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="4710.0" y="1160.0"/> </glyph> <glyph class="macromolecule" id="s3009_sa1181"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. References_end </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="4710.0" y="1110.0"/> </glyph> </glyph> <glyph class="complex" id="s5162_csa176" 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:RAGE*:S100A8:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A References_end </body> </html> </notes> <label text="RAGE*:S100A8:S100A9"/> <bbox w="120.0" h="180.0" x="4710.0" y="1655.0"/> <glyph class="macromolecule" id="s2889_sa1184"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:AGER Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function.. References_end </body> </html> </notes> <label text="RAGE*"/> <bbox w="80.0" h="50.0" x="4730.0" y="1760.0"/> <glyph class="unit of information" id="_e2254901-2675-4e71-a9d9-06c52756beb6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4747.5" y="1755.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1015_sa1185"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. References_end </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="4730.0" y="1675.0"/> </glyph> <glyph class="macromolecule" id="s2890_sa1186"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:S100A8 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. 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text="sa142_degraded"/> <bbox w="30.0" h="30.0" x="10820.0" y="3635.0"/> </glyph> <glyph class="source and sink" id="s3980_sa2430" compartmentRef="c15_ca15"> <label text="csa23_degraded"/> <bbox w="30.0" h="30.0" x="12495.0" y="6285.0"/> </glyph> <glyph class="source and sink" id="s4053_sa2585" compartmentRef="c12_ca12"> <label text="csa337_degraded"/> <bbox w="30.0" h="30.0" x="11721.25" y="5330.0"/> </glyph> <glyph class="source and sink" id="s4149_sa2667" compartmentRef="c12_ca12"> <label text="csa319_degraded"/> <bbox w="30.0" h="30.0" x="1590.0" y="3305.0"/> </glyph> <glyph class="source and sink" id="s4156_sa2674" compartmentRef="c13_ca13"> <label text="sa2673_degraded"/> <bbox w="30.0" h="30.0" x="14005.0" y="8090.0"/> </glyph> <glyph class="source and sink" id="s4175_sa2702"> <label text="csa346_degraded"/> <bbox w="30.0" h="30.0" x="3945.0" y="8195.0"/> </glyph> <glyph class="source and sink" id="s4179_sa2712" compartmentRef="c12_ca12"> <label text="csa30_degraded"/> <bbox w="30.0" h="30.0" x="12855.0" y="7655.0"/> </glyph> <glyph class="source and sink" id="s4185_sa2718" compartmentRef="c12_ca12"> <label text="csa284_degraded"/> <bbox w="30.0" h="30.0" x="9665.0" y="4830.0"/> </glyph> <glyph class="nucleic acid feature" id="s30_sa388" 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:BAG6 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:23414611, PMID:18055229 BAG6 (BAT3) is a NKp30 ligand expressed on tumor cells. NKp30 recognises BAG6, which leads to NK cell killing of the tumour cell. References_end </body> </html> </notes> <label text="BAG6"/> <bbox w="70.0" h="25.0" x="10805.0" y="447.5"/> </glyph> <glyph class="nucleic acid feature" id="s45_sa384" 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:NCR3LG1 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:23414611, PMID:19528259, PMID:19528259, PMID:23801635 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. References_end </body> </html> </notes> <label text="B7H6*"/> <bbox w="70.0" h="25.0" x="10675.0" y="447.5"/> </glyph> <glyph class="nucleic acid feature" id="s76_sa1313" 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:IL1B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1B. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="70.0" h="25.0" x="4695.0" y="6397.5"/> </glyph> <glyph class="nucleic acid feature" id="s109_sa1253" 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:IL6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:STING CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:9743347 IL-13 blocks NF-κB-dependent production of IL6 PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC PMID:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 PMID: 23986532 STING ablation abolished hallmark TGF-β and IL-10 regulatory cytokine induction (mRNA)by apoptotic cells, and proinflammatory IL-6 mRNA was expressed instead in DCs References_end </body> </html> </notes> <label text="IL6"/> <bbox w="70.0" h="25.0" x="2417.5" y="5785.0"/> </glyph> <glyph class="nucleic acid feature" id="s110_sa1263" 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:IL12B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MAP:DENDRITIC_CELL CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses ( CASCADE:MIF CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. 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. 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:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 PMID:16394015 , PMID:19667062, PMID:15067049 Fos inhibits the expression of IL-12 p40 and IFNB and upregulates IL10 production downstream of FOS in macrophages and 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="IL12p40*"/> <bbox w="70.0" h="25.0" x="12337.5" y="5227.5"/> </glyph> <glyph class="nucleic acid feature" id="s120_sa991" 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:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP: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:12907458, PMID:12193690 IL10 upregulates expression of IL4RA in STAT3 dependent manner. PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="70.0" h="25.0" x="1350.0" y="4827.5"/> </glyph> <glyph class="nucleic acid feature" id="s138_sa1103" 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:NOS2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:TGFB CASCADE:MIF CASCADE:IL10 CASCADE:IFNG Maps_Modules_end References_begin: PMID:17476345 NOS2, a heme-containing enzyme that catalyzes the synthesis of NO and citrulline from l‐Arg, is expressed by various cells of the immune system, and its activa- tion is considered a hallmark of classically activated macrophages (also known as M1 macrophages), a macrophage subset that pro- duces proinflammatory cytokines and acts as the effector cell in the killing of invading pathogens and tumor cells. PMID:17689680, PMID:12646658 STAT1 binds to INOS promoter and induces INOS expression and NO production downstream of IFNG in murine macrophages. Acetylation inhibits STAT1 binding to promotor.(). PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in mouse macrophages ( PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses NF-kB dependent expression NOS2, Ccl3, Ccl7, Cxcl10 PMID:17689680 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:16424049 iNOS expression was induced by IFN-gamma stimulation in MDSC, probably via STAT1. 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:11875494 IL10 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 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC PMID:24777831 IFN-γ induces the cytotoxic function of IL-4 DCs but not IL-15 DCs. iNOS expression was induced by IFN-gamma stimulation in IL4-DC but not in IL15DC via STAT1 References_end </body> </html> </notes> <label text="NOS2"/> <bbox w="113.0" h="67.5" x="6334.9688" y="5294.6875"/> </glyph> <glyph class="nucleic acid feature" id="s144_sa1381" 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:MMP9 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:MIF CASCADE:IL10 CASCADE:IL4 CASCADE:IFNAB MAP:NEUTROPHIL Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. MIF signaling induces angiogenesis probavly via upregulation of MMP9, VEGF expression in macrophages and activates tumor invasion IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="70.0" h="25.0" x="3055.0" y="6437.5"/> </glyph> <glyph class="nucleic acid feature" id="s145_sa1087" 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:ARG1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:LACTIC CASCADE:TGFB CASCADE:MIF CASCADE:IL4 Maps_Modules_end References_begin: PMID:12193690 Up-regulation of IL4RA by IL10 correlates with increased IL4-dependent expression of arginase-1 (ARG1). PMID:21670502 KLF4 together with STAT6 upregulates expression of PPARG and ARG1 downstream of IL4 in macrophages. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20644162 Human MDSC express AGR1 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). PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth 19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:23390297 MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 References_end </body> </html> </notes> <label text="ARG1"/> <bbox w="116.0" h="58.5" x="5525.8438" y="5275.9375"/> </glyph> <glyph class="nucleic acid feature" id="s146_sa1088" 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:ARG2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:IL10 Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces ARG2 (arginase-2) expression References_end </body> </html> </notes> <label text="ARG2"/> <bbox w="113.0" h="60.5" x="5687.3438" y="5275.4375"/> </glyph> <glyph class="nucleic acid feature" id="s152_sa1990" 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:NFKBID Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MAP:MACROPHAGE CASCADE:IL10 Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="70.0" h="25.0" x="12053.0" y="3216.5"/> </glyph> <glyph class="nucleic acid feature" id="s156_sa1287" 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:CSF3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="CSF3"/> <bbox w="70.0" h="25.0" x="4575.0" y="5257.5"/> </glyph> <glyph class="nucleic acid feature" id="s164_sa990" 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: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:IL10 CASCADE:KLRB1 Maps_Modules_end References_begin: PMID:20435894 IL10 inhibits miR155 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="MIR155"/> <bbox w="70.0" h="25.0" x="12180.0" y="4632.5"/> </glyph> <glyph class="nucleic acid feature" id="s216_sa1314" 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:IL18 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="IL18"/> <bbox w="70.0" h="25.0" x="13401.25" y="5222.5"/> </glyph> <glyph class="nucleic acid feature" id="s219_sa1273" 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:IL12A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TLR2_4 CASCADE:CSF2 Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="70.0" h="25.0" x="12431.25" y="5227.5"/> </glyph> <glyph class="nucleic acid feature" id="s318_sa2815" 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:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:STING CASCADE:IL4 CASCADE:IL13 CASCADE:TNF CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. PMID:21372296 HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. 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). References_end </body> </html> </notes> <label text="TGFB1"/> <bbox w="132.0" h="54.0" x="3096.5" y="5950.5"/> </glyph> <glyph class="nucleic acid feature" id="s320_sa1007" 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:IL13RA2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="70.0" h="25.0" x="1355.0" y="4412.5"/> </glyph> <glyph class="nucleic acid feature" id="s346_sa1003" 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:IL13RA1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE: Maps_Modules_end References_begin: 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 References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="70.0" h="25.0" x="1445.0" y="3612.5"/> </glyph> <glyph class="nucleic acid feature" id="s438_sa2471" 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:ALOX15 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:23124025 IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6 IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6. References_end </body> </html> </notes> <label text="ALOX15"/> <bbox w="70.0" h="25.0" x="2368.25" y="3660.5"/> </glyph> <glyph class="nucleic acid feature" id="s441_sa2470" 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:MAOA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:23124025 IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6 IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6. PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including ARole of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology MAOA, PPARG, SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. References_end </body> </html> </notes> <label text="MAOA"/> <bbox w="70.0" h="25.0" x="6308.5938" y="7064.9375"/> </glyph> <glyph class="nucleic acid feature" id="s444_sa2484" 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:CD36 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL13 CASCADE:IL4 Maps_Modules_end References_begin: PMID:10432118 ALOX15 activation results in induction of CD36 expression downstream of IL4 and IL13 via PRARG CD36 gene expression is directly controlled by 15-LO expression/activity in IL-13-driven monocytes/macrophages References_end </body> </html> </notes> <label text="CD36"/> <bbox w="70.0" h="25.0" x="7927.5" y="2017.5"/> </glyph> <glyph class="nucleic acid feature" id="s447_sa2493" 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:DUSP1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 CASCADE:IL10 Maps_Modules_end References_begin: PMID:23124025, PMID:16184516 IL13 induces DUSP1 expression via TYK2 and probably STAT6 In silico analysis identified a STAT6 binding site at position +99 (relative to the transcriptional start site) of the mouse DUSP1 promoter. PMID:16184516 IL-10 induces the expression of DUSP1, which negatively regulates p38 phosphorylation and thus limits IL-10 production References_end </body> </html> </notes> <label text="DUSP1"/> <bbox w="70.0" h="25.0" x="2975.0" y="3359.0"/> </glyph> <glyph class="nucleic acid feature" id="s450_sa2492" 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:TIMP3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:IL4 Maps_Modules_end References_begin: PMID:23124025 IL4 induces expression of TIMP3 via JAK1 pathway References_end </body> </html> </notes> <label text="TIMP3"/> <bbox w="70.0" h="25.0" x="3335.0" y="6437.5"/> </glyph> <glyph class="nucleic acid feature" id="s456_sa2477" 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: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:10432118, PMID:21093321 IL4 upregulates expression of PPARG via JAK3/STAT6 pathway. PMID:21670502 KLF4 together with STAT6 upregulates expression of PPARG and ARG1 downstream of IL4. References_end </body> </html> </notes> <label text="PPARG"/> <bbox w="70.0" h="25.0" x="2577.25" y="3677.5"/> </glyph> <glyph class="nucleic acid feature" id="s458_sa2377" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD163 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:IL4 CASCADE:IL10 PMID:22176642 CD163 is a M2 marker PMID:15749903 CD163 expression in macrophages is IL10 dependent PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4 References_end </body> </html> </notes> <label text="CD163"/> <bbox w="70.0" h="25.0" x="1896.75" y="528.125"/> </glyph> <glyph class="nucleic acid feature" id="s461_sa2380" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MRC1 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:MIF CASCADE:LGALS3 CASCADE:IL4 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:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4 References_end </body> </html> </notes> <label text="MRC1"/> <bbox w="70.0" h="25.0" x="2000.6488" y="528.125"/> </glyph> <glyph class="nucleic acid feature" id="s464_sa1248" 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:CCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:TGFB MODULE:RECRUITMENT_OF_IMMUNE_CELLS 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 PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="70.0" h="25.0" x="5765.0" y="2612.5"/> </glyph> <glyph class="nucleic acid feature" id="s467_sa1257" 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:CCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TGFB CASCADE:CSF1 Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages Stat3 activity is required for tumor factor–induced migration of ECs References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="70.0" h="25.0" x="5675.0" y="2612.5"/> </glyph> <glyph class="nucleic acid feature" id="s498_sa1270" 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:CCL7 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS 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="CCL7"/> <bbox w="70.0" h="25.0" x="6095.0" y="2612.5"/> </glyph> <glyph class="nucleic acid feature" id="s505_sa2496" 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:KDM6B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:19567879 IL-4 via STAT6 upregulates expression of H3K27me2/3-specific demethylase KDM6B ( Jmjd3). References_end </body> </html> </notes> <label text="KDM6B"/> <bbox w="70.0" h="25.0" x="2535.0" y="4577.5"/> </glyph> <glyph class="nucleic acid feature" id="s510_sa2511" 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:IRF4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:20580461, PMID:19567879 IL4 induces expression of IRF4 probably via STAT6/KDM6B ( Jmjd3) pathway. PMID:20729857 KDM6B ( Jmjd3) demethylates promoter region of IRF4 and upregulates its expression References_end </body> </html> </notes> <label text="IRF4"/> <bbox w="70.0" h="25.0" x="2865.0" y="4717.5"/> </glyph> <glyph class="nucleic acid feature" id="s520_sa1387" 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:CCL24 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IL4 Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="CCL24"/> <bbox w="70.0" h="25.0" x="6415.0" y="2612.5"/> </glyph> <glyph class="nucleic acid feature" id="s522_sa2517" 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:MPP6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:IL4 Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="MPP6"/> <bbox w="70.0" h="25.0" x="3175.0" y="6447.0"/> </glyph> <glyph class="nucleic acid feature" id="s524_sa1392" 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:IL1RN Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:IL10 CASCADE:IL4 Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 References_end </body> </html> </notes> <label text="IL1RN"/> <bbox w="70.0" h="25.0" x="3327.5" y="5345.0"/> </glyph> <glyph class="nucleic acid feature" id="s554_sa2384" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MRC2 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:TGFB PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="MRC2"/> <bbox w="70.0" h="25.0" x="2091.75" y="528.125"/> </glyph> <glyph class="nucleic acid feature" id="s560_sa2404" 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:MIF Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:TLR2_4 CASCADE:TNF CASCADE:IL4 CASCADE:IL13 PMID:24006507 HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression H2O2 induces MIF expression in macrophages (http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A2803) PMID:8195715 TNF and INFG induce MIF secretion in macrophages, TLR4 signaling induces MIF expression. PMID:23390297 MIF deficiency or small-molecule inhibition reduces splenic MDSC immune suppression in tumor-bearing mice References_end </body> </html> </notes> <label text="MIF"/> <bbox w="70.0" h="25.0" x="2627.5" y="5785.0"/> </glyph> <glyph class="nucleic acid feature" id="s571_sa2303" 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:HIF1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 CASCADE:IL13 CASCADE:IFNG Maps_Modules_end References_begin: PMID:20194441 IFNG enhanced the synthesis of HIF-1A mRNA. PMID:24006507 HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. IL4 downregulates HIF1a translation References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="70.0" h="25.0" x="3741.625" y="4595.0"/> </glyph> <glyph class="nucleic acid feature" id="s574_sa2300" 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:EPAS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 CASCADE:IL13 CASCADE:IFNG Maps_Modules_end References_begin: PMID:20194441 HIF2a expression is assosiated with M2 phenotype. PMID:11888900, PMID:20644254 HIF2A induces tumor growth and angiogenesis. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. INFG enhanced the synthesis of HIF-1 mRNA and strongly reduced HIF-2 mRNA synthesis. References_end </body> </html> </notes> <label text="HIF2A*"/> <bbox w="70.0" h="25.0" x="3565.625" y="4610.25"/> </glyph> <glyph class="nucleic acid feature" id="s580_sa1170" 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:CXCR4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MAP:MDSC MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:PGE2 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:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="70.0" h="25.0" x="5245.0" y="2102.5"/> </glyph> <glyph class="nucleic acid feature" id="s586_sa1169" 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:FN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:FN1 Maps_Modules_end References_begin: PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. References_end </body> </html> </notes> <label text="FN1"/> <bbox w="70.0" h="25.0" x="6175.0" y="2332.5"/> </glyph> <glyph class="nucleic acid feature" id="s684_sa1279" 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:CXCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:24006507 HIF2A upregulates expression of Pfkfb3, Ccr2, and Cxcl2 PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. Stat3 activity is required for tumor factor–induced migration of ECs References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="70.0" h="25.0" x="4955.0" y="2606.0"/> </glyph> <glyph class="nucleic acid feature" id="s693_sa1530" 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>References_begin: PMID:11964313, PMID:11672593, PMID:12811837. INFG upregulates mRNA level and surface expression of TLR4 and TLR2. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TLR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 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="TLR2"/> <bbox w="70.0" h="25.0" x="15080.0" y="2057.5"/> </glyph> <glyph class="nucleic acid feature" id="s700_sa1286" 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:CCL4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine CCL4 (MIP1B). References_end </body> </html> </notes> <label text="CLL4"/> <bbox w="70.0" h="25.0" x="5865.0" y="2616.0"/> </glyph> <glyph class="nucleic acid feature" id="s724_sa1534" 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:LY96 Identifiers_end Maps_Modules_begin: 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="70.0" h="25.0" x="15290.0" y="2047.5"/> </glyph> <glyph class="nucleic acid feature" id="s726_sa1536" 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:MYD88 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG CASCADE:IL15 Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. PMID:12244150 IL-15 up-regulates MyD88 gene expression in NK cells. Both IL-15 induces STAT binding to MyD88 GAS. Anti-STAT5 and anti-STAT1 Abs supershifted both of the IL-15-induced MyD88 GAS complexes. () References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="70.0" h="25.0" x="15390.0" y="2057.5"/> </glyph> <glyph class="nucleic acid feature" id="s734_sa2739" 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:RELA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IFNG Maps_Modules_end References_begin: PMID:8641346 IFNG did not affect the expression of p105 transcripts but enhanced the expression of p65 mRNA. References_end </body> </html> </notes> <label text="RELA"/> <bbox w="70.0" h="25.0" x="13310.0" y="3527.5"/> </glyph> <glyph class="nucleic acid feature" id="s767_sa2015" 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:FOS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:16713974 INFG signaling inhibits FOS expression PMID:16394015 PMID:19667062 TPL-2 ERK pathway induces Fos expression in macrophages ( References_end </body> </html> </notes> <label text="FOS"/> <bbox w="70.0" h="25.0" x="2765.0" y="4388.125"/> </glyph> <glyph class="nucleic acid feature" id="s777_sa1548" 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:SOCS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:12433365, PMID:10485906 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:21097505 IL-13 upregulates expression of SOCS1. PMID:14764699 SOCS1 and SOCS3 are upregulated in mature DC. SOCS2 in immature DC. SOCS1 and SOCS2 expression is induced by IL4 signaling, and SOCS3 expression is upregulated more by GM-CSF (CSF2). References_end </body> </html> </notes> <label text="SOCS1"/> <bbox w="70.0" h="25.0" x="15019.0" y="2602.5"/> </glyph> <glyph class="nucleic acid feature" id="s859_sa2096" 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:PTGS2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MIF CASCADE:TLR2_4 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:11668179 CREB, NF-kappa B, and both C/EBP beta and -delta as key factors in coordinately orchestrating transcription from the COX-2 promoter in activated macrophages. References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="70.0" h="25.0" x="4145.0" y="5747.5"/> </glyph> <glyph class="nucleic acid feature" id="s869_sa2407" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAB1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:MIF Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. References_end </body> </html> </notes> <label text="STAB1"/> <bbox w="70.0" h="25.0" x="2193.75" y="528.125"/> </glyph> <glyph class="nucleic acid feature" id="s872_sa2411" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCER2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:MIF Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="FCER2"/> <bbox w="70.0" h="25.0" x="2293.75" y="528.125"/> </glyph> <glyph class="nucleic acid feature" id="s917_sa981" 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:STAT6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expression of STAT6 ans enhances downstream IL4 signaling. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="70.0" h="25.0" x="1645.0" y="3812.5"/> </glyph> <glyph class="nucleic acid feature" id="s925_sa1297" 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:IFNA1 HUGO:IFNA2 HUGO:IFNA4 HUGO:IFNA5 HUGO:IFNA6 HUGO:IFNA7 HUGO:IFNA8 HUGO:IFNA10 HUGO:IFNA13 HUGO:IFNA14 HUGO:IFNA16 HUGO:IFNA17 HUGO:IFNA21 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induces IFNA expression in macrophages References_end </body> </html> </notes> <label text="IFNA*"/> <bbox w="70.0" h="25.0" x="13521.25" y="5222.5"/> </glyph> <glyph class="nucleic acid feature" id="s959_sa376" 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:ULBP2 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22754780, PMID:21764762 Wild-type p53, but not mutant p53 interacts with UDLPs promoters and induces UDLP2 and UDLP1 expression in tumor cells and increases tumor immunogenicity. UDLPs activate NKG2D* signaling in NK cells.Induction of wtp53 expression in tumor cells leads to their enhanced recognition by primary NK cells in a NKG2D-dependent manner. PMID:25277195 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumors. References_end </body> </html> </notes> <label text="ULBP2"/> <bbox w="70.0" h="25.0" x="12495.0" y="327.5"/> </glyph> <glyph class="nucleic acid feature" id="s970_sa365" 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:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID:25277195 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumor PMID:14607946 Additionally 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 via FN-alpha/betaR or -IL-15Ralpha, respectively References_end </body> </html> </notes> <label text="MICA"/> <bbox w="70.0" h="25.0" x="12155.0" y="327.5"/> </glyph> <glyph class="nucleic acid feature" id="s971_sa364" 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:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID:25277195 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumors. PMID:14607946 Additionally 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 via FN-alpha/betaR or -IL-15Ralpha, respectively References_end </body> </html> </notes> <label text="MICB"/> <bbox w="70.0" h="25.0" x="12275.0" y="327.5"/> </glyph> <glyph class="nucleic acid feature" id="s972_sa363" 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:ULBP1 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22754780, PMID:21764762 Wild-type p53, but not mutant p53 interacts with UDLPs promoters and induces UDLP2 and UDLP1 expression in tumor cells and increases tumor immunogenicity. UDLPs activate NKG2D* signaling in NK cells.Induction of wtp53 expression in tumor cells leads to their enhanced recognition by primary NK cells in a NKG2D-dependent manner. References_end </body> </html> </notes> <label text="UDLP1"/> <bbox w="70.0" h="25.0" x="12395.0" y="327.5"/> </glyph> <glyph class="nucleic acid feature" id="s973_sa362" 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:ULBP3 Identifiers_end References_begin: PMID:25277195 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumors. References_end </body> </html> </notes> <label text="UDLP3"/> <bbox w="70.0" h="25.0" x="12595.0" y="327.5"/> </glyph> <glyph class="nucleic acid feature" id="s983_sa346" 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:ADAM10 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22006996 Hypoxia-induced expression of ADAM10 is HIF-1-dependent. References_end </body> </html> </notes> <label text="ADAM10"/> <bbox w="70.0" h="25.0" x="11755.0" y="487.5"/> </glyph> <glyph class="nucleic acid feature" id="s1020_sa2125" 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:CEBPB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MDSC CASCADE:GSF3 PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. References_end </body> </html> </notes> <label text="CEBPB"/> <bbox w="70.0" h="25.0" x="4605.0" y="4524.375"/> </glyph> <glyph class="nucleic acid feature" id="s1083_sa2081" 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:IRF8 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:GSF3 CASCADE:GSF2 PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. PMID:8133040 In mouse macrophages, priming with IFN-γ drastically up-regulates expression of the transcription factor ICSBP (IRF8) References_end </body> </html> </notes> <label text="IRF8"/> <bbox w="70.0" h="25.0" x="10145.0" y="4524.0"/> </glyph> <glyph class="nucleic acid feature" id="s1131_sa1375" 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:FGF2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="70.0" h="25.0" x="3945.0" y="6597.5"/> </glyph> <glyph class="nucleic acid feature" id="s1167_sa236" 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:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 CASCADE:IL15 CASCADE:IFNAB CASCADE:IL2 PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:10544201, PMID:12372421 Perforin enhancers contain tandem Stat-like elements that are required for their IL-2 response and transactivation by Stat5. PMID:10072525 STAT5a/b and not STAT3 were binding to the STAT element downstream of IL2. IL-6 stimulation results in the detection of a complex on perforin promoter that can be blocked by the addition of anti-STAT1A antiserum. PMID:12372421 Activated STAT1, STAT3, STAT4, and STAT5 bound human perforin promoter in vitro. PMID:12133954 IL-2R signals can activate a pathway leading to NF-κB p50/p65 activation in NK cells, NF-κB binds to the upstream enhancer of the perforin gene and that this pathway is involved in the activation of perforin expression. PMID:12967644 IFNA induces perforin expression via STAT1 in NK cells. PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells IL-2R signals can activate a pathway leading to NF-κB p50/p65 activation in NK cells, 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 (). References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="70.0" h="25.0" x="8515.0" y="6487.5"/> </glyph> <glyph class="nucleic acid feature" id="s1243_sa1834" 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:IFNG 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:MACROPHAGE MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:IL4 CASCADE:Fc_gamma_RIII CASCADE:IL18 CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 PMID:25582338 IL15 induces IFNG expression in DC via STAT3. PMID:24829413 STAT5 is phosphorylated downstream IL2, It upregulate the promoter activity of both IL2RA and IFNG in dendritic cells downstream of IL2 PMID:12413632 IFNG is a major factor of M1 activation of macrophages PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 STAT4 induces IFNG production via binding of Stat4 to IFNG promoter GAS element downstream of IL12 in NK. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB in NK. TGFB signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter in NK cells PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="77.5" h="36.25" x="11386.25" y="5225.0"/> </glyph> <glyph class="nucleic acid feature" id="s1290_sa251" 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:FASLG Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:NKG2A CASCADE:Fc_gamma_RIII CASCADE:2B4 CASCADE:IFNAB CASCADE:IL18 CASCADE:LFA1 PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. PMID:8892629 IFN-gamma-inducing factor (IL18) up-regulates Fas ligand-mediated cytotoxic activity (via upregulation of FASL expression) of murine natural killer cell clones PMID:15120186 2B4 and LFA1 signalings upregulates FasL mRNA and surface expression in NK cells. FasL transcription is inhibited by NKG2A/CD94 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="FASL*"/> <bbox w="70.0" h="25.0" x="7730.0" y="7316.25"/> </glyph> <glyph class="nucleic acid feature" id="s1294_sa241" 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:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:IFNAB CASCADE:IFNG CASCADE:IL12 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL PMID:11257133 Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. PMID:10811870, PMID:17617740 I IFN induces TRAIL mRNA expression in DCs and enhances apoptosis of target tumor cells. Probably via STAT1 and IFR1 (PMID17617740 ) References_end </body> </html> </notes> <label text="TRAIL*"/> <bbox w="70.0" h="25.0" x="7630.0" y="7316.25"/> </glyph> <glyph class="nucleic acid feature" id="s1306_sa2400" 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:NFKBIZ Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: CASCADE:IL18 MAP:NATURAL_KILLER PMID:17027520 A promoter region of NFKBIZ (IκB‐ζ) gene harbors three NF‐κB binding site within 300‐bp upstream of the transcription initiation site PMID:20876105, PMID:17027520, IL18 induces expression of NFKBIZ in NK cells provavly via NFkB pathway or via increasing of mRNA stability.. References_end </body> </html> </notes> <label text="NFKBIZ"/> <bbox w="70.0" h="25.0" x="11835.0" y="4722.5"/> </glyph> <glyph class="nucleic acid feature" id="s1328_sa2393" 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:TBX21 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:Fc_gamma_RIII CASCADE:IL2 CASCADE:IL15 CASCADE:IL18 CASCADE:IL12 CASCADE:IL21 CASCADE:IFNG PMID:10761931, PMID:12055627, PMID:18768831, PMID:16713975, PMID:15084276, PMID:12244150 The pattern of T-bet expression correlates well with the production of IFNG in NK cells. The induction of T-bet expression and secretion of IFNγ in NK cells that produce IFNγ exists only upon treatment with IL-2, IL15,IL18, IL21 and IL-12 and CD16 pathway activation.. T-bet regulates IFNG expression in NK cells, probably via chromatin remodeling. PMID:18768831, PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. TBX21 is involeved in IFNG gene activation. 11752460 IFN-γ induces T-bet expression in monocytes, macrophages, and dendritic cells (DC) via STAT1. References_end </body> </html> </notes> <label text="TBX21"/> <bbox w="70.0" h="25.0" x="11647.5" y="4722.5"/> </glyph> <glyph class="nucleic acid feature" id="s1330_sa2390" 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:HLX Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:12055627, PMID:14614857 T-Bet induces HLX in T cells, and probably in NK cells. GATA-3-deficient NK cells produced less IFN-γ compared to control NK cells. T-bet expression was approximately 4-fold reduced in GATA-3° NK cells compared to controls, while Hlx expression was about 10-fold reduced (provavly via T-bet). References_end </body> </html> </notes> <label text="HLX"/> <bbox w="70.0" h="25.0" x="11520.0" y="4822.5"/> </glyph> <glyph class="nucleic acid feature" id="s1342_sa423" 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: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:12646700, PMID:15187109, PMID:18490724 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. 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:18490733 MIF inhibits NK cell activity through a transcriptional down-regulation of NKG2D References_end </body> </html> </notes> <label text="NKG2D*"/> <bbox w="70.0" h="25.0" x="12880.0" y="2107.5"/> </glyph> <glyph class="nucleic acid feature" id="s1349_sa2386" 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: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="70.0" h="25.0" x="3005.0" y="4438.125"/> </glyph> <glyph class="nucleic acid feature" id="s1350_sa743" 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: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. References_end </body> </html> </notes> <label text="DAP12*"/> <bbox w="70.0" h="25.0" x="11990.0" y="1997.5"/> </glyph> <glyph class="nucleic acid feature" id="s1372_sa899" 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:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:IL12 CASCADE:IL15 CASCADE:IL18 PMID:16713975 IL12,IL15 and IL18 significantly suppresse TGF-BRII mRNA expression and inhibit downstream signaling in NK. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="70.0" h="25.0" x="1440.0" y="2337.5"/> </glyph> <glyph class="nucleic acid feature" id="s1375_sa914" 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:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:IL12 CASCADE:IL18 PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="70.0" h="25.0" x="1645.0" y="2132.5"/> </glyph> <glyph class="nucleic acid feature" id="s1377_sa932" 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:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL12 CASCADE:IL18 CASCADE:IL15 PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 or with IL12 and IL15 downregulated SMAD3 transcript and protein level. References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="70.0" h="25.0" x="1885.0" y="2122.5"/> </glyph> <glyph class="nucleic acid feature" id="s1380_sa419" 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:NCR3 Identifiers_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level. References_end </body> </html> </notes> <label text="NKp30*"/> <bbox w="70.0" h="25.0" x="10640.0" y="1997.5"/> </glyph> <glyph class="nucleic acid feature" id="s1516_sa840" 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:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRB1 CASCADE:IL12 PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation References_end </body> </html> </notes> <label text="KLRB1"/> <bbox w="70.0" h="25.0" x="2370.0" y="2007.5"/> </glyph> <glyph class="nucleic acid feature" id="s1526_sa1926" 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: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="70.0" h="25.0" x="15202.5" y="3735.0"/> </glyph> <glyph class="nucleic acid feature" id="s1531_sa1931" 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: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="MIR212"/> <bbox w="70.0" h="25.0" x="12290.0" y="4632.5"/> </glyph> <glyph class="nucleic acid feature" id="s1532_sa1935" 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: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="70.0" h="25.0" x="12400.0" y="4632.5"/> </glyph> <glyph class="nucleic acid feature" id="s1533_sa1939" 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: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="MIR200A"/> <bbox w="70.0" h="25.0" x="12500.0" y="4632.5"/> </glyph> <glyph class="nucleic acid feature" id="s1570_sa841" 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: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. References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="70.0" h="25.0" x="2702.5" y="2847.5"/> </glyph> <glyph class="nucleic acid feature" id="s1575_sa439" 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:LCP2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24227772 mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. References_end </body> </html> </notes> <label text="LCP2"/> <bbox w="70.0" h="25.0" x="12490.0" y="2427.5"/> </glyph> <glyph class="nucleic acid feature" id="s1600_sa210" 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: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. References_end </body> </html> </notes> <label text="MIR27A*"/> <bbox w="70.0" h="25.0" x="4719.375" y="4316.875"/> </glyph> <glyph class="nucleic acid feature" id="s1602_sa208" 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: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="70.0" h="25.0" x="4849.375" y="4316.875"/> </glyph> <glyph class="nucleic acid feature" id="s1609_sa205" 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: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="70.0" h="25.0" x="4975.0" y="4325.375"/> </glyph> <glyph class="nucleic acid feature" id="s1610_sa204" 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: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="70.0" h="25.0" x="5065.0" y="4325.375"/> </glyph> <glyph class="nucleic acid feature" id="s1618_sa312" 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: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. References_end </body> </html> </notes> <label text="MIR223"/> <bbox w="70.0" h="25.0" x="4629.375" y="4316.875"/> </glyph> <glyph class="nucleic acid feature" id="s1624_sa191" 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 IFNG 3'UTR. PMID:22701882 IL2,IL15,IL21 upregulate MIR155, MIR15a, mir1246 in NK cells. References_end </body> </html> </notes> <label text="MIR15/16*"/> <bbox w="70.0" h="25.0" x="3235.0" y="4448.125"/> </glyph> <glyph class="nucleic acid feature" id="s1632_sa345" 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="70.0" h="25.0" x="12737.5" y="520.0"/> </glyph> <glyph class="nucleic acid feature" id="s1633_sa344" 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="70.0" h="25.0" x="12855.0" y="517.5"/> </glyph> <glyph class="nucleic acid feature" id="s1649_sa2680" 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:IL12RB2 Identifiers_end References_begin: CASCADE:IL15 CASCADE:IL21 CASCADE:IL12 MAP:NATURAL_KILLER PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. PMID:9834059 NK cells stimulated by IL12 accumulate much higher levels of the IL-12Rbeta2-chain mRNA and are significantly more responsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor. References_end </body> </html> </notes> <label text="IL12RB2"/> <bbox w="70.0" h="25.0" x="14985.0" y="3775.0"/> </glyph> <glyph class="nucleic acid feature" id="s1650_sa2679" 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:IL18RAP Identifiers_end References_begin: CASCADE:IL15 CASCADE:IL21 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNG PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. PMID:14662834 IL-18RA and IL-18RB mRNA expression is up-regulated by IFN-gamma in DC References_end </body> </html> </notes> <label text="IL18RAP"/> <bbox w="70.0" h="25.0" x="15311.0" y="2817.5"/> </glyph> <glyph class="nucleic acid feature" id="s1651_sa2678" 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:IL18R1 Identifiers_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNG CASCADE:IL15 CASCADE:IL21 PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. PMID:14662834 IL-18RA and IL-18RB mRNA expression is up-regulated by IFN-gamma in DC References_end </body> </html> </notes> <label text="IL18R1"/> <bbox w="70.0" h="25.0" x="15220.0" y="2817.5"/> </glyph> <glyph class="nucleic acid feature" id="s1660_sa2388" 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:ETS1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL2 PMID:15563472 Interleukins 15 and IL2 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end </body> </html> </notes> <label text="ETS1"/> <bbox w="70.0" h="25.0" x="11310.0" y="4652.5"/> </glyph> <glyph class="nucleic acid feature" id="s1666_sa437" 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:NCR1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end </body> </html> </notes> <label text="NKp46*"/> <bbox w="70.0" h="25.0" x="10920.0" y="2117.5"/> </glyph> <glyph class="nucleic acid feature" id="s1696_sa231" 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:GZMA Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24973821 mTOR has positive influence on GZMA level in the NK cells. References_end </body> </html> </notes> <label text="GZMA "/> <bbox w="70.0" h="25.0" x="8265.0" y="6487.5"/> </glyph> <glyph class="nucleic acid feature" id="s1754_sa457" 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:SH2D1A Identifiers_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB CASCADE:IL12 CASCADE:IL2 PMID:17171759 SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(IC))and to a lesser extent by IFN-α. References_end </body> </html> </notes> <label text="SH2D1A "/> <bbox w="70.0" h="25.0" x="13500.0" y="1997.5"/> </glyph> <glyph class="nucleic acid feature" id="s1833_sa2106" 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:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 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. Additionally CD16 signaling induces NF-AT mRNA expression and protein synthesis via Calmodulin/ Calcineurin. References_end </body> </html> </notes> <label text="NFAT*"/> <bbox w="70.0" h="25.0" x="12410.0" y="4722.5"/> </glyph> <glyph class="nucleic acid feature" id="s1838_sa1350" 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:CSF2 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 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="70.0" h="25.0" x="11941.25" y="5212.5"/> </glyph> <glyph class="nucleic acid feature" id="s1839_sa1341" 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: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 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="IL2"/> <bbox w="70.0" h="25.0" x="11811.25" y="5212.5"/> </glyph> <glyph class="nucleic acid feature" id="s1841_sa1357" 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:IL4 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG downstream of CD16.. References_end </body> </html> </notes> <label text="IL4"/> <bbox w="70.0" h="25.0" x="3722.745" y="5523.25"/> </glyph> <glyph class="nucleic acid feature" id="s1921_sa2548" 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:IL5 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL4 PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 expression. References_end </body> </html> </notes> <label text="IL5"/> <bbox w="70.0" h="25.0" x="4055.0" y="5507.5"/> </glyph> <glyph class="nucleic acid feature" id="s1963_sa1826" 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: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 CASCADE:IFNAB PMID:10811870, PMID:11466332, PMID:14607946 I IFN induces IL-15 and IL-15Rα in human and murine DCs via common receptor. References_end </body> </html> </notes> <label text="IL15"/> <bbox w="70.0" h="25.0" x="13991.25" y="5222.5"/> </glyph> <glyph class="nucleic acid feature" id="s1965_sa1824" 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: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 CASCADE:IFNAB PMID:11466332, PMID:14607946 I IFN induces IL-15 and IL-15Rα in human and murine DCs via common receptor. References_end </body> </html> </notes> <label text="IL15RA"/> <bbox w="70.0" h="25.0" x="15280.0" y="3687.5"/> </glyph> <glyph class="nucleic acid feature" id="s2042_sa1215" 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:CCR7 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNAB CASCADE:CATENINB PMID:17936032 Beta-catenin signaling 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 node PMID:11698286 IFNA induces mRNA expression both CCR7 and its ligand CCL19 in Dcs and induces Dcs migration References_end </body> </html> </notes> <label text="CCR7"/> <bbox w="70.0" h="25.0" x="6005.0" y="2092.5"/> </glyph> <glyph class="nucleic acid feature" id="s2059_sa1365" 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:INHBA Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 CASCADE:IL13 PMID:24204259 IL-4Rα-deficient DCs produced reduced IL-12, and IL18 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses. probably via STAT6 References_end </body> </html> </notes> <label text="INHBA"/> <bbox w="70.0" h="25.0" x="3625.0" y="5516.25"/> </glyph> <glyph class="nucleic acid feature" id="s2106_sa92" 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: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:24777831, PMID:19811323 The expression of MHC Class I molecules (controlled by STAT-1 and IRF-1) was increased following IFN-γ treatment References_end </body> </html> </notes> <label text="MHC class I*"/> <bbox w="70.0" h="25.0" x="14815.0" y="6065.0"/> </glyph> <glyph class="nucleic acid feature" id="s2115_sa2706" 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:SOCS2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 PMID:14764699 SOCS1 and SOCS3 are upregulated in mature DC. SOCS2 in immature DC. SOCS1 and SOCS2 expression is induced by IL4 signaling, and SOCS3 expression is upregulated more by GM-CSF (CSF2). References_end </body> </html> </notes> <label text="SOCS2"/> <bbox w="70.0" h="25.0" x="14790.0" y="2597.5"/> </glyph> <glyph class="nucleic acid feature" id="s2125_sa91" 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: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: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:IL10 CASCADE:IFNG 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:7902377, PMID:1655948 IL-10 down-regulates not only the constitutive class 2 MHC expression on mono- cytes , but also inhibites strongly the IL-13-induced class 2 MHC expression . PMID:8871614 IL13 induces MHC classe II expression via STAT6 pathway CASCADE:CSF2 PMID: 19224634 STAT5 promotes expression of MHC class II transactivator protein (CIITA) and upregulates MHC class II expression downstream of CSF2 PMID: 8624807 IFN-γ has been shown to up-regulate MHC class II expression on dendritic cells. Via CIITA. References_end </body> </html> </notes> <label text="MHC class II*"/> <bbox w="70.0" h="25.0" x="14635.0" y="6075.0"/> </glyph> <glyph class="nucleic acid feature" id="s2127_sa89" 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:CIITA Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL4 CASCADE:CSF2 CASCADE:IFNG PMID: 19224634 STAT5 promotes expression of MHC class II transactivator protein (CIITA) and upregulates MHC class II expression downstream of CSF2 ( PMID:16785500 ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages downstream of TLR4 MyD88-dependent signaling. PMID:11514596 Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (Ciita) Expression and down regulation of MHCII expression. ERK and p38 MAPK suppress CIITA expression by decreasing histone acetylation PMID:20580461 In macrophages IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN downstream of IL4. PMID: 8624807 IFN-γ has been shown to up-regulate MHC class II expression on dendritic cells. Probably via CIITA. PMID:11983150 IFNG signaling induces CIITA expression in Dcs probably via IRF-1, IRF-2, and STAT1 binding to CIITA gene promoter. References_end </body> </html> </notes> <label text="CIITA"/> <bbox w="70.0" h="25.0" x="14725.0" y="5905.0"/> </glyph> <glyph class="nucleic acid feature" id="s2264_sa97" 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: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: 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. References_end </body> </html> </notes> <label text="CD1*"/> <bbox w="70.0" h="25.0" x="14525.0" y="6067.5"/> </glyph> <glyph class="nucleic acid feature" id="s2295_sa1910" 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:FLT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:TLR2_4 CASCADE:FLT3LG PMID:20510871 PU.1 as 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. At The same time enforced expression of STAT3 or PU.1 in DC progenitors led to the up-regulation of Flt3 mRNA levels, so there is a positive loop in this signaling. Enforced STAT3 or PU.1 expression instructs progenitors to differentiate into Dcs. Additionaly it induces expression of cytokine receptors for G-CSF, M-CSF, and GM-CSF probably downstream of STAT3. PMID:25215878 Expression of FLT3 receptor mRNA is upregulated by FLT3L in DCs, but Flt-3 expression on mDC was significantly down-regulated by LPS (TLR4 signaling) and this was not reversed by the presence of FLT3L . References_end </body> </html> </notes> <label text="FLT3"/> <bbox w="70.0" h="25.0" x="14950.0" y="5717.5"/> </glyph> <glyph class="nucleic acid feature" id="s2302_sa2074" 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:GATA1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: CASCADE:FLT3LG 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="70.0" h="25.0" x="4276.0" y="4344.375"/> </glyph> <glyph class="nucleic acid feature" id="s2315_sa1214" 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:CCL19 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNAB PMID:11698286 IFNA induces mRNA expression both CCR7 and it's ligand CCL19 in Dcs and induces Dcs migration References_end </body> </html> </notes> <label text="CCL19"/> <bbox w="70.0" h="25.0" x="6315.0" y="2612.5"/> </glyph> <glyph class="nucleic acid feature" id="s2320_sa1326" 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:CCL18 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNAB PMID:11698286 IFNA upregulates chemokine mRNA expression CCL18 (DC-DK1), CXCL10 (IP10) in DC, References_end </body> </html> </notes> <label text="CCL18"/> <bbox w="70.0" h="25.0" x="6215.0" y="2612.5"/> </glyph> <glyph class="nucleic acid feature" id="s2415_sa2144" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE:STING Maps_Modules_end References_begin: PMID:25517615, PMID:25517609, PMID:24766893 DNA from dying cells activates cGAS to form a dimeric cGAS-DNA complex which synthesizes 2′3′-cGAMP from ATP and GTP. cGAMP binds to STING and activates two pathways, NfkB activation (via IKK activation) and IRF3 via TBK1 activation. IRF3 induces IFNB expression in DC downsteam of STING signaling PMID:24799564, PMID:15967784, PMID:16237046, PMID:2398653 But at the same time STING signaling induces IDO activation (production) probably via IFN I/STAT1 pathway and suppress local immunity. References_end </body> </html> </notes> <label text="TUMOR_DNA"/> <bbox w="115.0" h="22.5" x="7205.0" y="923.75"/> </glyph> <glyph class="nucleic acid feature" id="s2700_sa922" 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:RUNX1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15084276 Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="RUNX1"/> <bbox w="70.0" h="25.0" x="3445.0" y="4398.125"/> </glyph> <glyph class="nucleic acid feature" id="s2748_sa964" 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:MAF Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 Maps_Modules_end References_begin: PMID:15749884 IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="MAF"/> <bbox w="70.0" h="25.0" x="4405.0" y="4344.375"/> </glyph> <glyph class="nucleic acid feature" id="s2751_sa971" 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:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:TGFB CASCADE:MIF CASCADE:LGALS1 CASCADE:CSF1 CASCADE:STING CASCADE:TLR2_4 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:20547845 TLR4 signaling downstream of HMGB1 induces secretion of IL10. PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via PMID:15749884 c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. AP1. PMID:25164013 HMGB1 activates MDSCs via the NF-κB pathway It increases MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. significantly increased IL-10 promoter activity was noted in CD14+ monocytes in the presence of A459-CM, NCI-H460-CM, or galectin-1. Increased IL-10 promoter activity was also found in cells overexpressing Id3 PMID:23390297 MIF induces expression of M2 markers as IL10, stabilin-1, MRC-1, CD206, CD23 PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages PMID:16394015 , PMID:19667062, PMID:15067049 Fos inhibits the expression of IL-12 p40 and IFNB and upregulates IL10 production downstream of FOS in macrophages and DCs PMID: 23986532 STING ablation abolished hallmark TGF-β and IL-10 regulatory cytokine induction (mRNA)by apoptotic cells, and proinflammatory IL-6 mRNA was expressed instead in DCs 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: 25215878 FL partially antagonized IL-10-mediated inhibition on DCs function (probably via STAT3) and downregulates IL10 mRNA expression in DCs. PMID:16713974, PMID:14607900 INFG inhibits Il-10 exspression upregulated by TLR signaling partially via STAT1. STAT1 overexpression prevents STAT3 homodimerization in macrophages. PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="118.75" h="42.25" x="2153.125" y="5766.375"/> </glyph> <glyph class="nucleic acid feature" id="s2754_sa978" 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:KLF4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:21670502 IL4 upregulates expression of KLF4 via STAT6 in M2 macrophages. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. References_end </body> </html> </notes> <label text="KLF4"/> <bbox w="70.0" h="25.0" x="4425.0" y="4617.5"/> </glyph> <glyph class="nucleic acid feature" id="s2884_sa1171" 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:CCR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TNF Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. TNF inhibit CCR2 expression in tumor associated macrophages. PMID:24006507 HIF2A upregulates expression of Pfkfb3, Ccr2, and Cxcl2 References_end </body> </html> </notes> <label text="CCR2"/> <bbox w="70.0" h="25.0" x="5675.0" y="2092.5"/> </glyph> <glyph class="nucleic acid feature" id="s2917_sa1810" 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:IL1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TLR2_4 Maps_Modules_end References_begin: 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. PMID:15465827 BCL3 inhibits expression of IL1B. References_end </body> </html> </notes> <label text="IL1A"/> <bbox w="70.0" h="25.0" x="4424.0" y="6577.5"/> </glyph> <glyph class="nucleic acid feature" id="s2921_sa1294" 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:IL23A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses Maps_Modules_end References_begin: PMID:11477091 TLR2 stimulation additionally resulted in preferential induction of IL-8 and p19/IL-23. () 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="IL23A"/> <bbox w="70.0" h="25.0" x="2985.0" y="5377.5"/> </glyph> <glyph class="nucleic acid feature" id="s2924_sa1298" 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:IFNB1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:STING CASCADE:TLR2_4 CASCADE:TNF Maps_Modules_end References_begin: PMID:18345002 TNF induced IFNB expression through IRF1. TNF-induced Ifnb1 expression was completely abrogated in IRF1-deficient macrophages. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. PMID:16394015 , PMID:19667062, PMID:15067049 Fos inhibits the expression of IL-12 p40 and IFNB and upregulates IL10 production downstream of FOS in macrophages and PMID:25517615, PMID:25517609, PMID:24766893 IRF3 induces IFNB expression in DC downsteam of STING signaling PMID:17114424, PMID: 16306937 Myeloid dendritic cells, but not plasmacytoid dendritic cells, express IL-10 and probably IFNB in response to TRIF-dependent TLR signals via TRAF3 probably downstream of HMGB1. References_end </body> </html> </notes> <label text="IFNB*"/> <bbox w="70.0" h="25.0" x="13642.25" y="5222.5"/> </glyph> <glyph class="nucleic acid feature" id="s2930_sa1812" 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:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID:25277195 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumor PMID:14607946 Additionally 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 via FN-alpha/betaR or -IL-15Ralpha, respectively References_end </body> </html> </notes> <label text="MICA"/> <bbox w="70.0" h="25.0" x="13761.25" y="5222.5"/> </glyph> <glyph class="nucleic acid feature" id="s2931_sa1813" 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:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID:25277195 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumors. PMID:14607946 Additionally 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 via FN-alpha/betaR or -IL-15Ralpha, respectively References_end </body> </html> </notes> <label text="MICB"/> <bbox w="70.0" h="25.0" x="13881.25" y="5222.5"/> </glyph> <glyph class="nucleic acid feature" id="s2950_sa1354" 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:IL13 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:IL13 CASCADE:IL4 PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end </body> </html> </notes> <label text="IL13"/> <bbox w="70.0" h="25.0" x="3935.0" y="5507.5"/> </glyph> <glyph class="nucleic acid feature" id="s2996_sa1376" 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:VEGFA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:LACTIC CASCADE:MIF CASCADE:IL4 CASCADE:CSF2 CASCADE:IFNAB MAP:NEUTROPHIL Maps_Modules_end References_begin: PMID:21372296 HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth MIF signaling induces angiogenesis probavly via upregulation of MMP9, VEGF expression in macrophages and activates tumor invasion PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="70.0" h="25.0" x="4145.0" y="6577.5"/> </glyph> <glyph class="nucleic acid feature" id="s3074_sa1521" 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:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12193701 INFG upregulates TNFR1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1.MAP:MACROPHAGE CASCADE:IFNG References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="70.0" h="25.0" x="15295.0" y="3134.0"/> </glyph> <glyph class="nucleic acid feature" id="s3077_sa1537" 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:IRAK3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TGFB Maps_Modules_end References_begin: PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling References_end </body> </html> </notes> <label text="IRAK3"/> <bbox w="70.0" h="25.0" x="10510.0" y="2847.5"/> </glyph> <glyph class="nucleic acid feature" id="s3083_sa1553" 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:RIPK1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IFNG Maps_Modules_end References_begin: PMID:12193701 INFG upregulates RIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="70.0" h="25.0" x="15290.0" y="3187.5"/> </glyph> <glyph class="nucleic acid feature" id="s3287_sa1816" 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: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:24829413 STAT5 is phosphorylated downstream IL2, It upregulate the promoter activity of both IL2RA and IFNG in dendritic cells downstream of IL2 PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells (). References_end </body> </html> </notes> <label text="IL2RA"/> <bbox w="70.0" h="25.0" x="14790.0" y="4767.5"/> </glyph> <glyph class="nucleic acid feature" id="s3462_sa1970" 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:TNIP3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:17485448 IL10 upregulates expression of TNIP3 (ABIN3) 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="TNIP3"/> <bbox w="70.0" h="25.0" x="12460.0" y="3297.5"/> </glyph> <glyph class="nucleic acid feature" id="s3539_sa1269" 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:CXCL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IFNAB CASCADE:TLR2_4 MAP:DENDRITIC_CELL 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 PMID:11698286 IFNA upregulates chemokine mRNA expression CCL18 (DC-DK1), CXCL10 (IP10) in DC, References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="70.0" h="25.0" x="5045.0" y="2602.5"/> </glyph> <glyph class="nucleic acid feature" id="s3568_sa2079" 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:SPI1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL 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. At The same time enforced expression of STAT3 or PU.1 in DC progenitors led to the up-regulation of Flt3 mRNA levels, so there is a positive loop in this signaling. Enforced STAT3 or PU.1 expression instructs progenitors to differentiate into Dcs. Additionaly it induces expression mRNAs of cytokine receptors for G-CSF, M-CSF, and GM-CSF probably downstream of STAT3 () References_end </body> </html> </notes> <label text="SPI1"/> <bbox w="70.0" h="25.0" x="9630.0" y="4512.5"/> </glyph> <glyph class="nucleic acid feature" id="s3571_sa2083" 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:IRF5 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:MIF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as IRF5 PMID:21240265 GM-CSF upregulates IRF5 expression. References_end </body> </html> </notes> <label text="IRF5"/> <bbox w="70.0" h="25.0" x="10280.0" y="4522.5"/> </glyph> <glyph class="nucleic acid feature" id="s3575_sa1518" 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:IRF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:IL2 CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:12433365 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 PMID:10358173, PMID:7479881 IL2 signaling induces IRF1 expression in NK cells, probably via STAT5 ( PMID:17985330 IFN-β induces IRF1 expression, probably via STAT1in DCs.() References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="70.0" h="25.0" x="10450.0" y="4532.5"/> </glyph> <glyph class="nucleic acid feature" id="s3601_sa2129" 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:MYC Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:GSF3 CASCADE:IL4 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:11340171 MYC inhibits myeloid cells differentiation. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="MYC"/> <bbox w="70.0" h="25.0" x="5075.0" y="4574.375"/> </glyph> <glyph class="nucleic acid feature" id="s3605_sa2134" 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:CEBPD Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:11668179 CEBPD syntesis and activity are induced downstream of TLR4/p38 signaling. It regulates COX2 expression. References_end </body> </html> </notes> <label text="CEBPD"/> <bbox w="70.0" h="25.0" x="4146.0" y="4344.375"/> </glyph> <glyph class="nucleic acid feature" id="s3917_sa2332" 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: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: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. References_end </body> </html> </notes> <label text="cREL*"/> <bbox w="70.0" h="25.0" x="12720.0" y="3527.5"/> </glyph> <glyph class="nucleic acid feature" id="s3919_sa2334" 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: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: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. References_end </body> </html> </notes> <label text="RELB"/> <bbox w="70.0" h="25.0" x="13050.0" y="3547.5"/> </glyph> <glyph class="nucleic acid feature" id="s3938_sa2353" 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:ID3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:LGALS1 CASCADE:IL10 PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. At the same tyme IL10 siglaning also participates in ID3 upregulation via PI3K/AKT pathway (autocrine loop) References_end </body> </html> </notes> <label text="ID3"/> <bbox w="70.0" h="25.0" x="4036.0" y="4344.375"/> </glyph> <glyph class="nucleic acid feature" id="s3955_sa2371" 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:TNF Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:MIF CASCADE:IL10 CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 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:1431106 TNF is ploinfammatory cytokine induced tumoricidal activity of macrophages PMID:10754326 Human TNF-alpha gene has binding sites for NF-kappa B. By transient transfection, NF-kappa B p65 and p50 synergistically activated the TNF-alpha promoter. Although both the kappa B1 and kappa B3 sites bound transcriptionally active NF-kappa B p50/p65 heterodimers, only the kappa B1 site contributed to down-regulation by NF-kappa B p50 homodimers. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:7594497 TGFB1 and IL10 dowregulate expression of TNF in macrophages. 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:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. PMID: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="TNF"/> <bbox w="105.0" h="57.5" x="12743.75" y="5423.75"/> </glyph> <glyph class="nucleic acid feature" id="s3957_sa2375" 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:LGALS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:TGFB PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as MCR2 and LGALS3 (Galectin-3) and induces AKT activation in macrophages Maps_Modules_end References_begin: Identifiers_end References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="70.0" h="25.0" x="3835.0" y="5577.5"/> </glyph> <glyph class="nucleic acid feature" id="s3959_sa2402" 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:CCL5 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:TGFB PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="70.0" h="25.0" x="5975.0" y="2617.5"/> </glyph> <glyph class="nucleic acid feature" id="s3961_sa1531" 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:TLR4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:MIF MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 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. PMID:10734131, PMID:12803886, PMID:16283355 MIF upregulates expression of TLR4 in macrothages via PU.1 (SPI1) activation via PU.1 (SPI1) activation; PU.1 (SPI1) together with IRF8 relulates TLR4 expression in myeloid cells References_end </body> </html> </notes> <label text="TLR4"/> <bbox w="70.0" h="25.0" x="15190.0" y="2047.5"/> </glyph> <glyph class="nucleic acid feature" id="s3978_sa2428" 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:GST3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL6 PMID:16286017 Cystatin C is an inhibitor of cathepsin S. IL-6-Mediated STAT3 Activation Reduced Cystatin C mRNA Level in DCs and upregulates cathepsin S activity References_end </body> </html> </notes> <label text="CST3"/> <bbox w="70.0" h="25.0" x="12705.0" y="5797.5"/> </glyph> <glyph class="nucleic acid feature" id="s3991_sa2442" 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:HMOX1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. References_end </body> </html> </notes> <label text="HMOX1"/> <bbox w="70.0" h="25.0" x="3617.25" y="3332.5"/> </glyph> <glyph class="nucleic acid feature" id="s3995_sa2447" 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:SOCS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:TLR2_4 CASCADE:TNF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12907458, PMID:16713974 IL10 induces SOCS3 expression in STAT3 dependent manner. SOCS3 binds to gp130 and inhibits inflammatory IL6 signaling in macrophages. Probabaly downstream of IL10 PMID:14764699 SOCS1 and SOCS3 are upregulated in mature DC. SOCS2 in immature DC. SOCS1 and SOCS2 expression is induced by IL4 signaling, and SOCS3 expression is upregulated more by GM-CSF (CSF2). References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="70.0" h="25.0" x="14630.0" y="2587.5"/> </glyph> <glyph class="nucleic acid feature" id="s3996_sa2451" 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:BCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL10 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. NFkB p50 is needfull for BCL3 expression . PMID:12907458, PMID:22323479 STAT3 directly up-regulates BCL3 expression downstream of IL10 . References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="70.0" h="25.0" x="3585.0" y="4318.125"/> </glyph> <glyph class="nucleic acid feature" id="s4010_sa2466" 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:MARCH1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL10 PMID:22076556, PMID:21220452, PMID:24218453 In immature DCs, internalization of MHC class II molecules from the plasma membrane may require the ubiquitin ligase MARCH1, which is controlled by interleukin-10 (Measurement of March1 mRNA by quantitative PCR in these DC cultures demonstrated that IL-10 increased March1 mRNA by approximately sixfold). CD83 on mature DCs prevents this ubiquitylation of MHC class II molecules and thus stabilizes MHC class II molecules on the cell surface. Addidionally it prevents CD86 ubiquitinqtion by MARCH1. References_end </body> </html> </notes> <label text="MARCH1"/> <bbox w="70.0" h="25.0" x="13535.0" y="7737.5"/> </glyph> <glyph class="nucleic acid feature" id="s4016_sa2489" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD209 CASCADE:IL4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expresion of CD209 downstream of IL4, probably via STAT6. in macrophages References_end </body> </html> </notes> <label text="CD209"/> <bbox w="70.0" h="25.0" x="2383.75" y="528.125"/> </glyph> <glyph class="nucleic acid feature" id="s4034_sa2544" 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:CSF1R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:GSF1 Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. References_end </body> </html> </notes> <label text=" CSF1R"/> <bbox w="70.0" h="25.0" x="1395.0" y="2597.5"/> </glyph> <glyph class="nucleic acid feature" id="s4061_sa2589" 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:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC MAP:MACROPHAGE PMID:18809714 STAT3 depletion resulted in the down-regulation of S100A8 and S100A9 gene expression The promoter regions of S100A8 and S100A9 contain several potential STAT3 binding sites (TTCCC G/A G/T AA). In chromatin immunoprecipitation assays of 32D myeloid cells, STAT3 interacted with the promoter regions of both S100A8 and S100A9. References_end </body> </html> </notes> <label text="S100A9"/> <bbox w="70.0" h="25.0" x="4845.0" y="2262.5"/> </glyph> <glyph class="nucleic acid feature" id="s4062_sa2590" 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:S100A8 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC MAP:MACROPHAGE PMID:18809714 STAT3 depletion resulted in the down-regulation of S100A8 and S100A9 gene expression The promoter regions of S100A8 and S100A9 contain several potential STAT3 binding sites (TTCCC G/A G/T AA). In chromatin immunoprecipitation assays of 32D myeloid cells, STAT3 interacted with the promoter regions of both S100A8 and S100A9. References_end </body> </html> </notes> <label text="S100A8"/> <bbox w="70.0" h="25.0" x="4945.0" y="2262.5"/> </glyph> <glyph class="nucleic acid feature" id="s4098_sa2629" 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: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 PMID:18003603 RUNX proteins down-regulates IFNG expression in NK cells and upregulates expression of CD122 (IL-2/IL-15 common receptor beta subunit) via direct binding to its promoter. PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. References_end </body> </html> </notes> <label text="IL2RB"/> <bbox w="70.0" h="25.0" x="15400.0" y="3687.5"/> </glyph> <glyph class="nucleic acid feature" id="s4100_sa2631" 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:LTB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end </body> </html> </notes> <label text="LTB"/> <bbox w="70.0" h="25.0" x="7509.375" y="7316.25"/> </glyph> <glyph class="nucleic acid feature" id="s4170_sa2693" 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:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="70.0" h="25.0" x="8385.0" y="6487.5"/> </glyph> <glyph class="nucleic acid feature" id="s4176_sa2703" 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:FLT1 Identifiers_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL 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 in TAM. References_end </body> </html> </notes> <label text="FLT1"/> <bbox w="70.0" h="25.0" x="1370.0" y="6192.5"/> </glyph> <glyph class="nucleic acid feature" id="s4183_sa972" 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:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NEUTROPHIL CASCADE:IL10 CASCADE:FLT3LG PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. PMID:16418395 FLT3L induces PU.1 and STAT3 mRNA expression in DC progenitors and downregulates GATA1 mRNA expression. At The same time enforced expression of STAT3 or PU.1 in DC progenitors led to the up-regulation of Flt3 mRNA levels, so there is a positive loop in this signaling. Enforced STAT3 or PU.1 expression instructs progenitors to differentiate into Dcs. Additionaly it induces expression mRNAs of cytokine receptors for G-CSF, M-CSF, and GM-CSF probably downstream of STAT3 () PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="70.0" h="25.0" x="1695.0" y="4272.5"/> </glyph> <glyph class="nucleic acid feature" id="s4183_sa2716" 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:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NEUTROPHIL CASCADE:IL10 CASCADE:FLT3LG PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. PMID:16418395 FLT3L induces PU.1 and STAT3 mRNA expression in DC progenitors and downregulates GATA1 mRNA expression. At The same time enforced expression of STAT3 or PU.1 in DC progenitors led to the up-regulation of Flt3 mRNA levels, so there is a positive loop in this signaling. Enforced STAT3 or PU.1 expression instructs progenitors to differentiate into Dcs. Additionaly it induces expression mRNAs of cytokine receptors for G-CSF, M-CSF, and GM-CSF probably downstream of STAT3 () PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="70.0" h="25.0" x="14730.0" y="5167.5"/> </glyph> <glyph class="nucleic acid feature" id="s4198_sa2732" 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:IRF9 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB PMID:25960930 INFA induced expression of IRF9 is PKC-θ-dependent in NK. References_end </body> </html> </notes> <label text="IRF9"/> <bbox w="70.0" h="25.0" x="10020.0" y="4532.5"/> </glyph> <glyph class="nucleic acid feature" id="s4209_sa2750" 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:IDO1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IFNG CASCADE:TLR2_4 CASCADE:TNF PMID:11477543 TLR4 -induced systemic IDO is largely dependent on TNF-alpha rather than IFN-gamma in macrophages. PMID:8663541 IFNG induces IDO expression via STAT1 and IRF-1 PMID:19075017 Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-γ (IFNγ)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. References_end </body> </html> </notes> <label text="IDO1"/> <bbox w="70.0" h="25.0" x="4525.0" y="5747.5"/> </glyph> <glyph class="nucleic acid feature" id="s4228_sa1264" 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:CXCL8 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 mRNA expression and protein production by NK cells downstream of integrin signaling References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="70.0" h="25.0" x="4275.0" y="6582.5"/> </glyph> <glyph class="nucleic acid feature" id="s4258_sa2793" 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:CXCL16 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. References_end </body> </html> </notes> <label text="CXCL16"/> <bbox w="70.0" h="25.0" x="5185.0" y="2602.5"/> </glyph> <glyph class="nucleic acid feature" id="s4278_sa912" 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="70.0" h="25.0" x="2905.0" y="4438.125"/> </glyph> <glyph class="nucleic acid feature" id="s4279_sa916" 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: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="70.0" h="25.0" x="3135.0" y="4448.125"/> </glyph> <glyph class="nucleic acid feature" id="s4952_sa2145" 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> Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS CASCADE:STING Maps_Modules_end References_begin: PMID:25517615, PMID:25517609, PMID:24766893 DNA from dying cells activates cGAS to form a dimeric cGAS-DNA complex which synthesizes 2′3′-cGAMP from ATP and GTP. cGAMP binds to STING and activates two pathways, NfkB activation (via IKK activation) and IRF3 via TBK1 activation. IRF3 induces IFNB expression in DC downsteam of STING signaling PMID:24799564, PMID:15967784, PMID:16237046, PMID:2398653 But at the same time STING signaling induces IDO activation (production) probably via IFN I/STAT1 pathway and suppress local immunity. References_end </body> </html> </notes> <label text="TUMOR_DNA"/> <bbox w="115.0" h="22.5" x="6960.0" y="1908.75"/> </glyph> <glyph class="simple chemical" id="s3592_sa565" 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>References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL13 CASCADE:SLAMF7 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KIR2DS4 CASCADE:Fc_gamma_RIII CASCADE:CR1 PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PMID:12740575, PMID:15972651 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release. The calcium signal generated by PLCG is required for NKG2D-initiated killing. Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:11265639 Cross-linking of NKp80 induces Ca 2+ mobilization and triggering of cytotoxicity in both resting and activated NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. PMID:7890616, PMID:10925299 PCL (probably PCLG1) induces hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. Intracellular Ca2+ release release induces cAMP Accumulation in Human monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="6052.5" y="3932.5"/> </glyph> <glyph class="simple chemical" id="s4905_sa577" 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>References_begin: 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. 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) ). (PMID10089876). This signaling is activated downstream of CD16 References_end </body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="6057.5" y="4077.5"/> </glyph> <glyph class="phenotype" id="s1_sa10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:17948027, PMID:22437871, PMID:17204652 Dendritic Cells are critical Antigen-Presenting Cells in tumor Immunity. They present processed protein and lipid antigens to T cells via both classical (major histocompatibility complex (MHC) class I and class II) and non-classical (CD1 family) antigen-presenting molecules.When compared with other APCs, such as macrophages, DCs are extremely efficient and can elicit very low numbers of T cells to respond thus explaining their nickname of 'professional APCs'. PMID:17204652 CD8- DC demonstrates overexpression of MHC class II–associated molecules and CD8+ demonstrates expression pattern of MHC class II–associated molecules. References_end </body> </html> </notes> <label text="Antigen_presentation"/> <bbox w="460.0" h="165.0" x="13240.0" y="8327.5"/> </glyph> <glyph class="phenotype" id="s5_sa83"> <label text="T-cell_activation"/> <bbox w="380.0" h="125.0" x="12930.0" y="8537.5"/> </glyph> <glyph class="phenotype" id="s141_sa1110"> <notes> <html xmlns="http://www.w3.org/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: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:1431106 NO production is associated with tumoricidal activity of macrophages. PMID:20856220 NO production is a marker of M1 phenotype of macrophages. References_end </body> </html> </notes> <label text="NO_production"/> <bbox w="176.0" h="42.0" x="6482.0" y="8259.0"/> </glyph> <glyph class="phenotype" id="s379_sa1117"> <notes> <html xmlns="http://www.w3.org/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: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:23124025 MAOA activation incuces generation of intracellular ROS during the oxidation of biogenic amines. PMID:18501881, PMID:7890616 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="ROS_production"/> <bbox w="97.0" h="33.0" x="6031.5" y="8153.5"/> </glyph> <glyph class="phenotype" id="s380_sa1113"> <notes> <html xmlns="http://www.w3.org/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: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. References_end </body> </html> </notes> <label text="L-ornitine_production"/> <bbox w="170.0" h="45.0" x="5495.0" y="8257.5"/> </glyph> <glyph class="phenotype" id="s585_sa1157" 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>References_begin: PMID:18633355 For Macrophages -CCL2,CCL3,CC4,CCL5, S100A8, S100A9, and probably VEGF For MDSC - BV8, CCL2, CXCL12, CXCL5 (ENA-78) and stem cell factor (SCF, also known as KIT ligand (KITL)) that bind to and activate their respective receptors CCR2, CXCR4, CXCR2 (also known as IL8RB) and CD117 on MDSC NEUtrophiles - CXC chemokines ( that bind to and activate CXCR1 (also know as IL8RA) and/or CXCR2, CXCL8 (IL8) Mast-cells - SCF, IL3, Adrenomedullin, iDC - A number of cytokines released by tumours, including VEGF, defensin, CXCL12, HGF and CXCL8, are thought to recruit these iDC References_end </body> </html> </notes> <label text="RECRUITMENT_OF_IMMUNE_CELLS"/> <bbox w="220.0" h="35.0" x="5430.0" y="2317.5"/> </glyph> <glyph class="phenotype" id="s837_sa238" 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>References_begin: PMID:14612578 In NK cells actin and microtubule polymerization are required for cytotoxic function. References_end </body> </html> </notes> <label text="Granules_exocytosis"/> <bbox w="160.0" h="45.0" x="9465.0" y="8047.5"/> </glyph> <glyph class="phenotype" id="s858_sa15" 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>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="Actin polymerization"/> <bbox w="160.0" h="35.0" x="12590.0" y="7752.5"/> </glyph> <glyph class="phenotype" id="s871_sa221" 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>References_begin: PMID:16887996 Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. PMID:19689731 MTOC polarization is a significant step of exocytosis References_end </body> </html> </notes> <label text="MTOC_polarization"/> <bbox w="160.0" h="35.0" x="8670.0" y="6262.5"/> </glyph> <glyph class="phenotype" id="s974_sa343" 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>References_begin: MAP:NATURAL_KILLER PMID:25277195, PMID:22006996, PMID:25103413 Hypoxia down-regulates level of MICA, MICB, ULBP2 and ULBP3 transcripts in tumors and reduces the sensitivity of tumor cell lines against NK cell-mediated lysis PMID:22006996, PMID:19704417 Hypoxia prevents HIF1A degradation and induces accumulation of HIF1A in tumor cells. PMID:25103413 Hypoxia downregulates HSP70 level in membrane. PMID:18633355 Hypoxic macrophages are known to respond to hypoxia by upregulating hypoxia-inducible transcription factors (mainly hypoxia-inducible factors HIF1 and HIF2)38, 39, the activation of which leads to increased transcription of many genes that regulate cell proliferation, metabolism and angiogenesis40. Hypoxia induces a distinct pro-angiogenic phenotype in human macrophages in vitro42, 43 including the upregulation of VEGF, bFGF, CXCL8, COX2, hepatocyte growth factor (HGF), VEGFR1, tissue factor (F3) and MMP12. References_end </body> </html> </notes> <label text="Hypoxia"/> <bbox w="450.0" h="252.5" x="13415.0" y="528.75"/> </glyph> <glyph class="phenotype" id="s1206_sa412" 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>References_begin: PMID:22683124 PLCG2-deficient NK cells avd VAV1-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:19454690 Stimulation through either FcR or NKG2D increases β1 and β2 integrin-mediated adhesion of human NK cells. References_end </body> </html> </notes> <label text="Conjugate_formation"/> <bbox w="260.0" h="75.0" x="7860.0" y="7962.5"/> </glyph> <glyph class="phenotype" id="s2023_sa791" 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>References_begin: PMID:23510023 RODENT Recently, in an effort to unravel the regulatory signaling pathways involved in the regulation of mouse bone marrow-derived DC cytotoxic function we have partly deconstructed the molecular machinery controlling iNOS in DC generated with GM-CSF and IL-4 (IL-4 DC) or IL-15 (IL-15 DC). We demonstrated that LPS-induced iNOS expression required the activation of the transcription factors NF-κB and ISGF3 only in IL-15 DC and that distinct signaling pathways such as AP-1 may be required in IL-4 DC. IFN-γ induced iNOS expression in IL-4 DC by a STAT-1 dependent mechanism. However in IL-15 DC, the cooperation of PIAS-1 and STAT-3 prevented iNOS expression in response to IFN-γ stimulation HUMAN The mechanisms of cancer cell killing primarily involved the death receptor ligands, perforin/granzyme B and NO. Recent studies have further highlighted the possibility that human pDC producting type I interferons may also function as tumor cell killers.117 Immature CD4+HLA-DR+Lin− DC have also been shown to trigger apoptosis of different cancer cells, but not normal cells, by four different TNF family member ligands (TRAIL, TNF, FasL, and Lymphotoxin (LT)-α1β2) PMID:24777831 Cytotoxic DCs are more efficient than noncytotoxic DCs at activating T cells References_end </body> </html> </notes> <label text="TUMOR_KILING"/> <bbox w="430.0" h="155.0" x="7295.0" y="8642.5"/> </glyph> <glyph class="phenotype" id="s2164_sa1436" 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>References_begin: PMID:22437871 There are currently four sets of molecules that are known to be released by apoptotic cells that function as 'find me' signals: lipid lysophosphatidylcholine (LPC), sphingosine 1-phosphate (S1P), CX3CL1 (also known as fractalkine), and the nucleotides ATP and UTP References_end </body> </html> </notes> <label text="FIND_ME"/> <bbox w="210.0" h="95.0" x="6837.5" y="587.5"/> </glyph> <glyph class="phenotype" id="s2165_sa1435" 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>References_begin: PMID:22437871 The eat me signals are membrane-bound and serve as markers for phagocytes for recognizing and internalizing dying cells. These signals include phosphatidylserine, alterations in cell-surface charge, αvβ5 integrin and CD36. The eat me signals also include molecules such as milk fat globule-EGF factor 8 (MFG-E8; also known as lactadherin), which bridge the phosphatidylserine of apoptotic cells with the integrin αvβ3 of DCs References_end </body> </html> </notes> <label text="EAT_ME"/> <bbox w="222.5" h="98.75" x="7621.25" y="575.625"/> </glyph> <glyph class="phenotype" id="s2166_sa1443" compartmentRef="c38_ca38"> <label text="DYING_TUMOR_CELL"/> <bbox w="240.0" h="85.0" x="7222.5" y="282.5"/> </glyph> <glyph class="phenotype" id="s2245_sa73"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:22437870 References_end </body> </html> </notes> <label text="Immune_checkpoints_T_cells_Activators"/> <bbox w="295.0" h="80.0" x="14082.5" y="8380.0"/> </glyph> <glyph class="phenotype" id="s2246_sa780" 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>References_begin: PMID:22437870 References_end </body> </html> </notes> <label text="Immune_checkpoints_T_cells_Inhibitors"/> <bbox w="290.0" h="75.0" x="1615.0" y="8012.5"/> </glyph> <glyph class="phenotype" id="s2418_sa217" 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>References_begin: PMID:14612578 In NK cells actin and microtubule polymerization are required for cytotoxic function. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. References_end </body> </html> </notes> <label text="Actin_polymerization"/> <bbox w="160.0" h="35.0" x="9450.0" y="7312.5"/> </glyph> <glyph class="phenotype" id="s2970_sa1428" compartmentRef="c38_ca38"> <label text="KEEP_OUT"/> <bbox w="210.0" h="115.0" x="4275.0" y="572.5"/> </glyph> <glyph class="phenotype" id="s3799_sa1396" 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>References_begin: PMID:21910624 References_end </body> </html> </notes> <label text="EXOCYTOSIS_AND_PHAGOCYTOSIS"/> <bbox w="360.0" h="145.0" x="9860.0" y="8147.5"/> </glyph> <glyph class="phenotype" id="s3841_sa2289"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:18633355 Hypoxic macrophages are known to respond to hypoxia by upregulating hypoxia-inducible transcription factors (mainly hypoxia-inducible factors HIF1 and HIF2)38, 39, the activation of which leads to increased transcription of many genes that regulate cell proliferation, metabolism and angiogenesis40. Hypoxia induces a distinct pro-angiogenic phenotype in human macrophages in vitro42, 43 including the upregulation of VEGF, bFGF, CXCL8, COX2, hepatocyte growth factor (HGF), VEGFR1, tissue factor (F3) and MMP12. References_end </body> </html> </notes> <label text="ANGIOGENESIS"/> <bbox w="270.0" h="75.0" x="4225.0" y="8332.5"/> </glyph> <glyph class="phenotype" id="s4230_sa2765" compartmentRef="c43_ca43"> <label text="TUMOR_GROWTH"/> <bbox w="300.0" h="102.5" x="3430.0" y="8698.75"/> </glyph> <glyph class="phenotype" id="s4231_sa2766"> <label text="MATRIX_REMODELLING"/> <bbox w="280.0" h="95.0" x="2835.0" y="8182.5"/> </glyph> <glyph class="phenotype" id="s4346_sa2872"> <label text="IMMUNE_SUPRESSION"/> <bbox w="490.0" h="165.0" x="1965.0" y="8377.5"/> </glyph> <glyph class="phenotype" id="s4347_sa2873"> <label text="IMMUNE_ACTIVATION"/> <bbox w="590.0" h="127.5" x="11985.0" y="8446.25"/> </glyph> <glyph class="macromolecule" id="s4_sa230" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:MIF CASCADE:LFA1 CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 CASCADE:IFNAB PMID:21350056, PMID:23906377 Human perforin is expressed in natural killer cells.NK cytotoxicity is mediated by the directed exocytosis of cytolytic granules to release perforins and granzymes, which perforate the target cell plasma cell membrane and trigger apoptosis, respectively. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. PMID:9637476, PMID:10878343 MIF prevented the release of perforin granules by NK cells but not CTLs. Tumor cells produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells. References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="80.0" h="40.0" x="8850.0" y="7390.0"/> </glyph> <glyph class="macromolecule" id="s7_sa228" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMK Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:16106370, PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end </body> </html> </notes> <label text="GZMK"/> <bbox w="80.0" h="40.0" x="8480.0" y="7560.0"/> </glyph> <glyph class="macromolecule" id="s8_sa825" 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: HUGO:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL1 MAP:NATURAL_KILLER PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor PMID:12917349, PMID:18835194 Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end </body> </html> </notes> <label text="KIR2DL1"/> <bbox w="80.0" h="50.0" x="2935.0" y="1345.0"/> <glyph class="state variable" id="_0ee2af2b-6502-41cf-93fd-bd8d8f155dd0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2930.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_f2757d98-c204-44d7-acf1-49a2ad5a516f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2952.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s9_sa826" 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: HUGO::KIR2DL2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL2 MAP:NATURAL_KILLER PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:21339333 KIR2DL2 signaling blocks the initiation of activating responses downstream of HLA-C via SHP-1,SHP-2. KIR2DL2 signaling inhibits IFNG secretion and Ca2+ mobilization, probably via inhibition of NKG2D-DAP10 signaling. PMID:9605119 Interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3) with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor cell lysis. References_end </body> </html> </notes> <label text="KIR2DL2"/> <bbox w="80.0" h="50.0" x="2805.0" y="1345.0"/> <glyph class="unit of information" id="_c8fca332-617b-4b56-a71e-79ae057d4383"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2822.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s10_sa824" 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: HUGO:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL3 MAP:NATURAL_KILLER PMID:11513144, PMID:8574854 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. KIR2DL3 inhibits NK cells downstream of HLA-C via SHP-1 binding and activation. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end </body> </html> </notes> <label text="KIR2DL3"/> <bbox w="80.0" h="50.0" x="2645.0" y="1345.0"/> <glyph class="state variable" id="_f538e036-d8c0-4da9-9903-b189ff36f9aa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2640.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_1e61bf68-7460-4538-b478-9f36461e4a88"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2662.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s11_sa817" 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: HUGO:KIR3DL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: KIR3DL1 MAP:NATURAL_KILLER PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. Recognition of Inhibitory HLA-B Allotypes (Bw4+) by the KIR NKB1 Alters Stimulatory Signal Transduction Pathways in NK Cells via inhibition of PI3K pathway and Ca2+ mobilization. Probably it acts via LAT inhibition.KIR recognition of inhibitory class I molecules disrupted the ability of pp36 (LAT) to associate with Grb2 in vitro. PTP-1C (SHP-1) activated by KIR3DL1 binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2. PMID:11994457 Tyrosine-phosphorylated KIR3DL1 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2, SHP-1.3DL1-mediated inhibition of cytotoxicity was abolished upon overexpression of SHP-1. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end </body> </html> </notes> <label text="KIR3DL1"/> <bbox w="80.0" h="50.0" x="3495.0" y="1345.0"/> <glyph class="state variable" id="_d65f5a1e-8875-4168-b279-4e7a750a2366"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3490.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_43af7143-5f8d-4216-8233-d7834c8eb19d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3512.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s15_sa835" 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: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KLRB1 CASCADE:IL12 PMID:18159636 Transcription of the KLRB1 gene is suppressed in human cancer tissues PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:22378844, PMID:24227772 miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. IL15 and KLRB1 (NK1.1) ligation also induce MIR155 expression. References_end </body> </html> </notes> <label text="KLRB1"/> <bbox w="80.0" h="50.0" x="2365.0" y="1705.0"/> <glyph class="unit of information" id="_f79b42f7-62b9-4bb2-989c-1c435e106f3c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2382.5" y="1700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s21_sa1986" 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:CREBBP Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL 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. References_end </body> </html> </notes> <label text="CREBBP"/> <bbox w="80.0" h="40.0" x="10895.0" y="4645.0"/> </glyph> <glyph class="macromolecule" id="s22_sa45" 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: HUGO:LGMN Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16181339, PMID:12705852 Processing of CD74 includes its initial cleavage by Legumain, followed by late stage cleavage by Cathepsin S and Cathepsin L PMID:12776207, PMID:10795737, PMID:17204652 Cathepsins B,D,L, S and AEP (LGMN) are the lysosomal proteases implicated in antigen presentation in DC. References_end </body> </html> </notes> <label text="LGMN"/> <bbox w="80.0" h="40.0" x="12283.125" y="6507.5"/> </glyph> <glyph class="macromolecule" id="s23_sa51" 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: HUGO:CTSL Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22157818 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 PMID:12776207 Cathepsins B,D,L, S and AEP (LGMN) are the lysosomal proteases implicated in antigen presentation in DC. References_end </body> </html> </notes> <label text="CTSL"/> <bbox w="80.0" h="40.0" x="11698.125" y="6507.5"/> </glyph> <glyph class="macromolecule" id="s24_sa44" 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: HUGO:CTSS Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL6 PMID:22157818 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 PMID:22424724 Cathepsin S dominates autoantigen processing in human thymic dendritic cells. PMID:10072073, PMID:10562280 Cathepsin S provides Ii (CD74) degradation in dendritic cells. PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. References_end </body> </html> </notes> <label text="CTSS"/> <clone/> <bbox w="80.0" h="40.0" x="12283.125" y="6417.5"/> </glyph> <glyph class="macromolecule" id="s24_sa2427" 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: HUGO:CTSS Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL6 PMID:22157818 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 PMID:22424724 Cathepsin S dominates autoantigen processing in human thymic dendritic cells. PMID:10072073, PMID:10562280 Cathepsin S provides Ii (CD74) degradation in dendritic cells. PMID:16286017 cathepsin S activity was responsible for the IL-6-mediated decrease in MHCII αβ dimer, Ii, and H2-DM levels in DCs. References_end </body> </html> </notes> <label text="CTSS"/> <clone/> <bbox w="80.0" h="40.0" x="12280.0" y="6330.0"/> </glyph> <glyph class="macromolecule" id="s25_sa43" 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: HUGO:IFI30 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11701933, PMID:12198183, PMID:10639150, PMID:17142755, PMID:17204652 Gamma-interferon-inducible lysosomal thiol reductase IFI30 (GILT) facilitates unfolding of endocytosed antigens in MHC class II -containing compartments by enzymatic cleavage of disulfide bonds in DC. References_end </body> </html> </notes> <label text="IFI30"/> <bbox w="80.0" h="40.0" x="11803.125" y="6507.5"/> </glyph> <glyph class="macromolecule" id="s35_sa769" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PCNA 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:23414611, PMID:22021614 Proliferating cell nuclear antigen (PCNA), which is overexpressed by cancer cells, has been reported as an inhibitory ligand of NKp44. References_end </body> </html> </notes> <label text="PCNA"/> <bbox w="80.0" h="40.0" x="11490.0" y="965.0"/> </glyph> <glyph class="macromolecule" id="s51_sa450" 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:LCK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL3 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KNP44 CASCADE:NKP30 CASCADE:NKP46 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:12740575 Src kinaze LCK participate in activation of NKG2D signaling and induction of PLCG phosphorylation, probably via DAP10 phosphorylation. PMID:9751747, PMID:8986721 LCK phosphorylates KIR receptors in NK cells downstream of HLA binding. PMID:22513334 Probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 in NK cells (demonstrated in T cells). PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK. References_end </body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="11045.0" y="2500.0"/> <glyph class="state variable" id="_71b89022-7336-4651-b18f-a8d457355826"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11037.5" y="2515.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s52_sa451" 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:FYN 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:NKP30 CASCADE:NKP46 CASCADE:SLAMF7 CASCADE:LFA1 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:10591186, PMID:24440149 Cross-Linking of LFA-1 induces tyrosine Phosphorylation of DNAM-,FYN probably phosphorylates DNAM1 Y322 in NK cells PMID:22683124 Fyn-deficient NK cells exhibited defective killing. PMID:19909365 FYN is adaptor protein f Fc epsilon RI signaling in mast cells References_end </body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="11225.0" y="2490.0"/> <glyph class="state variable" id="_6fdc8c5c-2ca2-4d49-9738-35639f31fd27"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11217.5" y="2505.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s53_sa471" 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:SYK Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL MAP:DENDRITIC_CELL CASCADE:NKP80 CASCADE:NKG2A CASCADE:KIR2DS2 CASCADE:KLRC2 CASCADE:NKP44 CASCADE:NKP46 CASCADE:NKP30 CASCADE:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII 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:9396765 Syk-dependent signaling plays a critical role in NK cytotoxicity. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:21149606, PMID:23609447 Syk kinase is part of the NKp80-signaling pathway, and phosphorylation of Syk requires integrity of the Y7-containing motif of NKp80. NKp80 activates PI33/ERK pathway probably via SYK. PMID:21910624 The event that follows FcγR phosphorylation by Src-family kinases involves the spleen tyrosine kinase (Syk) (Figure 1). Syk displays two Src homology 2 (SH2) domains, which bind doubly phosphorylated ITAMs (43). This cytosolic kinase is expressed mostly in hematopoietic cells and becomes activated by phosphorylation upon FcγR cross-linking (43, 44) PMID:8226994, PMID:9314552, PMID:9632805, PMID:8189062 tyrosine kinase Syk associates with FcγRII ((10)) and with the tyrosine phosphorylated γ chain of FcγRI ((11)) and FcγRIII ((12)), and has been implicated in FcγR-mediated phagocytosis. Studies in macrophages from syk−/− mice demonstrated that Syk is required for FcγR-mediated phagocytosis Syk-deficient macrophages were defective in phagocytosis induced by FcgammaR but showed normal phagocytosis in response to complement. PMID:8189062 Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:12524384 FCAR induces SYK activation PMID:9000133 Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. PMID:19909365 Syk is adaptor protein f Fc epsilon RI signaling in mast cells References_end </body> </html> </notes> <label text="SYK"/> <bbox w="80.0" h="40.0" x="9155.0" y="2860.0"/> <glyph class="state variable" id="_7d32bd1f-df80-4dad-9a02-1c1934669f6f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9150.0" y="2875.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s57_sa1983" 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: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="12310.0" y="4250.0"/> </glyph> <glyph class="macromolecule" id="s73_sa40" 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:ERAP1 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:22790179, PMID:17277129 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)) References_end </body> </html> </notes> <label text="ERAP1"/> <bbox w="80.0" h="40.0" x="13900.0" y="6030.0"/> </glyph> <glyph class="macromolecule" id="s81_sa1979" 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: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="12555.0" y="4210.0"/> <glyph class="state variable" id="_a14186a7-2a18-42c8-b867-0138cb551cd2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12547.5" y="4225.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s84_sa468" 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:ZAP70 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DS2 CASCADE:NKP44 CASCADE:NKP46 CASCADE:NKP30 MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:Fc_gamma_RIII PMID:20814939, PMID:12731048 Phosphorylation of the ITAM sequence in the associated partner chains induces binding and phosphorylation of tyrosine kinases Syk and ZAP70 to the ITAM downstream of NKp30 or NKp46 or NKp44 References_end </body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="12035.0" y="2500.0"/> <glyph class="state variable" id="_79df5b64-a399-4de4-adfb-3076294a263b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12030.0" y="2515.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s85_sa469" 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:SYK Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL MAP:DENDRITIC_CELL CASCADE:NKP80 CASCADE:NKG2A CASCADE:KIR2DS2 CASCADE:KLRC2 CASCADE:NKP44 CASCADE:NKP46 CASCADE:NKP30 CASCADE:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII 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:9396765 Syk-dependent signaling plays a critical role in NK cytotoxicity. PMID:11907067, PMID:15536084 SYK kinaze directly interacts with PI3K(p85) and activates perforin granule movement and polarization via PI3K /RAC1/PAK1/MEK /ERK pathway PMID:21149606, PMID:23609447 Syk kinase is part of the NKp80-signaling pathway, and phosphorylation of Syk requires integrity of the Y7-containing motif of NKp80. NKp80 activates PI33/ERK pathway probably via SYK. PMID:21910624 The event that follows FcγR phosphorylation by Src-family kinases involves the spleen tyrosine kinase (Syk) (Figure 1). Syk displays two Src homology 2 (SH2) domains, which bind doubly phosphorylated ITAMs (43). This cytosolic kinase is expressed mostly in hematopoietic cells and becomes activated by phosphorylation upon FcγR cross-linking (43, 44) PMID:8226994, PMID:9314552, PMID:9632805, PMID:8189062 tyrosine kinase Syk associates with FcγRII ((10)) and with the tyrosine phosphorylated γ chain of FcγRI ((11)) and FcγRIII ((12)), and has been implicated in FcγR-mediated phagocytosis. Studies in macrophages from syk−/− mice demonstrated that Syk is required for FcγR-mediated phagocytosis Syk-deficient macrophages were defective in phagocytosis induced by FcgammaR but showed normal phagocytosis in response to complement. PMID:8189062 Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:12524384 FCAR induces SYK activation PMID:9000133 Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. PMID:19909365 Syk is adaptor protein f Fc epsilon RI signaling in mast cells References_end </body> </html> </notes> <label text="SYK"/> <bbox w="80.0" h="40.0" x="9155.0" y="3000.0"/> <glyph class="state variable" id="_f31a2007-5033-4288-aab5-83ab601ed810"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9147.5" y="3015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s86_sa470" 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:ZAP70 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DS2 CASCADE:NKP44 CASCADE:NKP46 CASCADE:NKP30 MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:Fc_gamma_RIII PMID:20814939, PMID:12731048 Phosphorylation of the ITAM sequence in the associated partner chains induces binding and phosphorylation of tyrosine kinases Syk and ZAP70 to the ITAM downstream of NKp30 or NKp46 or NKp44 References_end </body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="12035.0" y="2420.0"/> <glyph class="state variable" id="_a258ffe4-620d-4afa-b83a-f5153fb3071b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12027.5" y="2435.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s90_sa530" 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:MAP2K1 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 GENECARDS:MAP2K1 HUGO:MAP2K2 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 GENECARDS:MAP2K2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:59503 KEGG:5604 ATLASONC:GC_MAP2K1 WIKI:MAP2K1 REACTOME:59505 KEGG:5605 ATLASONC:GC_MAP2K2 WIKI:MAP2K2 MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:17395718, PMID:11062502, PMID: 15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:10843677 IL2 activates MEK (MKK)/ERK pathway in NK cells. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. PMID:11034387 MAPK activation in NK cells resulted in lysis is Ras-independent. PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="MEK*"/> <bbox w="80.0" h="40.0" x="10000.0" y="3770.0"/> <glyph class="state variable" id="_b9647e6c-e221-46f7-9e84-a9645d1a49bf"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9995.0" y="3784.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s91_sa531" 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:MAPK3 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 GENECARDS:MAPK3 HUGO:MAPK1 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 GENECARDS:MAPK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:VEGFA CASCADE:MIF CASCADE:NKP80 CASCADE:KIR2DS4 CASCADE:NKP46 CASCADE:Fc_gamma_RIII CASCADE:LFA1 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:TLR2_4 CASCADE:IL15 CASCADE:IL2 CASCADE:IFNG PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:17395718, PMID:11062502, PMID:15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:21149606 NKp80 activates PI33/ERK pathway probably via SYK. PMID:22786724 DNAM1 induces ERK pathway probably via VAV1. PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. PMID:10903731 IL18 signaling induces activation of ERK1/2 kinases. The cytolytic activity of NK cells downstream of IL18 is inhibited by ERK inhibitors. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. PMID:11489965, PMID:10843677 The IFN-γ secretion by NK cells induced by IL-2 depends on an ERK mitogen-activated protein kinase pathway. IL-2 activation of an MKK/ERK pathway is required for NK cells to acquire enhanced cytolytic function (LAK activity). IL-2-driven IFN-γ secretion and induction of CD25 and CD69 (CLEC2C) activation markers require intact MKK/ERK pathway. PMID:9862693 CD16-induced ERK activation provides IFN-γ mRNA accumulation and ADCC and spontaneous cytotoxicity of NK cells PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 PMID:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells. PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. PMID:12048245 IFN-γ-Induced Gene Expression is MEKK1/p38 dependent and MEKK1/ERK dependent MEKK1 upregulates CEBPB activation via ERK PMID:10733514 ERK2 activated MLCK, resulting in phosphorylation of the MLCK substrate or of the myosin light chain itself. And induces phagocytosis. PMID:17086423 VEGF treatment enhanced the phospho-Erk 1 and 2 via KDR in DC PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation in macrophages. PMID:23508573 HMGB1 induces activation (phosphorylation) of ERK, JNK and p38 via TLR4 in macrophages 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:21826665 ERK is activated in TAN References_end </body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="10220.0" y="3870.0"/> <glyph class="state variable" id="_cfe2b485-653a-4782-995b-47b3c67037c7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10215.0" y="3885.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s92_sa552" 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:MAPK3 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 GENECARDS:MAPK3 HUGO:MAPK1 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 GENECARDS:MAPK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:VEGFA CASCADE:MIF CASCADE:NKP80 CASCADE:KIR2DS4 CASCADE:NKP46 CASCADE:Fc_gamma_RIII CASCADE:LFA1 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:TLR2_4 CASCADE:IL15 CASCADE:IL2 CASCADE:IFNG PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:17395718, PMID:11062502, PMID:15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:21149606 NKp80 activates PI33/ERK pathway probably via SYK. PMID:22786724 DNAM1 induces ERK pathway probably via VAV1. PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. PMID:10849428 IL-2 and IL-15 are able to induce the phosphorylation of ERK1/2. probably via PI3K pathway. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and IL2RA (CD25) and CLEC2C(CD69) expression. PMID:10903731 IL18 signaling induces activation of ERK1/2 kinases. The cytolytic activity of NK cells downstream of IL18 is inhibited by ERK inhibitors. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. PMID:11489965, PMID:10843677 The IFN-γ secretion by NK cells induced by IL-2 depends on an ERK mitogen-activated protein kinase pathway. IL-2 activation of an MKK/ERK pathway is required for NK cells to acquire enhanced cytolytic function (LAK activity). IL-2-driven IFN-γ secretion and induction of CD25 and CD69 (CLEC2C) activation markers require intact MKK/ERK pathway. PMID:9862693 CD16-induced ERK activation provides IFN-γ mRNA accumulation and ADCC and spontaneous cytotoxicity of NK cells PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 PMID:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells. PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. PMID:12048245 IFN-γ-Induced Gene Expression is MEKK1/p38 dependent and MEKK1/ERK dependent MEKK1 upregulates CEBPB activation via ERK PMID:10733514 ERK2 activated MLCK, resulting in phosphorylation of the MLCK substrate or of the myosin light chain itself. And induces phagocytosis. PMID:17086423 VEGF treatment enhanced the phospho-Erk 1 and 2 via KDR in DC PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation in macrophages. PMID:23508573 HMGB1 induces activation (phosphorylation) of ERK, JNK and p38 via TLR4 in macrophages 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:21826665 ERK is activated in TAN References_end </body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="10220.0" y="3990.0"/> <glyph class="state variable" id="_576474fc-d0c1-4b74-a325-51928075520d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10212.5" y="4005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s93_sa551" 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:MAP2K1 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 GENECARDS:MAP2K1 HUGO:MAP2K2 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 GENECARDS:MAP2K2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:59503 KEGG:5604 ATLASONC:GC_MAP2K1 WIKI:MAP2K1 REACTOME:59505 KEGG:5605 ATLASONC:GC_MAP2K2 WIKI:MAP2K2 MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:17395718, PMID:11062502, PMID: 15536084 PAK1 activates classical MEK/ERK cascad resulted in granule movement and polarization and tumor cel lysis downstream of Nkp30, Syk and PI3K. PMID:10843677 IL2 activates MEK (MKK)/ERK pathway in NK cells. MKK/ERK pathway is necessary for IL-2 to activate NK cells to express at least four known biological responses: LAK generation, IFN-gamma secretion, and CD25 and CD69 expression. PMID:11034387 MAPK activation in NK cells resulted in lysis is Ras-independent. PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="MEK*"/> <bbox w="80.0" h="40.0" x="9996.5" y="3888.0"/> <glyph class="state variable" id="_82bf5da0-a62f-47dd-98f5-a9f9e9b90764"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9989.0" y="3902.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s117_sa1260" 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:IL12B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:MIF CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. 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. References_end </body> </html> </notes> <label text="IL12p40*"/> <bbox w="80.0" h="40.0" x="12332.75" y="5375.0"/> </glyph> <glyph class="macromolecule" id="s122_sa988" 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: 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). References_end </body> </html> </notes> <label text="IL4R"/> <clone/> <bbox w="80.0" h="50.0" x="670.0" y="4960.0"/> <glyph class="state variable" id="_1b1a6d6a-6f4d-4d24-91e9-9f15dff4cdc3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="745.0" y="4994.389"/> </glyph> <glyph class="unit of information" id="_b1d1eb61-a38d-4a5e-bdc8-2d287afd1b9e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="687.5" y="4955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s122_sa1848" 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: 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). References_end </body> </html> </notes> <label text="IL4R"/> <clone/> <bbox w="80.0" h="50.0" x="16205.0" y="5195.0"/> <glyph class="state variable" id="_a8bb7b50-5517-4f0f-9149-222ecd2f8126"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16280.0" y="5229.389"/> </glyph> <glyph class="unit of information" id="_0ba0a9d3-5981-4e1a-8dc1-fee2403afe6d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16222.5" y="5190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s133_sa2110" 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:MAPK11 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 GENECARDS:MAPK11 HUGO:MAPK12 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 GENECARDS:MAPK12 HUGO:MAPK13 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 GENECARDS:MAPK13 HUGO:MAPK14 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 GENECARDS:MAPK14 REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 Identifiers_end Maps_Modules_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL10 CASCADE:KIR2DL4 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:TNF CASCADE:TLR2_4 CASCADE:IL18 CASCADE:IFNG Maps_Modules_end References_begin: 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. PMID:11489965 The induction by KIR2DL4 of IFN-gamma production by resting NK cells was blocked by an inhibitor of the p38 mitogen-activated protein kinase signaling pathway PMID:10961885, PMID:15345584, PMID:10903731 IL-12 and IL18 activate p38 in NK cells. IFNG mRNA is stabilized by MAPK p38. MAPK p38 signaling downstream of IL18 and IL 12 increases IFNG production. PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. PMID:9379049 MKK3 and MKK4 are capable of phosphorylating p38mapk in macrophages, downstream of TNF/Tnf receptor signaling. PMID:15170913, PMID:9582321, PMID:11668179 MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway upregulates COX2 expression and PGE2 production in macrophages, via activation of transcription factors C/EBP beta and CEBPD. PMID:12048245 IFN-γ-Induced Gene Expression is MEKK1/p38 dependent and MEKK1/ERK dependent MEKK1 upregulates CEBPB activation PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. HO-1 mediates IL-10-induced suppression of TNF- production and IL-10-induced suppression of MMP9 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:17073741 DUSP1 inhibits p38 and JNK pathways of innate innunity PMID:16184516 Increased expression of DUSP1 in IL-10-treated activated macrophages was correlated with a faster down-regulation of p38 MAPK activation. PMID:10606755 LPS and TNFalpha were found to induce the expression of SOCS3 mRNA in each of the investigated type of macrophages but not in HepG2 cells. Using a specific inhibitor, evidence is presented that the p38 MAP kinase might be involved, especially for the inhibitory effect of TNFalpha. 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:23508573 HMGB1 induces activation (phosphorylation) of ERK, JNK and p38 via TLR4 in macrophages 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. 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 References_end </body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="10451.0" y="3620.0"/> <glyph class="state variable" id="_b65e87a0-bcd1-4710-a6a6-cc35f8430de5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10446.0" y="3634.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s134_sa2111" 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:MAPK11 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 GENECARDS:MAPK11 HUGO:MAPK12 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 GENECARDS:MAPK12 HUGO:MAPK13 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 GENECARDS:MAPK13 HUGO:MAPK14 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 GENECARDS:MAPK14 REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 Identifiers_end Maps_Modules_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL10 CASCADE:KIR2DL4 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:TNF CASCADE:TLR2_4 CASCADE:IL18 CASCADE:IFNG Maps_Modules_end References_begin: 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. PMID:11489965 The induction by KIR2DL4 of IFN-gamma production by resting NK cells was blocked by an inhibitor of the p38 mitogen-activated protein kinase signaling pathway PMID:10961885, PMID:15345584, PMID:10903731 IL-12 and IL18 activate p38 in NK cells. IFNG mRNA is stabilized by MAPK p38. MAPK p38 signaling downstream of IL18 and IL 12 increases IFNG production. PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. PMID:9379049 MKK3 and MKK4 are capable of phosphorylating p38mapk in macrophages, downstream of TNF/Tnf receptor signaling. PMID:15170913, PMID:9582321, PMID:11668179 MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway upregulates COX2 expression and PGE2 production in macrophages, via activation of transcription factors C/EBP beta and CEBPD. PMID:12048245 IFN-γ-Induced Gene Expression is MEKK1/p38 dependent and MEKK1/ERK dependent MEKK1 upregulates CEBPB activation PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. HO-1 mediates IL-10-induced suppression of TNF- production and IL-10-induced suppression of MMP9 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:17073741 DUSP1 inhibits p38 and JNK pathways of innate innunity PMID:16184516 Increased expression of DUSP1 in IL-10-treated activated macrophages was correlated with a faster down-regulation of p38 MAPK activation. PMID:10606755 LPS and TNFalpha were found to induce the expression of SOCS3 mRNA in each of the investigated type of macrophages but not in HepG2 cells. Using a specific inhibitor, evidence is presented that the p38 MAP kinase might be involved, especially for the inhibitory effect of TNFalpha. 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:23508573 HMGB1 induces activation (phosphorylation) of ERK, JNK and p38 via TLR4 in macrophages 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. 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 References_end </body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="10451.0" y="3700.0"/> <glyph class="state variable" id="_abf1bac9-51d8-4b04-920d-1c66d0a9f33a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10443.5" y="3714.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s137_sa2444" 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:HMOX1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL10 MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. HMOX1 mediates IL-10-induced suppression of TNF production, and MMP9 and INOS expression. References_end </body> </html> </notes> <label text="HMOX1"/> <bbox w="80.0" h="40.0" x="3612.25" y="3475.0"/> </glyph> <glyph class="macromolecule" id="s140_sa1105" 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:NOS2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:MIF CASCADE:IL10 CASCADE:IFNG Maps_Modules_end References_begin: PMID:17476345 NOS2, a heme-containing enzyme that catalyzes the synthesis of NO and citrulline from l‐Arg, is expressed by various cells of the immune system, and its activa- tion is considered a hallmark of classically activated macrophages (also known as M1 macrophages), a macrophage subset that pro- duces proinflammatory cytokines and acts as the effector cell in the killing of invading pathogens and tumor cells. PMID:11875494 HMOX1 (HO1) mediates the inhibitory effect of IL10 on LPS-induced NOS2 (INOS) expression. PMID:6357187 Macrophage tumoricidal activity is attributed to NOS2 (iNOS) production. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:21680779, PMID:22816309 Myeloid-derived suppressor cell inhibit the IFN response in immune cells (splenocytes, macrophages) via inhibition of STAT1 phosphorylation by NO (downstream of iNOS).. References_end </body> </html> </notes> <label text="NOS2"/> <bbox w="120.0" h="70.0" x="6333.5938" y="5500.9375"/> </glyph> <glyph class="macromolecule" id="s142_sa1383" 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:MMP9 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS MODULE:MATRIX_REMODELLING CASCADE:MIF CASCADE:IL10 CASCADE:IL4 CASCADE:IFNAB MAP:NEUTROPHIL Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. PMID:18633355 MMP7, MMP9 and MMP12 from macrophages drives angiogenesis MDSC isolated from murine tumours express higher levels of various MMPs (MMP2, MMP9, MMP13 and MMP14 than MDSC from healthy mice PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis probavly via upregulation of MMP9, VEGF expression in macrophages and activates tumor invasion PMID:21896641 mast cells and mast cell derived MMP-9 contribute to the development of well-differentiated prostate tumors PMID:22425643 A key mediator secreted from neutrophils and involved in carcinogenesis is MMP-9. It was demonstrated to be involved in skin tumorigenesis, by regulation of oncogene-induced keratinocyte hyperproliferation and their progression to invasive cancer (71). In addition to its effects on matrix, it has been shown that MMP-9 secreted from neutrophils (among other bone marrow cells) prevents apoptosis of tumor cells in the lung (72). References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="80.0" h="40.0" x="3050.0" y="6560.0"/> </glyph> <glyph class="macromolecule" id="s149_sa1101" 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:ARG1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:LACTIC CASCADE:TGFB CASCADE:MIF Maps_Modules_end References_begin: PMID:12193690, PMID:17476345 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. ARG1 activation has been regarded as one of the most specific markers of M2 macrophages. PMID:20644162 Human MDSC express AGR1 PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:26819959 TANs (G-MDSC) produced much more ARG1 and ROS than autologous neutrophils and inhibited proliferation of activated autologous T cells and IFN-γ productionReferences_end References_end </body> </html> </notes> <label text="ARG1"/> <bbox w="110.0" h="60.0" x="5528.5938" y="5445.9375"/> </glyph> <glyph class="macromolecule" id="s150_sa1100" 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:ARG2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:IL10 Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces ARG2 (arginase-2) expression References_end </body> </html> </notes> <label text="ARG2"/> <bbox w="107.0" h="61.0" x="5690.0938" y="5445.4375"/> </glyph> <glyph class="macromolecule" id="s151_sa1989" 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:NFKBID Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="80.0" h="40.0" x="12045.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s218_sa1321" 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: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="13406.25" y="5395.0"/> </glyph> <glyph class="macromolecule" id="s221_sa1271" 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:IL12A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TLR2_4 CASCADE:CSF2 Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="80.0" h="40.0" x="12426.25" y="5375.0"/> </glyph> <glyph class="macromolecule" id="s236_sa959"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL10 CASCADE:TGFB CASCADE:MIF CASCADE:CSF1 CASCADE:IL12 CASCADE:STING CASCADE:TLR2_4 CASCADE:IFNAB CASCADE:FLT3LG CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. 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:16713974 Production of IL10 is partially ERK dependent. PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. At the same tyme IL10 siglaning also participates in ID3 upregulation via PI3K/AKT pathway PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages PMID:9834059 NK cells stimulated by IL12 induces IL10 production. PMID:11207245 IFNA induces IL10 production in Dcs (negative loop) PMID:21220452 that IL-10 increased March1 mRNA by approximately six fold PMID:15579430 Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) protein Molecules on Dendritic Cells in Metastatic Tumor Lesions ( PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="238.5" y="3935.0"/> </glyph> <glyph class="macromolecule" id="s240_sa975" 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: 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="680.0" y="5240.0"/> <glyph class="unit of information" id="_5a79dc79-d33d-4f6a-90cf-b1a20d4e32bc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="697.5" y="5235.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s240_sa1853" 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: 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="16030.0" y="4700.0"/> <glyph class="unit of information" id="_a7c34b20-b3f7-45b8-ab75-d1c7991cebb6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16047.5" y="4695.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s317_sa2817" 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:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:STING Maps_Modules_end References_begin: PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. References_end </body> </html> </notes> <label text="TGFB1"/> <bbox w="130.0" h="80.0" x="3097.5" y="5757.5"/> </glyph> <glyph class="macromolecule" id="s385_sa1004" 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: HUGO:IL13RA2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175 IL13 signaling via IL13RA2 induces TGFB production in MDSC. References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="80.0" h="50.0" x="670.0" y="4330.0"/> <glyph class="unit of information" id="_ff41c103-b2f6-4417-9d93-3f2712b6798f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="687.5" y="4325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s395_sa2563" 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: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="4570.0" y="3800.0"/> </glyph> <glyph class="macromolecule" id="s396_sa500" 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:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:IL13 CASCADE:SLAMF7 CASCADE:2B4 CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:IFNAB 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:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP 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:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616, PMID:10925299 PCL (probably PCLG1) induces hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. Intracellular Ca2+ release release induces cAMP Accumulation in Human monocytes and activation of PKA signaling downstream of IL13. PMID:7890616 IL13 inhibits ROI production downstream of cAMP/PKA in all macrophage types PMID:19909365 The phosphorylation of LAT1 together with the generation of PIP3 in the lipid raft environment recruits proteins such as PLC-γ1 and PLC-γ2 References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="5400.0" y="2890.0"/> <glyph class="state variable" id="_b305da27-5f55-4950-9db6-e2b4291d89de"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5395.0" y="2905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s408_sa527" 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:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:IL13 CASCADE:SLAMF7 CASCADE:2B4 CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:IFNAB 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:11169415, PMID:10072481, PMID:8649391 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP 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:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616, PMID:10925299 PCL (probably PCLG1) induces hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. Intracellular Ca2+ release release induces cAMP Accumulation in Human monocytes and activation of PKA signaling downstream of IL13. PMID:7890616 IL13 inhibits ROI production downstream of cAMP/PKA in all macrophage types PMID:19909365 The phosphorylation of LAT1 together with the generation of PIP3 in the lipid raft environment recruits proteins such as PLC-γ1 and PLC-γ2 References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="5400.0" y="3060.0"/> <glyph class="state variable" id="_e7e2853b-705f-48e6-b97b-325e545d8702"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5392.5" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s409_sa983" 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:IRS2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="IRS2"/> <bbox w="80.0" h="40.0" x="9775.0" y="2820.0"/> <glyph class="state variable" id="_55d26b92-d40d-4934-814f-0ec5166b2c48"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9770.0" y="2835.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s411_sa982" 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:IRS2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="IRS2"/> <bbox w="80.0" h="40.0" x="9775.0" y="2890.0"/> <glyph class="state variable" id="_a1c13e5e-38e8-4970-b829-5942886224b9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9767.5" y="2905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s440_sa2473" 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:ALOX15 CASCADE:IL4 CASCADE:IL13 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:10432118 ALOX15 activation results in induction of CD36 expression downstream of IL4 and IL13 via PRARG Linoleic acid is oxygenated by ALOX15 to 13-HODE which activates PPARG. References_end </body> </html> </notes> <label text="ALOX15"/> <bbox w="80.0" h="40.0" x="2367.25" y="3781.5"/> </glyph> <glyph class="macromolecule" id="s443_sa2468" 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:MAOA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:23124025 MAOA activation incuces generation of intracellular ROS during the oxidation of biogenic amines. References_end </body> </html> </notes> <label text="MAOA"/> <bbox w="80.0" h="40.0" x="6303.5938" y="7185.9375"/> </glyph> <glyph class="macromolecule" id="s449_sa2494" 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:DUSP1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 CASCADE:IL10 Maps_Modules_end References_begin: PMID:16184516 In silico analysis identified a STAT6 binding site at position +99 (relative to the transcriptional start site) of the mouse DUSP1 promoter. References_end </body> </html> </notes> <label text="DUSP1"/> <bbox w="80.0" h="40.0" x="2970.0" y="3480.0"/> </glyph> <glyph class="macromolecule" id="s460_sa2381" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD163 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE CASCADE:IL4 CASCADE:IL10 Maps_Modules_end References_begin: PMID:22176642 CD163 is a M2 marker PMID:15749903 CD163 expression in macrophages is IL10 dependent PMID:17681149 In macrophages PPARG upregulates expression of M2 markers CD163 and MRC1 References_end </body> </html> </notes> <label text="CD163"/> <bbox w="80.0" h="40.0" x="1891.75" y="645.625"/> </glyph> <glyph class="macromolecule" id="s463_sa2382" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MRC1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE CASCADE:MIF CASCADE:LGALS3 CASCADE:IL4 Maps_Modules_end References_begin: 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:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. References_end </body> </html> </notes> <label text="MRC1"/> <bbox w="80.0" h="40.0" x="1995.6488" y="645.625"/> </glyph> <glyph class="macromolecule" id="s469_sa2520"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TGFB CASCADE:CSF1 CASCADE:CCR2 CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:19915063 Phosphorylated STAT1 is critical for IFN-gamma-induced (CCL2)MCP-1 production PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="80.0" h="40.0" x="5751.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s497_sa2524" 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:UBE2I Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE 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="UBE2I"/> <bbox w="80.0" h="40.0" x="3042.25" y="3900.0"/> </glyph> <glyph class="macromolecule" id="s500_sa2523" 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:PIAS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE 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="PIAS1"/> <bbox w="80.0" h="40.0" x="3072.25" y="3960.0"/> </glyph> <glyph class="macromolecule" id="s502_sa1267" 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:CCL7 MODULE:RECRUITMENT_OF_IMMUNE_CELLS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end </body> </html> </notes> <label text="CCL7"/> <bbox w="80.0" h="40.0" x="6080.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s507_sa2498" 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:KDM6B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. References_end </body> </html> </notes> <label text="KDM6B"/> <bbox w="80.0" h="40.0" x="2530.0" y="4710.0"/> </glyph> <glyph class="macromolecule" id="s508_sa2499" 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:HIST1H3A HUGO:HIST1H3B HUGO:HIST1H3C HUGO:HIST1H3D HUGO:HIST1H3E HUGO:HIST1H3F HUGO:HIST1H3G HUGO:HIST1H3H HUGO:HIST1H3I HUGO:HIST1H3J HUGO:HIST2H3A HUGO:HIST2H3C HUGO:HIST2H3D HUGO:H3F3A HUGO:H3F3B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. References_end </body> </html> </notes> <label text="H3*"/> <bbox w="100.0" h="50.0" x="2600.0" y="4795.0"/> <glyph class="state variable" id="_b7a2c327-f7bc-4ab9-ac49-a4a5d0323f14"> <state value="" variable="K27"/> <bbox w="25.0" h="10.0" x="2634.3765" y="4840.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s509_sa2500" 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:HIST1H3A HUGO:HIST1H3B HUGO:HIST1H3C HUGO:HIST1H3D HUGO:HIST1H3E HUGO:HIST1H3F HUGO:HIST1H3G HUGO:HIST1H3H HUGO:HIST1H3I HUGO:HIST1H3J HUGO:HIST2H3A HUGO:HIST2H3C HUGO:HIST2H3D HUGO:H3F3A HUGO:H3F3B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. References_end </body> </html> </notes> <label text="H3*"/> <bbox w="100.0" h="50.0" x="2440.0" y="4795.0"/> <glyph class="state variable" id="_941f2ada-79f9-40b7-a91b-73406553e95e"> <state value="Me" variable="K27"/> <bbox w="35.0" h="10.0" x="2469.3765" y="4840.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s512_sa2509" 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:IRF4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes in macrophages. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. References_end </body> </html> </notes> <label text="IRF4"/> <bbox w="80.0" h="40.0" x="2860.0" y="4820.0"/> </glyph> <glyph class="macromolecule" id="s528_sa1493" 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: 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="16225.0" y="2715.0"/> <glyph class="state variable" id="_64ad25f2-0b85-4b9e-b769-f137e27c0024"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16220.0" y="2734.9602"/> </glyph> <glyph class="unit of information" id="_174ad13d-a8b1-4431-b79e-cd76f680b1f1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16242.5" y="2710.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s529_sa1494" 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: HUGO:IFNGR2 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="IFNGR2"/> <bbox w="80.0" h="50.0" x="16225.0" y="2655.0"/> <glyph class="unit of information" id="_2bf577f2-7513-491c-8cdb-a122363b7d5f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16242.5" y="2650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s535_sa1581"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:IL4 CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 CASCADE:KLRG1 CASCADE:KIR2DL2 CASCADE:KIR2DL4 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:Fc_gamma_RIII CASCADE:IL18 CASCADE:IL2 Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID:16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 expression. NK cells stimuletad by IL4 have NK2 subtype PMID:21149606 Nkp80 signaling induces marked IFNG production PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:11489965, PMID:15778339 KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells 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 References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="80.0" h="40.0" x="16600.0" y="3065.0"/> </glyph> <glyph class="macromolecule" id="s544_sa1644"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE: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:NKG2D CASCADE:KIR2DS2 CASCADE:Fc_gamma_RIII CASCADE:CSF2 PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway via NKG2D. PMID:11015446 Cross-linking of the KIR2DS2/DAP12 receptor on NKL cells resulted in the dose-dependent secretion of IFNG and GM-CSF PMID:21765015, PMID:22869907 CSF2 signaling can have both positive and negative influence on angiogenesis in tumors. First, CSF2 upregulates angiogenic factor VEGF expression via HIF1a, specific inhibition of PHD2 increases VEGF production. Second, CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. ( PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. 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. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="16600.0" y="5470.0"/> </glyph> <glyph class="macromolecule" id="s545_sa1062"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:GSF1 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling blocks CSF (M-CSF) production in DC induced by tumor cells. PMID:24669294 SCF1 (M-CSF) is assosiated with M2 phenotype of macrophages References_end </body> </html> </notes> <label text="CSF1"/> <bbox w="80.0" h="40.0" x="238.5" y="2390.0"/> </glyph> <glyph class="macromolecule multimer" id="s546_sa1993" 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: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="141.5" h="141.5" x="11669.25" y="4179.25"/> <glyph class="unit of information" id="_2537bfee-bbfb-4b3a-b280-488e386fd05d"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="11730.0" y="4174.25"/> </glyph> <glyph class="unit of information" id="_83601046-5568-4689-8d93-07e14308ab57"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="11715.0" y="4174.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s548_sa901" 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: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="1530.0" y="1520.0"/> <glyph class="unit of information" id="_df7eb30e-6614-438a-9a51-f3380df05098"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1547.5" y="1515.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s556_sa2385" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MRC2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE CASCADE:TGFB Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="MRC2"/> <bbox w="80.0" h="40.0" x="2098.75" y="645.625"/> </glyph> <glyph class="macromolecule" id="s605_sa2296" 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:EGLN2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:21765015 Hydroxylated by EGLN2 (PHD3) HIF2A is then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. References_end </body> </html> </notes> <label text="EGLN3"/> <bbox w="80.0" h="40.0" x="3440.625" y="4622.75"/> </glyph> <glyph class="macromolecule" id="s606_sa2306" 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:EGLN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:21765015 The protein encoded by this gene catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. This protein functions as a cellular oxygen sensor, and under normal oxygen concentration, modification by prolyl hydroxylation is a key regulatory event that targets HIF subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylation complex. References_end </body> </html> </notes> <label text="EGLN1"/> <bbox w="80.0" h="40.0" x="3855.625" y="4637.5"/> </glyph> <glyph class="macromolecule" id="s641_sa1502" 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:IRAK1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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. References_end </body> </html> </notes> <label text="IRAK1"/> <bbox w="80.0" h="40.0" x="10985.0" y="2840.0"/> <glyph class="state variable" id="_d083c7e9-cf02-473f-a34d-588386469934"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10980.0" y="2855.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s652_sa1526" 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: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="11485.0" y="3070.0"/> </glyph> <glyph class="macromolecule" id="s653_sa1527" 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: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="11365.0" y="3070.0"/> </glyph> <glyph class="macromolecule" id="s667_sa1503" 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: 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="15845.0" y="1540.0"/> </glyph> <glyph class="macromolecule" id="s668_sa1525" 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: 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="15855.0" y="1460.0"/> </glyph> <glyph class="macromolecule" id="s669_sa1499" 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:IRAK1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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. References_end </body> </html> </notes> <label text="IRAK1"/> <bbox w="80.0" h="40.0" x="10825.0" y="2840.0"/> <glyph class="state variable" id="_58a53a0f-bfed-455e-beb5-f0684e507a70"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10817.5" y="2855.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s683_sa2672"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="80.0" h="40.0" x="4860.0" y="1180.0"/> </glyph> <glyph class="macromolecule" id="s686_sa1505" 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: 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="15190.0" y="1380.0"/> <glyph class="unit of information" id="_6ff3304b-ac81-423c-bfe6-19ce54710057"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15207.5" y="1375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s687_sa1528" 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: HUGO:TLR2 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, PMID:11672593, PMID:12032143, PMID:12811837. INFG upregulates mRNA level and surface expression of TLR4 and TLR2. References_end </body> </html> </notes> <label text="TLR2"/> <bbox w="80.0" h="50.0" x="15040.0" y="1410.0"/> <glyph class="unit of information" id="_a5b169bb-e1c8-4a28-8c04-3b4de7826bd5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15057.5" y="1405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s688_sa1529" 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: 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="15040.0" y="1320.0"/> <glyph class="unit of information" id="_d803352e-b16e-4a49-b570-125ff1052a01"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15057.5" y="1315.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s690_sa1507" 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: 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="15190.0" y="1445.0"/> </glyph> <glyph class="macromolecule" id="s691_sa1508" 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: 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="15190.0" y="1495.0"/> </glyph> <glyph class="macromolecule" id="s697_sa1395" 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:IL1RN Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL10 CASCADE:IL4 CASCADE:TLR2_4 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses. PMID:10952726 HMGB1 induces expression of proinflammotory cytokines IL1A,IL1B,IL1RA,IL6, IL8, MIP1A,MIP1B References_end </body> </html> </notes> <label text="IL1RN"/> <bbox w="80.0" h="40.0" x="3322.5" y="5457.5"/> </glyph> <glyph class="macromolecule" id="s703_sa1509" 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>Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 Maps_Modules_end ----- content merged by Celldesigner to SBGN-ML translation ------ 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="15190.0" y="1595.0"/> </glyph> <glyph class="macromolecule multimer" id="s711_sa1545"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:IL4 CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 CASCADE:KLRG1 CASCADE:KIR2DL2 CASCADE:KIR2DL4 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:Fc_gamma_RIII CASCADE:IL18 CASCADE:IL2 Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID:16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 expression. NK cells stimuletad by IL4 have NK2 subtype PMID:21149606 Nkp80 signaling induces marked IFNG production PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:11489965, PMID:15778339 KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells 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 References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="86.0" h="46.0" x="16597.0" y="2867.0"/> <glyph class="unit of information" id="_6e350539-275a-4838-9365-cf6ced99b927"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="16630.0" y="2862.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s718_sa1511" 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:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <bbox w="80.0" h="40.0" x="14515.0" y="3100.0"/> <glyph class="state variable" id="_6e8bf4c9-949b-4bd9-9b5e-a6bdfe8d0a08"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="14584.806" y="3135.0"/> </glyph> <glyph class="state variable" id="_3df676d6-bcec-4157-a6f9-fb5f172f5f91"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14507.5" y="3113.7124"/> </glyph> </glyph> <glyph class="macromolecule" id="s719_sa1512" 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:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <bbox w="80.0" h="40.0" x="14685.0" y="3100.0"/> <glyph class="state variable" id="_c8b9ff54-688b-4cc8-b28f-6afe9e3db636"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="14754.806" y="3135.0"/> </glyph> <glyph class="state variable" id="_39d1707e-9954-4bb8-adab-0f732805575c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14680.0" y="3113.7124"/> </glyph> </glyph> <glyph class="macromolecule" id="s720_sa1513" 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: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="14415.0" y="3150.0"/> </glyph> <glyph class="macromolecule" id="s722_sa1514" 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:PTPN2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19833085, PMID:15699106, PMID:12138178 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. PMID:19833085 Probably, acetylation of STAT1 on lysine residues 410 and 413 in the nucleus results in enhanced interaction with TCP45 (PTPN2) and increased dephosphorylation References_end </body> </html> </notes> <label text="PTPN2"/> <bbox w="80.0" h="40.0" x="14555.0" y="3030.0"/> </glyph> <glyph class="macromolecule" id="s729_sa1517" 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:SOCS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: SOCS-1 decreases IFNG signaling via inhiviting the catalytic activity of JAKs. PMID:12811837 SOCS-1 overexpression resulted in a nearly complete loss of IFNG responsiveness in macrophages. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:12193701 INFG upregulates TNFR1 and RIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <label text="SOCS1"/> <bbox w="100.0" h="70.0" x="15005.0" y="2385.0"/> </glyph> <glyph class="macromolecule" id="s740_sa2581" 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:GSK3B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. GSK3B is activated downstrean of IFNG via PI3K pathway. PMID:16007092 GSK3B inhibits CREB1 interaction with CBP and inhibits CREB1 dependent IL10 expression. CREB1/CBP complex formation prevents binding CBP to RELA (p65) and inhibits downstream NF-kB signaling. References_end </body> </html> </notes> <label text="GSK3β*"/> <bbox w="80.0" h="40.0" x="9590.0" y="4060.0"/> <glyph class="state variable" id="_e709fed0-86b5-4a27-82b5-71387c28379c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9585.0" y="4075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s742_sa2108" 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>References_begin: PMID:16713974 TLR2 activates (induses phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAPK8 HGNC:6881 ENTREZ:5599 UNIPROT:P45983 GENECARDS:MAPK8 HUGO:MAPK9 HGNC:6886 ENTREZ:5601 UNIPROT:P45984 GENECARDS:MAPK9 HUGO:MAPK10 HGNC:6872 ENTREZ:5602 UNIPROT:P53779 GENECARDS:MAPK10 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:59293 KEGG:5599 ATLASONC:JNK1ID196 WIKI:MAPK8 mitogen-activated protein kinase 9 REACTOME:59295 KEGG:5601 ATLASONC:JNK2ID426 WIKI:MAPK9 mitogen-activated protein kinase 10 REACTOME:59297 KEGG:5602 ATLASONC:JNK3ID427 WIKI:MAPK10 MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:TLR2_4 CASCADE:IL18 CASCADE:NKG2D CASCADE:TNF CASCADE:IFNG PMID:18287025 JNK is localized to the centrosome. JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. Inhibition of JNK activity by D-JNK-1, SP600125, Or JNK-1-specific siRNA blocked polarization of granzyme B, PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. PMID:17379190 MEK4/JNK/AP-1 path way is active in mactophages downstream of TLR4, and induces iNOS expression. PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:17073741 DUSP1 inhibits p38 and JNK pathways of innate innunity downstream of IL10. PMID:9743347 IL13 inhibits JNK phosphorylation and AP1 activation (provavly via dusp1) 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:23508573 HMGB1 induces activation (phosphorylation) of ERK, JNK and p38 via TLR4 in macrophages. 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. 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 References_end </body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="10585.0" y="3620.0"/> <glyph class="state variable" id="_d25e604d-968e-4e3d-a07b-cdb139fa94ae"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10580.0" y="3635.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s754_sa2582" 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:GSK3B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. GSK3B is activated downstrean of IFNG via PI3K pathway. PMID:16007092 GSK3B inhibits CREB1 interaction with CBP and inhibits CREB1 dependent IL10 expression. CREB1/CBP complex formation prevents binding CBP to RELA (p65) and inhibits downstream NF-kB signaling. References_end </body> </html> </notes> <label text="GSK3β*"/> <bbox w="80.0" h="40.0" x="9590.0" y="3980.0"/> <glyph class="state variable" id="_ee45a6ab-c7b8-4ffd-854e-a34237c3d247"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9582.5" y="3995.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s757_sa2580" 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:GSK3A HUGO:GSK3B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. References_end </body> </html> </notes> <label text="GSK3*"/> <bbox w="80.0" h="40.0" x="9530.0" y="4160.0"/> </glyph> <glyph class="macromolecule" id="s758_sa503" 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:VAV1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:KIR2DL1 CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D CASCADE:LFA1 CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:12740575, PMID:16887996 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:20189481, PMID:22786724 NKG2D, DNAM1, 2B4 signalings induce PLCG2 phosphorylation and Ca2+ release via LCP2/VAV1 pathway. CBL inhibited Vav1-dependent activation signals in NK. Vav-deficient NK cells exhibited nearly abolished conjugate formation and cytotoxicity toward target cells. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1 (probably via LCP2),CBL. This phosphorylation is dependent on SAP adn FYN. PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Vav1 phosphorylation is induced by beta2 integrin (CD18)engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. PMID:8189062 Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:19909365 LAT1 binds to multiple signaling proteins including GEFs such as Vav1 and SOS, which regulate the activity of small GTPases in Mast cells References_end </body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="7320.0" y="2925.0"/> <glyph class="state variable" id="_459ee31f-ede7-43ab-ae93-fcca699494a8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7315.0" y="2940.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s759_sa467" 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:LCP2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MAST_CELL CASCADE:2B4 CASCADE:INTEGRIN_A4B1 CASCADE:LFA1 PMID:24343663, PMID:22786724, PMID:20189481 Selective phosphorylation of tyrosine 113 or tyrosine 128 in LCP2 (SLP-76) enabled binding of SLP-76 to Vav1 and induces downstream of NKG2D and 2B4 receptors and DNAM1. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs. PMID:19909365 One of the main components of LAT1-scaffolded signaling complexes formed after FcεRI stimulation of Mast Cells is the adapter protein SLP-76 References_end </body> </html> </notes> <label text="LCP2"/> <bbox w="80.0" h="40.0" x="12195.0" y="2500.0"/> <glyph class="state variable" id="_381d434d-065e-4a85-91aa-8ff9c4226773"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12190.0" y="2515.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s761_sa2697" 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: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="1670.0" y="6180.0"/> <glyph class="unit of information" id="_0089a380-4f28-45b1-bb19-96d2efad06be"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1685.0" y="6175.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s769_sa770" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KMT2E 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:23958951 NKp44L is a novel isoform of the mixed-lineage leukemia-5 protein, a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. References_end </body> </html> </notes> <label text="NKp44L*"/> <bbox w="80.0" h="40.0" x="11590.0" y="960.0"/> <glyph class="unit of information" id="_aaa4912c-2205-44d1-bfc8-a14191841e86"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="11605.0" y="955.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s772_sa1000" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 CASCADE:IL15 CASCADE:IL21 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IFNAB Maps_Modules_end References_begin: ‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:15573129 Constitutively active STAT3 inhibited the functional maturation of DCs in vitro. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation. 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter Stat3 activity is required for tumor factor–induced migration of ECs. PMID:14670306, PMID:16418395 FLT3 sidnaling in Dcs acts via STAT3 PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="124.5" h="80.0" x="1957.75" y="4405.0"/> <glyph class="unit of information" id="_18e2e923-1075-4b6c-a740-94640923a4e5"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2010.0" y="4400.0"/> </glyph> <glyph class="state variable" id="_04d8ad39-ffc1-4b1e-a801-8a54b8bc1c2c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1950.25" y="4439.9365"/> </glyph> </glyph> <glyph class="macromolecule" id="s775_sa1808" 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:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:IL15 MAP:DENDRITIC_CELL CASCADE:IFNAB PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end </body> </html> </notes> <label text="MICA"/> <bbox w="80.0" h="40.0" x="13743.75" y="5395.0"/> </glyph> <glyph class="macromolecule" id="s776_sa1814" 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:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end </body> </html> </notes> <label text="MICB"/> <bbox w="80.0" h="40.0" x="13863.75" y="5395.0"/> </glyph> <glyph class="macromolecule" id="s778_sa1546" 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: 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="16225.0" y="3095.0"/> <glyph class="unit of information" id="_3ac3cc15-52ac-4a95-b5c2-a8e6a191062e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16242.5" y="3090.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s779_sa1571" 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: 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="16205.0" y="3365.0"/> <glyph class="unit of information" id="_57bfa325-c9cf-4d21-a790-61039d944bd1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16222.5" y="3360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s781_sa1550" 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: 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="16140.0" y="3280.0"/> <glyph class="state variable" id="_5ed97bfb-34ca-44d4-b7b8-791d1444ebba"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16215.0" y="3293.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s787_sa502" 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:VAV1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:KIR2DL1 CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D CASCADE:LFA1 CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:12740575, PMID:16887996 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:20189481, PMID:22786724 NKG2D, DNAM1, 2B4 signalings induce PLCG2 phosphorylation and Ca2+ release via LCP2/VAV1 pathway. CBL inhibited Vav1-dependent activation signals in NK. Vav-deficient NK cells exhibited nearly abolished conjugate formation and cytotoxicity toward target cells. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1 (probably via LCP2),CBL. This phosphorylation is dependent on SAP adn FYN. PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Vav1 phosphorylation is induced by beta2 integrin (CD18)engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. PMID:8189062 Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:19909365 LAT1 binds to multiple signaling proteins including GEFs such as Vav1 and SOS, which regulate the activity of small GTPases in Mast cells References_end </body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="7322.5" y="3130.0"/> <glyph class="state variable" id="_65c55e13-fbd7-4805-9307-c2352f85d10d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7315.0" y="3145.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s789_sa466" 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:LCP2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MAST_CELL CASCADE:2B4 CASCADE:INTEGRIN_A4B1 CASCADE:LFA1 PMID:24343663, PMID:22786724, PMID:20189481 Selective phosphorylation of tyrosine 113 or tyrosine 128 in LCP2 (SLP-76) enabled binding of SLP-76 to Vav1 and induces downstream of NKG2D and 2B4 receptors and DNAM1. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs. PMID:19909365 One of the main components of LAT1-scaffolded signaling complexes formed after FcεRI stimulation of Mast Cells is the adapter protein SLP-76 References_end </body> </html> </notes> <label text="LCP2"/> <bbox w="80.0" h="40.0" x="12195.0" y="2410.0"/> <glyph class="state variable" id="_c01a5a2e-2659-4829-aab2-ee834339f9b2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12187.5" y="2425.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s793_sa501" 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:PLCG2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:IFNAB MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL 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:12740575, PMID:15972651, PMID:20189481 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release via VAV1. The calcium signal generated by PLCG is required for NKG2D-initiated killing. PMID:20189481, PMID:22786724, PMID:20189481 DNAM1 signaling stimulate Ca2+ mobilization provably via VAV1/PLC-GAMMA2 pathway in NK cells, PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:11169415, PMID:10072481, PMID:8649391, PMID:1281218 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:19909365 The phosphorylation of LAT1 together with the generation of PIP3 in the lipid raft environment recruits proteins such as PLC-γ1 and PLC-γ2 References_end </body> </html> </notes> <label text="PLCG2"/> <bbox w="80.0" h="40.0" x="5600.0" y="2890.0"/> <glyph class="state variable" id="_cdc5517b-968f-419b-b12c-d0ca6c114518"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5595.0" y="2905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s794_sa528" 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:PLCG2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:IFNAB MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL 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:12740575, PMID:15972651, PMID:20189481 NKG2D signaling inducese PLCG2 phosphorylation and Ca2+ release via VAV1. The calcium signal generated by PLCG is required for NKG2D-initiated killing. PMID:20189481, PMID:22786724, PMID:20189481 DNAM1 signaling stimulate Ca2+ mobilization provably via VAV1/PLC-GAMMA2 pathway in NK cells, PMID:22683124 PLCG2-deficient NK cells displayed a partial reduction of conjugate formationwith target tumor cells probably via regulation of Ca2+ fluxes, because a chelator of intracellular Ca2+ also provokes a partial reduction of conjugate formation. PMID:11169415, PMID:10072481, PMID:8649391, PMID:1281218 Tyrosine phosphorylation of LAT led to the recruitment of intracytoplasmic signaling molecules including phospholipase Cgamma and Grb2 and activation of phosphatidylinositol pathway in NK cells. PMID:2536067, PMID:1281218 Ligation of Fc gamma RIII alpha (CD16) induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells and stimulates expression of many cytokines via Ca('2+) -depend mechanism. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:19909365 The phosphorylation of LAT1 together with the generation of PIP3 in the lipid raft environment recruits proteins such as PLC-γ1 and PLC-γ2 References_end </body> </html> </notes> <label text="PLCG2"/> <bbox w="80.0" h="40.0" x="5600.0" y="3070.0"/> <glyph class="state variable" id="_bdf10743-3701-4e3c-a5ef-fd94b2462072"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5592.5" y="3085.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s796_sa401" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RAET1E 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:12732206 RAET1E (ULBP4) is a ligand of NKG2D. References_end </body> </html> </notes> <label text="RAET1E"/> <bbox w="80.0" h="40.0" x="12830.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s801_sa737" 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: 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="11525.0" y="1695.0"/> <glyph class="unit of information" id="_1b686a8a-039b-4d90-97d7-8bc48beb07db"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11542.5" y="1690.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s851_sa900" 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: HUGO:TGFBR1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end </body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="1520.0" y="1365.0"/> <glyph class="unit of information" id="_c8dbef05-6bde-4a21-b7bb-22b99156847f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1537.5" y="1360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s857_sa328" 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:CFL1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. LIMK1 phosphorylates CLF1 (cofilin) downstream of killer cell-activating receptors via RHOA/ROCK1 pathway. Inhibition of the p160ROCK/LIMK1 pathway results in decreased actin polymerization at the effector/target interface. References_end </body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="9738.125" y="6735.0"/> <glyph class="state variable" id="_ab87068f-4712-4cc1-b444-4d86c77702d3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9733.125" y="6750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s863_sa330" 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:CFL1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. LIMK1 phosphorylates CLF1 (cofilin) downstream of killer cell-activating receptors via RHOA/ROCK1 pathway. Inhibition of the p160ROCK/LIMK1 pathway results in decreased actin polymerization at the effector/target interface. References_end </body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="9738.125" y="6555.0"/> <glyph class="state variable" id="_cf59af23-927c-4149-b0c1-24e61fa95ef5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9730.625" y="6570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s865_sa224" 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: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="9780.0" y="6040.0"/> <glyph class="state variable" id="_6244b83f-66a7-412d-a8f9-708f9cee4b1c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9775.0" y="6055.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s867_sa202" 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: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="9320.0" y="5600.0"/> </glyph> <glyph class="macromolecule" id="s870_sa2412" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MACROPHAGE Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MIF PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="FCER2"/> <bbox w="80.0" h="50.0" x="2288.75" y="645.625"/> <glyph class="unit of information" id="_45f7f187-354b-4e3d-bd0d-04e7ad83f81c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2306.25" y="640.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s903_sa212" 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:PRKCQ Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB PMID:25960930 IFNα induces PKC-θ auto-phosphorylation in NK cells via P3K and PLC pathways and improves the degranulation via PKC-θ signaling Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice PMID:19201850 Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression. PRKCQ upregulates granzyme A and B expression in NK cells recruited to the tumor environment. PRKCQ could be activated downstream of IL15 and TLR3 signaling. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. PMID:18784374; PMID:23077238, PMID:17548359 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2. PMID:18784374 PKC-theta–mediated signals activate AP-1 and NFAT1. The capacity of NFAT to bind DNA was reduced in PKC-theta–deﬁcient NK cells. There is a signiﬁcant decrease in AP-1 activation in PKC-theta–deﬁcient NK cells. References_end </body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="6120.0" y="3235.0"/> <glyph class="state variable" id="_da47a2a6-2bd4-41d4-9ca5-16fda28b9191"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6115.0" y="3250.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s908_sa1838" 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:IFNG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:IL4 CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 CASCADE:KLRG1 CASCADE:KIR2DL2 CASCADE:KIR2DL4 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KIR2DS2 CASCADE:KIR3DS1 CASCADE:Fc_gamma_RIII CASCADE:IL18 CASCADE:IL2 Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID:16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 expression. NK cells stimuletad by IL4 have NK2 subtype PMID:21149606 Nkp80 signaling induces marked IFNG production PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:11489965, PMID:15778339 KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells 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 References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="82.5" h="42.5" x="11384.0" y="5373.75"/> </glyph> <glyph class="macromolecule" id="s919_sa324" 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:MYH9 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 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end </body> </html> </notes> <label text="MYH9"/> <bbox w="80.0" h="40.0" x="10450.0" y="6100.0"/> </glyph> <glyph class="macromolecule" id="s924_sa220" 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: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="9930.0" y="5990.0"/> <glyph class="state variable" id="_30071cf2-9116-4d0c-94a3-5db1eaf0b007"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9925.0" y="6004.9683"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s933_sa431" 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: 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="13222.0" y="1392.0"/> <glyph class="unit of information" id="_8d70f749-7e9e-49a6-8f00-9e9f660bf454"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="13255.0" y="1387.0"/> </glyph> <glyph class="state variable" id="_d73c4fdb-1472-4ade-b42d-292527cb3772"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13217.0" y="1415.0"/> </glyph> <glyph class="unit of information" id="_17ad2825-ce28-4468-b680-48309351411e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13242.5" y="1387.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s941_sa547" 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: 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="9042.5" y="1305.0"/> <glyph class="state variable" id="_c7f2430a-ee56-4f70-bd8e-cb9c1bba5760"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9037.5" y="1307.2045"/> </glyph> <glyph class="state variable" id="_9850cd0c-579f-4feb-b7fc-8557bfd89c9c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9035.0" y="1333.554"/> </glyph> <glyph class="unit of information" id="_34667d4d-da9a-4ac6-a3ca-30de56693c9a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9060.0" y="1300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s944_sa546" 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:PRKCA HGNC:9393 ENTREZ:5578 UNIPROT:P17252 GENECARDS:PRKCA HUGO:PRKCB HGNC:9395 ENTREZ:5579 UNIPROT:P05771 GENECARDS:PRKCB HUGO:PRKCE HGNC:9401 ENTREZ:5581 UNIPROT:Q02156 GENECARDS:PRKCE HUGO:PRKCG HGNC:9402 ENTREZ:5582 UNIPROT:P05129 GENECARDS:PRKCG HUGO:PRKCZ HGNC:9412 ENTREZ:5590 UNIPROT:Q05513 GENECARDS:PRKCZ HUGO:PRKCD HGNC:9399 ENTREZ:5580 UNIPROT:Q05655 GENECARDS:PRKCD HUGO:PRKCH HGNC:9403 ENTREZ:5583 UNIPROT:P24723 GENECARDS:PRKCH HUGO:PRKCQ HGNC:9410 ENTREZ:5588 UNIPROT:Q04759 GENECARDS:PRKCQ HUGO:PRKCI HGNC:9404 ENTREZ:5584 UNIPROT:P41743 GENECARDS:PRKCI Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: REACTOME:58197 KEGG:5578 ATLASONC:GC_PRKCA WIKI:PRKCA REACTOME:58199 KEGG:5579 ATLASONC:GC_PRKCB WIKI:PRKCB REACTOME:58203 KEGG:5581 ATLASONC:GC_PRKCE WIKI:PRKCE REACTOME:58205 KEGG:5582 ATLASONC:GC_PRKCG WIKI:PRKCG REACTOME:58219 KEGG:5590 ATLASONC:GC_PRKCZ WIKI:PRKCZ REACTOME:58201 KEGG:5580 ATLASONC:PRKCDID42901ch3p21 WIKI:PRKCD REACTOME:58209 KEGG:5583 ATLASONC:GC_PRKCH WIKI:PRKCH REACTOME:58217 KEGG:5588 ATLASONC:GC_PRKCQ WIKI:PRKCQ REACTOME:58207 KEGG:5584 ATLASONC:PRKCIID41857ch3q26 WIKI:PRKCI MAP:NATURAL_KILLER CASCADE:LFA1 PMID:24343663, PMID:9712030, PMID:10591186 The phosphorylation of the Ser329 of DNAM-1 by protein kinase C (PKC) was shown to be critical for DNAM-1-mediated intracellular signalling and functions References_end </body> </html> </notes> <label text="PKC*"/> <bbox w="80.0" h="40.0" x="9122.5" y="1910.0"/> </glyph> <glyph class="macromolecule" id="s952_sa465" 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: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="7160.0" y="2955.0"/> <glyph class="state variable" id="_1f33a8ad-5594-44cf-b486-b51216b576ee"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7155.0" y="2970.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s961_sa374" 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:TP53 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22754780, PMID:21764762 Wild-type p53, but not mutant p53 interacts with UDLPs promoters and induces UDLP2 and UDLP1 expression in tumor cells and increases tumor immunogenicity. UDLPs activate NKG2D* signaling in NK cells.Induction of wtp53 expression in tumor cells leads to their enhanced recognition by primary NK cells in a NKG2D-dependent manner. PMID:22102694 Activation of p53 by Nutlin3a resulted in upregulation of Mir34a/c expression and decreased ULBP2 expression in several tumor models (but not in the all models). References_end </body> </html> </notes> <label text="p53*"/> <bbox w="80.0" h="40.0" x="12790.0" y="210.0"/> </glyph> <glyph class="macromolecule" id="s975_sa361" 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:ADAM10 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22006996, PMID:18676862 Tumor-Associated MICA Is shed by ADAM10 and ADAM17 proteases. Downstream of HIF1 and hypoxia (ADAM10) References_end </body> </html> </notes> <label text="ADAM10"/> <bbox w="80.0" h="40.0" x="11770.0" y="320.0"/> </glyph> <glyph class="macromolecule" id="s977_sa360" 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:ADAM17 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:18676862 Tumor-Associated MICA Is shed by ADAM10 and ADAM17 proteases. ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cell, and from within the intracellular membranes of the trans-Golgi network. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane-bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. References_end </body> </html> </notes> <label text="ADAM17"/> <bbox w="80.0" h="40.0" x="11900.0" y="320.0"/> </glyph> <glyph class="macromolecule" id="s991_sa1524" 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:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 GENECARDS:HDAC1 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 GENECARDS:HDAC2 HUGO:HDAC3 HGNC:4854 ENTREZ:8841 UNIPROT:O15379 GENECARDS:HDAC3 HUGO:HDAC4 HGNC:14063 ENTREZ:9759 UNIPROT:P56524 GENECARDS:HDAC4 HUGO:HDAC5 HGNC:14068 ENTREZ:10014 UNIPROT:Q9UQL6 GENECARDS:HDAC5 HUGO:HDAC6 HGNC:14064 ENTREZ:10013 UNIPROT:Q9UBN7 GENECARDS:HDAC6 HUGO:HDAC7 HGNC:14067 ENTREZ:51564 UNIPROT:Q8WUI4 GENECARDS:HDAC7 HUGO:HDAC8 HGNC:13315 ENTREZ:55869 UNIPROT:Q9BY41 GENECARDS:HDAC8 HUGO:HDAC10 HGNC:18128 ENTREZ:83933 UNIPROT:Q969S8 GENECARDS:HDAC10 HUGO:HDAC11 HGNC:19086 ENTREZ:79885 UNIPROT:Q96DB2 GENECARDS:HDAC11 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: histone deacetylase 1 REACTOME:56408 KEGG:3065 ATLASONC:GC_HDAC1 WIKI:HDAC1 histone deacetylase 2 REACTOME:56410 KEGG:3066 ATLASONC:HDAC2ID40803ch6q22 WIKI:HDAC2 histone deacetylase 3 REACTOME:401336 KEGG:8841 ATLASONC:HDAC3ID40804ch5q31 WIKI:HDAC3 histone deacetylase 4 REACTOME:56414 KEGG:9759 ATLASONC:GC_HDAC4 WIKI:HDAC4 histone deacetylase 5 REACTOME:415622 KEGG:10014 ATLASONC:GC_HDAC5 WIKI:HDAC5 histone deacetylase 6 REACTOME:56418 KEGG:10013 ATLASONC:GC_HDAC6 WIKI:HDAC6 histone deacetylase 7 REACTOME:412089 KEGG:9734 ATLASONC:GC_HDAC7 WIKI:HDAC7 histone deacetylase 8 REACTOME:148335 KEGG:55869 ATLASONC:GC_HDAC8 WIKI:HDAC8 histone deacetylase 10 0 0 REACTOME:412605 KEGG:83933 ATLASONC:GC_HDAC10 WIKI:HDAC10 histone deacetylase 11 1 1 REACTOME:56406 KEGG:79885 ATLASONC:GC_HDAC11 WIKI:HDAC11 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:23801635 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. References_end </body> </html> </notes> <label text="HDAC*"/> <bbox w="80.0" h="40.0" x="14620.0" y="3160.0"/> </glyph> <glyph class="macromolecule" id="s995_sa1055"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:LGALS3 CASCADE:TGFB CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. 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 CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="230.0" y="3690.0"/> </glyph> <glyph class="macromolecule" id="s1004_sa1162" 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: HUGO:AGER Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function.. References_end </body> </html> </notes> <label text="RAGE*"/> <bbox w="80.0" h="50.0" x="4730.0" y="1530.0"/> <glyph class="unit of information" id="_699b7250-cd09-4a4a-b386-d1f241df2429"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4747.5" y="1525.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1008_sa1175" 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:S100A8 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. References_end </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="4940.0" y="2125.0"/> </glyph> <glyph class="macromolecule" id="s1009_sa1176" 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:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:S100A PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function in tumor. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. References_end </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="4840.0" y="2125.0"/> </glyph> <glyph class="macromolecule" id="s1011_sa492" 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:VAV1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:MAST_CELL CASCADE:KIR2DL1 CASCADE:SLAMF7 CASCADE:2B4 CASCADE:NKG2D CASCADE:LFA1 CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:12740575, PMID:16887996 VAV1 activates RHOA and RAC1 downstream of NKG2D. PMID:11698448 RHOA signaling in NK cells provides development of natural cytotoxicity against tumor cells. PMID:16887996 Vav1 is required for actin accumulation at the NK-target contact site in response to NKG2D-DAP10 signals, probably via RHOA pathway. Vav1 induces MTOC polarization at the NK-target contact site in response to NKG2D-DAP10 signals. PMID:20189481, PMID:22786724 NKG2D, DNAM1, 2B4 signalings induce PLCG2 phosphorylation and Ca2+ release via LCP2/VAV1 pathway. CBL inhibited Vav1-dependent activation signals in NK. Vav-deficient NK cells exhibited nearly abolished conjugate formation and cytotoxicity toward target cells. PMID:15169881 2B4 signaling induces phosphorylation of SHIP1,VAV1 (probably via LCP2),CBL. This phosphorylation is dependent on SAP adn FYN. PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, provavli via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:12885870, PMID:22786724 LFA1 signaling induces tyrosine phosphorylation of Vav1 via Src-family kinases but not Syk or ZAP70. Probably it acts via DNAM1 which can induce selective phosphorylation of SLP-76. Vav1 phosphorylation is induced by beta2 integrin (CD18)engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. PMID:8189062 Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein. PMID:8226994 Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP PMID:19909365 LAT1 binds to multiple signaling proteins including GEFs such as Vav1 and SOS, which regulate the activity of small GTPases in Mast cells References_end </body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="7320.0" y="2805.0"/> <glyph class="state variable" id="_89e59899-51ac-45ef-97ee-0ac9cdde04f9"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="7310.0" y="2820.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1014_sa493" 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: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="7160.0" y="2865.0"/> <glyph class="state variable" id="_cf85eb9e-5b2b-40e4-a050-c1552d702a9a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7152.5" y="2880.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1016_sa430" 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: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="9445.0" y="2885.0"/> <glyph class="state variable" id="_45ac53e2-0bac-4e82-b20c-9291ac418f54"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9440.0" y="2905.0"/> </glyph> <glyph class="unit of information" id="_e7dbf896-ffa9-4343-b7cc-b3bf00d85103"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9462.5" y="2880.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1017_sa393" 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: 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="1600.0"/> </glyph> <glyph class="macromolecule" id="s1018_sa2127" 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:CEBPB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MDSC CASCADE:GSF3 PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. References_end </body> </html> </notes> <label text="CEBPB"/> <bbox w="80.0" h="40.0" x="4820.0" y="4516.875"/> <glyph class="state variable" id="_78878a94-1710-4d90-926f-72671649461a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4815.0" y="4531.8433"/> </glyph> </glyph> <glyph class="macromolecule" id="s1021_sa464" 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: 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="13485.0" y="1710.0"/> </glyph> <glyph class="macromolecule" id="s1031_sa833" 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: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="2697.5" y="3050.0"/> <glyph class="state variable" id="_139d23c6-7838-45c1-8e91-bb3347a3d84d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2692.5" y="3065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1045_sa744" 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: 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="11985.0" y="1785.0"/> <glyph class="state variable" id="_030c4e66-56c6-4fe2-9237-9b43b6433509"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11980.0" y="1805.0"/> </glyph> <glyph class="unit of information" id="_c898cc92-edac-47ac-aa44-d469735e7cf0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12002.5" y="1780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1052_sa1096" 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: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="5813.5938" y="6445.9375"/> </glyph> <glyph class="macromolecule" id="s1061_sa2128" 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:CEBPA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MDSC PMID:20581311, PMID:11340171 CEBPA downregulates MYC gene expression and provides granulocytic differentiation of myeloid cells.. References_end </body> </html> </notes> <label text="CEBPA"/> <bbox w="80.0" h="40.0" x="4970.0" y="4616.875"/> </glyph> <glyph class="macromolecule" id="s1066_sa1060" 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: HUGO:CSF3R Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:20237318 GSF3R is a receptor for GSF3 in myeloid cells. The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. References_end </body> </html> </notes> <label text="CSF3R"/> <bbox w="80.0" h="50.0" x="725.0" y="2495.0"/> <glyph class="unit of information" id="_4edc3e2c-4619-4db7-9701-a24377e9ef8b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="742.5" y="2490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1077_sa2085" 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:IRF8 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:GSF3 CASCADE:GSF2 CASCADE:IFNG CASCADE:TLR2_4 PMID:24091328 (a) Irf8-deficient mice generated myeloid populations highly homologous to tumor-induced MDSCs with respect to phenotype, function, and gene expression profiles; (b) IRF-8 overexpression in mice attenuated MDSC accumulation and enhanced immunotherapeutic efficacy; (c) the MDSC-inducing factors G-CSF and GM-CSF facilitated IRF-8 downregulation via STAT3- and STAT5-dependent pathways; and (d) IRF-8 levels in MDSCs of breast cancer patients declined with increasing MDSC frequency, implicating IRF-8 as a negative regulator in human MDSC biology. IRF-8 levels are depressed in MDSCs of breast cancer patients. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. PMID:10734131 PU.1 (SPI1) together with IRF8 relulates TLR4 expression in myeloid cells References_end </body> </html> </notes> <label text="IRF8"/> <bbox w="80.0" h="40.0" x="10150.0" y="4626.5"/> </glyph> <glyph class="macromolecule" id="s1084_sa427" 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: 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="10635.0" y="1835.0"/> <glyph class="unit of information" id="_629e5e88-91b5-4316-99ba-6f641522c7be"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10652.5" y="1830.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1085_sa409" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="10895.0" y="1345.0"/> <glyph class="state variable" id="_3d2cc042-6dbf-46ac-86be-38af2c229df3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10890.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_96361311-2ec1-48b6-9ebe-e1e7666123e8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10912.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1085_sa2239" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="10137.5" y="1385.0"/> <glyph class="state variable" id="_c746cadb-538f-4ddb-ad1e-4313b567a2ea"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10132.5" y="1405.0"/> </glyph> <glyph class="unit of information" id="_eb8ca228-7fb8-4f7d-af3a-9ee92f3c5ff3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10155.0" y="1380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1085_sa2883" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="3760.0" y="1375.0"/> <glyph class="state variable" id="_f542be41-4125-4e58-ac4a-feb242a6131b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3755.0" y="1395.0"/> </glyph> <glyph class="unit of information" id="_fe8116c9-c80d-42c2-bd2c-2b34a2fcae85"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3777.5" y="1370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1090_sa1161" 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> 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="4880.0" y="1590.0"/> <glyph class="unit of information" id="_9ba04ffd-827d-493c-8cca-aef38e5b232a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4897.5" y="1585.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1113_sa490" 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:AKT1 HUGO:AKT2 HUGO:AKT3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:NEUTROPHIL CASCADE:TGFB CASCADE:LGALS3 CASCADE:IL4 CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNG PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. 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 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. 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:21826665 TLR4/PI3K /AKT signaling in TAN promotes motility of cancer cells References_end </body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="8800.0" y="3789.0"/> <glyph class="state variable" id="_f1690f9d-3990-402d-be97-024b852030ca"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8795.0" y="3804.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1114_sa489" 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: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="8720.0" y="3610.0"/> </glyph> <glyph class="macromolecule" id="s1118_sa526" 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:AKT1 HUGO:AKT2 HUGO:AKT3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:NEUTROPHIL CASCADE:TGFB CASCADE:LGALS3 CASCADE:IL4 CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNG PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. 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 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). PMID:24795729 IL15 induces IFNG production via PI3K/AKT/MTOR pathway. PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. Treatment with PI3K inhibitor abrogated the priming effect. Such inhibition was also observed with blocking mTOR and AKT, downstream signaling components of PI3K pathway, suggesting that PI3K–AKT–mTOR pathway is critical for optimal responses of “primed” NK cells to cytokine stimulations. PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway. 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:21826665 TLR4/PI3K /AKT signaling in TAN promotes motility of cancer cells References_end </body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="8970.0" y="3790.0"/> <glyph class="state variable" id="_72cfbe50-2fb6-4b19-a207-c6403ab0db1c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8962.5" y="3805.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1126_sa1919"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="16600.0" y="3710.0"/> </glyph> <glyph class="macromolecule" id="s1127_sa1929" 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: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 CASCADE:IL2 CASCADE:IL15 PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. 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="STAT4"/> <bbox w="80.0" h="40.0" x="15200.0" y="3967.5"/> <glyph class="state variable" id="_256848fd-4fe0-4e6e-9af7-01a9513bb3e2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15275.0" y="3978.885"/> </glyph> <glyph class="state variable" id="_136c0093-6967-410c-8128-2cc4814542c3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15192.5" y="3982.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1128_sa1379" 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:FGF2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. PMID:19508171 FGF drives tumor growth PMID:11874475 Mast cells express end secrete FGF2 References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="80.0" h="40.0" x="3940.0" y="6720.0"/> </glyph> <glyph class="macromolecule" id="s1136_sa463" 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:GAB2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MAST_CELL MAP:NATURAL_KILLER PMID:16212621, PMID:10982827 Phosphorylation of Gab2 was enhanced by both IL-2 and IL-15 in T cells. IL-2- and IL-15-induced Gab2-PI3K association and downstream AKT activation in T cells and B cells. PMID:10849428 IL-2 but not IL-4, IL-12, or IFN-α/β, was able to induce the phosphorylation of Gab2 in NK cells and induces its association with PI3K (p85). JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. PMID:19909365 GAB2 lthough it has been long recognized that PI3K signaling is important for the regulation of FcεRI-mediated activation of MCs (161–163), the molecular link between FcεRI and activation of PI3K References_end </body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="9200.0" y="3155.0"/> <glyph class="state variable" id="_00a3d4c4-e989-463b-9f46-70ae75912826"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9195.0" y="3170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1137_sa488" 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:GAB2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MAST_CELL MAP:NATURAL_KILLER PMID:16212621, PMID:10982827 Phosphorylation of Gab2 was enhanced by both IL-2 and IL-15 in T cells. IL-2- and IL-15-induced Gab2-PI3K association and downstream AKT activation in T cells and B cells. PMID:10849428 IL-2 but not IL-4, IL-12, or IFN-α/β, was able to induce the phosphorylation of Gab2 in NK cells and induces its association with PI3K (p85). JAK3 probably plays a pivotal role for in IL-2-dependent Gab2 phosphorylation. PMID:19909365 GAB2 lthough it has been long recognized that PI3K signaling is important for the regulation of FcεRI-mediated activation of MCs (161–163), the molecular link between FcεRI and activation of PI3K References_end </body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="9200.0" y="3265.0"/> <glyph class="state variable" id="_89f5570e-ea0e-489f-8e65-a62f605962bd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9192.5" y="3280.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1149_sa1670"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNA1 HUGO:IFNA2 HUGO:IFNA4 HUGO:IFNA5 HUGO:IFNA6 HUGO:IFNA7 HUGO:IFNA8 HUGO:IFNA10 HUGO:IFNA13 HUGO:IFNA14 HUGO:IFNA16 HUGO:IFNA17 HUGO:IFNA21 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 MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IFNAB PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. PMID:11449378 IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. IFN-α and IL-12 induce tyrosine phosphorylation and DNA binding of Stat4 to IFN-γ promoter GAS element PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. http://www.tandfonline.com/doi/abs/10.4161/21624011.2014.948705#.VJLI5efuK2s IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells. PMID:11207245 IFNA induces IL10 production in Dcs 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="IFNA*"/> <bbox w="80.0" h="40.0" x="16600.0" y="2340.0"/> </glyph> <glyph class="macromolecule" id="s1158_sa1818" 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: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="14775.0" y="4575.0"/> <glyph class="unit of information" id="_4c584044-9944-4ed9-8aff-dbedbe470772"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14792.5" y="4570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1189_sa246" 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> Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL2 PMID:21383498 IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function. References_end </body> </html> </notes> <label text="WASF2"/> <bbox w="80.0" h="40.0" x="9638.125" y="6385.0"/> <glyph class="state variable" id="_90f5bba9-312c-472a-a5b6-3067917935de"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9633.125" y="6400.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1240_sa1928" 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: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 CASCADE:IL2 CASCADE:IL15 PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. 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="STAT4"/> <bbox w="80.0" h="40.0" x="15200.0" y="3847.5"/> <glyph class="state variable" id="_15b06cc0-6606-4bd1-b190-e53530659c5e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15275.0" y="3858.885"/> </glyph> <glyph class="state variable" id="_ce19692a-03b0-4c01-9c5d-d20e4d949af6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15195.0" y="3862.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1241_sa1930" 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: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 CASCADE:IL2 CASCADE:IL15 PMID:10961885 Phosphorylation of tyrosine 693 and serine 721 is required for IL-12-induced STAT4 activation. Expression of the S721A mutant reduced IL-12 induction of the reporter, whereas mutation of serine 723 had no effect on STAT4-mediated transactivation. Mutation of tyrosine 693 completely abolished IL-12–induced STAT4 transcriptional activity. MKK6/p38, but not other MAPKs, enhance STAT4 transcriptional activity via Ser721 phosphorylation downstream of il12. PMID:8700208, PMID:9715265, PMID:11449378, PMID:8683106 IL-12 and IFNA signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:12372421, The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. 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="STAT4"/> <bbox w="80.0" h="40.0" x="15197.5" y="4067.5"/> <glyph class="state variable" id="_e09fdbfe-c207-4460-843c-3ffa3b623358"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15270.0" y="4078.885"/> </glyph> <glyph class="state variable" id="_32b20231-4988-44b1-89ad-56ce909f7cd9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15190.0" y="4082.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1291_sa247" 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:FASLG Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:NKG2A CASCADE:Fc_gamma_RIII CASCADE:2B4 CASCADE:IFNAB CASCADE:IL18 CASCADE:LFA1 PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. PMID:9858524 Mature CD56(+) NK cells mediate TRAIL-dependent and FasL-dependent cytotoxicity of tumor cells. PMID:8892629 IFN-gamma-inducing factor (IL18) up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones PMID:23510023, PMID:23170255 TRAIL, FASL and TNF provides Dendritic cell tumor killing activity. PMID:11823516 Human immature dendritic cells express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or R:Fc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. TRAIL, FASL and TNF provides Dendritic cell tumor killing activity.() References_end </body> </html> </notes> <label text="FASL*"/> <bbox w="80.0" h="40.0" x="7725.0" y="7665.0"/> </glyph> <glyph class="macromolecule" id="s1292_sa234" 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:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:NEUTROPHIL CASCADE:IFNAB CASCADE:IFNG CASCADE:IL12 PMID:9858524 Mature CD56(+) NK cells mediate TRAIL-dependent and FasL-dependent cytotoxicity of tumor cells. PMID:11257133 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. PMID:11823516 Human immature dendritic cells express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or RFc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. PMID:10811870 I IFN induces TRAIL mRNA expression in DCs and enhances apoptosis of target tumor cells. PMID:23510023, PMID:23170255 TRAIL, FASL and TNF provides Dendritic cell tumor killing activity.() PMID:26819959, PMID:25001536 Neutrophils kill tumor cells by TRAIL References_end </body> </html> </notes> <label text="TRAIL*"/> <bbox w="80.0" h="40.0" x="7615.0" y="7665.0"/> </glyph> <glyph class="macromolecule" id="s1295_sa1671"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNB1 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 MAP:NEUTROPHIL CASCADE:IFNAB CASCADE:IL15 PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. PMID: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:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="IFNB*"/> <bbox w="80.0" h="40.0" x="16600.0" y="2510.0"/> </glyph> <glyph class="macromolecule" id="s1305_sa887"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:MIF CASCADE:TNF CASCADE:IFNG CASCADE:IL4 CASCADE:IL13 CASCADE:TLR2_4 PMID:9637476, PMID:10878343 MIF prevented the release of perforin granules by NK cells but not CTLs. Tumor cells produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells. PMID:18490733 MIF inhibits NK cell activity through a transcriptional down-regulation of NKG2D PMID:16283355, PMID:12803886 MIF upregulates expression of TLR4 in macrothages via PU.1 (SPI1) activation PMID:12782713 MIF signal transduction initiated by binding to CD74. PMID:23390297 MIF deficiency or small-molecule inhibition reduces splenic MDSC immune suppression in tumor-bearing mice PMID:8195715 TNF and INFG induce MIF secretion in macrophages, TLR4 signaling induces MIF expression. 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 References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="238.5" y="3495.0"/> </glyph> <glyph class="macromolecule" id="s1308_sa2397" 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> Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: CASCADE:IL18 MAP:NATURAL_KILLER PMID:20876105 NFKBIZ induced by IL18 together with STAT4 induced by IL12 activates IFNG expression in NK cells. STAT4 was not recruited to the Ifng gene regions in Nfkbiz−/− NK cells. NFKBIZ is Required for change in histone 3 lysine 9 acetylation in response to IL-12 and IL-18 in NK Cells. PMID:21224476 NFKBIZ binds to the IFNG promoter in response to IL-12 and IL-18 and encreases promoter activity. NFKBIZ regulates IFNG expression by binding to NF-κB p65/p50. References_end </body> </html> </notes> <label text="NFKBIZ"/> <bbox w="80.0" h="40.0" x="11820.0" y="4865.0"/> </glyph> <glyph class="macromolecule" id="s1312_sa924" 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:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:16713975 TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. 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. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="1880.0" y="2255.0"/> <glyph class="state variable" id="_af7b09ea-a440-4f59-b321-be6346fa8cd8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1875.0" y="2270.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1315_sa2389" 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:ETS1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL2 PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end </body> </html> </notes> <label text="ETS1"/> <bbox w="80.0" h="40.0" x="11535.0" y="4645.0"/> </glyph> <glyph class="macromolecule" id="s1317_sa2395" 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:TBX21 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:Fc_gamma_RIII CASCADE:IL2 CASCADE:IL15 CASCADE:IL18 CASCADE:IL12 CASCADE:IL21 CASCADE:IFNG PMID:10761931, PMID:12055627, PMID:18768831 The pattern of T-bet expression correlates well with the production of IFNG in NK cells. The induction of T-bet expression and secretion of IFNγ in NK cells that produce IFNγ exists only upon treatment with IL-2 and IL-12 and CD16 pathway activation.. T-bet regulates IFNG expression in NK cells, probably via chromatin remodeling. PMID:14614857 T-bet expression was approximately 4-fold reduced in GATA-3 deficient NK cells compared to controls, while Hlx expression was about 10-fold reduced. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. 20675595 Tbet overexpression in Dcs induces their antitumor abilities ; PMID:12802010 T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells (positive feedback) PMID:16410834 T-bet regulates the production of proinflammatory cytokine IL-1α and chemokines macrophage inflammatory protein-1α (MIP-1α) and thymus- and activation-related chemokine (TARC) by DCs. References_end </body> </html> </notes> <label text="TBX21"/> <bbox w="80.0" h="40.0" x="11650.0" y="4865.0"/> </glyph> <glyph class="macromolecule" id="s1318_sa2396" 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> References_begin: PMID:14614857 GATA-3-deficient NK cells produced less IFN-γ compared to control NK cells. T-bet expression was approximately 4-fold reduced in GATA-3° NK cells compared to controls, while Hlx expression was about 10-fold reduced (provavly via T-bet). References_end </body> </html> </notes> <label text="GATA3"/> <bbox w="80.0" h="40.0" x="11765.0" y="4645.0"/> </glyph> <glyph class="macromolecule" id="s1319_sa2399" 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:HLX Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:12055627, PMID:14614857 T-Bet induces HLX in T cells, and probably in NK cells. HLX activates IFNG expression. T-bet expression was approximately 4-fold reduced in GATA-3 deficient NK cells compared to controls, while Hlx expression was about 10-fold reduced References_end </body> </html> </notes> <label text=" HLX"/> <bbox w="80.0" h="40.0" x="11515.0" y="4935.0"/> </glyph> <glyph class="macromolecule" id="s1326_sa923" 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:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:18768831 TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation. PMID:16713975 TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. 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. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="1880.0" y="2325.0"/> <glyph class="state variable" id="_f89d6f06-5cea-4fb7-ad1f-eb5848d8c9b5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1872.5" y="2340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1331_sa921" 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:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="1760.0" y="2315.0"/> </glyph> <glyph class="macromolecule" id="s1343_sa422" 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: 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="12765.0" y="1765.0"/> <glyph class="state variable" id="_ade2bf75-029a-4a2a-8238-00d1948a7076"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12760.0" y="1785.0"/> </glyph> <glyph class="unit of information" id="_89334128-0945-494c-ba22-10d1bdaf79a2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12782.5" y="1760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1358_sa918" 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> Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL12 CASCADE:IL18 PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. 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. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="1640.0" y="2335.0"/> <glyph class="state variable" id="_10932fc8-18cb-47d9-8886-224c985dd80c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1632.5" y="2349.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s1359_sa919" 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> Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL12 CASCADE:IL18 PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. 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. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="1640.0" y="2255.0"/> <glyph class="state variable" id="_bd148705-270d-4839-9467-1f500260c45f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1635.0" y="2269.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s1378_sa425" 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: 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="12875.0" y="1755.0"/> <glyph class="unit of information" id="_a59d3663-78f3-4d68-9a29-fac29b061a72"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12892.5" y="1750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1385_sa446" 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: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="6890.0" y="4060.0"/> <glyph class="state variable" id="_ce6e9d68-c2e1-445e-9cab-3a8ad11a35c8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6882.5" y="4075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1387_sa445" 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: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="7240.0" y="4050.0"/> </glyph> <glyph class="macromolecule" id="s1390_sa443" 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: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="7020.0" y="4050.0"/> <glyph class="state variable" id="_00140674-1a2d-4886-9e68-1cd5fc313251"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7012.5" y="4065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1403_sa544" 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: 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="9032.5" y="1605.0"/> <glyph class="unit of information" id="_eade2417-b20e-4e8b-8a6f-953d84b039ff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9050.0" y="1600.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1406_sa459" 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: HUGO:ITGA4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end </body> </html> </notes> <label text="ITGA4"/> <bbox w="80.0" h="50.0" x="8497.5" y="1505.0"/> <glyph class="unit of information" id="_2ccc521a-a837-4eaa-90a7-31993c57d8cb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8515.0" y="1500.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1419_sa482" 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: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="8235.0" y="4495.0"/> </glyph> <glyph class="macromolecule" id="s1420_sa486" 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: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="8340.0" y="4500.0"/> <glyph class="state variable" id="_3b403c3d-a821-419e-a390-47e16ccba6b9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8335.0" y="4515.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1454_sa442" 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:LCK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL3 CASCADE:NKP80 CASCADE:NKG2D CASCADE:KNP44 CASCADE:NKP30 CASCADE:NKP46 CASCADE:Fc_gamma_RIII MAP:NATURAL_KILLER PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:12740575 Src kinaze LCK participate in activation of NKG2D signaling and induction of PLCG phosphorylation, probably via DAP10 phosphorylation. PMID:9751747, PMID:8986721 LCK phosphorylates KIR receptors in NK cells downstream of HLA binding. PMID:22513334 Probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 in NK cells (demonstrated in T cells). PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:8478617 Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells. CD3 zeta is phosphorilated by LCK. References_end </body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="11045.0" y="2400.0"/> <glyph class="state variable" id="_bc3fc647-7658-4bad-ba0b-a6b953cc403c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11040.0" y="2415.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1492_sa739" 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: 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="11875.0" y="1325.0"/> <glyph class="unit of information" id="_b3cfa7a5-b6d9-454a-b8d1-66286357d7db"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11892.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1493_sa738" 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: 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="11745.0" y="1325.0"/> <glyph class="unit of information" id="_b05b8e28-8f84-4d9d-9d46-2362bf7f3435"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11762.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1494_sa740" 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: 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="12045.0" y="1335.0"/> <glyph class="unit of information" id="_f0a79d15-9f40-43c5-bdaf-223e370927d8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12062.5" y="1330.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1495_sa432" 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: 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*"/> <clone/> <bbox w="80.0" h="50.0" x="13845.0" y="1535.0"/> <glyph class="state variable" id="_f5bcb86e-8220-496a-bc96-8809879bb10e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13840.0" y="1555.0"/> </glyph> <glyph class="unit of information" id="_00719eb9-0033-411d-bc61-cb94c616ff37"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13862.5" y="1530.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1495_sa844" 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: 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*"/> <clone/> <bbox w="80.0" h="50.0" x="4125.0" y="1405.0"/> <glyph class="state variable" id="_ed1a28a4-6935-4cc6-aa3b-0209e90ba0d3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4120.0" y="1425.0"/> </glyph> <glyph class="unit of information" id="_55c849d2-ed3c-470c-85f7-2cbde5aeb418"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4142.5" y="1400.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1510_sa839" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CLEC2D Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KLRB1 PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. References_end </body> </html> </notes> <label text="CLEC2D"/> <bbox w="80.0" h="40.0" x="2270.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s1554_sa408" 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: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="9891.25" y="730.0"/> </glyph> <glyph class="macromolecule" id="s1562_sa559" 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: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="8265.0" y="2830.0"/> <glyph class="state variable" id="_431797e6-e67f-4e2b-aae3-dd3e6632042f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8260.0" y="2845.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1662_sa543" 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:MKNK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:IL15 CASCADE:IL2 PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. 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 References_end </body> </html> </notes> <label text="MNK1"/> <bbox w="80.0" h="40.0" x="10340.0" y="4080.0"/> <glyph class="state variable" id="_9ba2565a-b1b8-478e-81e5-1e4aa1e379f5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10335.0" y="4095.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1663_sa542" 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:MKNK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:IL15 CASCADE:IL2 PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. 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 References_end </body> </html> </notes> <label text="MNK1"/> <bbox w="80.0" h="40.0" x="10340.0" y="4200.0"/> <glyph class="state variable" id="_5f178cd6-765b-4319-b64e-612a1de71ae6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10332.5" y="4215.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1664_sa541" 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:EIF4E Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end </body> </html> </notes> <label text="EIF4E"/> <bbox w="80.0" h="40.0" x="10505.0" y="4275.0"/> <glyph class="state variable" id="_5d63223d-ccbc-4ca4-8d39-5ce796e6a3aa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10500.0" y="4290.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1665_sa560" 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:EIF4E Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15563472 Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. Phosphorylation by MNK1 serves to activate eIF4E.eIF4E induces translation of ETS1by recruiting mRNAs to the ribosome, and upregulates ETS1 protein level. References_end </body> </html> </notes> <label text="EIF4E"/> <bbox w="80.0" h="40.0" x="10505.0" y="4385.0"/> <glyph class="state variable" id="_136b1850-d3ef-4bc7-b249-250ab6616bd5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10497.5" y="4400.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1668_sa243" 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> Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL2 PMID:21383498 IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function. References_end </body> </html> </notes> <label text="WASF2"/> <bbox w="80.0" h="40.0" x="9640.0" y="6500.0"/> <glyph class="state variable" id="_791abf87-b9df-44e6-abe3-b858ae6d193b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9632.5" y="6515.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1678_sa540" 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: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="8255.0" y="2920.0"/> <glyph class="state variable" id="_115bde42-a3f3-4298-a399-c34ecefb9df1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8247.5" y="2935.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1681_sa525" 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: 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="9372.5" y="1375.0"/> <glyph class="unit of information" id="_a0f9a036-1ebb-43f0-b46c-a894cb9280b3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9390.0" y="1370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1683_sa436" 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:FYN 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:NKP30 CASCADE:NKP46 CASCADE:SLAMF7 CASCADE:LFA1 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:12731048, PMID:20814939 Upon engagement of activating receptors, the tyrosine-containing adapters undergo tyrosine phosphorylation mediated by Src family kinases (SFKs) . Cross-linking of Nkp30 or Nkp46 or NKp44 resulted in strong tyrosine phosphorylation of LCK anf FYN kinases. PMID:10591186, PMID:24440149 Cross-Linking of LFA-1 induces tyrosine Phosphorylation of DNAM-,FYN probably phosphorylates DNAM1 Y322 in NK cells PMID:22683124 Fyn-deficient NK cells exhibited defective killing. PMID:19909365 FYN is adaptor protein f Fc epsilon RI signaling in mast cells References_end </body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="11225.0" y="2410.0"/> <glyph class="state variable" id="_d3035def-b99b-4523-b6e0-e02ca68b0192"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11220.0" y="2425.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1686_sa487" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="8497.5" y="1665.0"/> <glyph class="unit of information" id="_61f0d15c-9cad-4f2c-9e30-a2941d194d20"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8515.0" y="1660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1705_sa214" 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: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="9780.0" y="6160.0"/> <glyph class="state variable" id="_0b06527d-33df-4336-84e6-0573702a3620"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9772.5" y="6175.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1710_sa2627" 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:CSF2 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:NKG2D CASCADE:KIR2DS2 CASCADE:Fc_gamma_RIII CASCADE:CSF2 PMID:11777960 ULBP2 induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway via NKG2D. PMID:11015446 Cross-linking of the KIR2DS2/DAP12 receptor on NKL cells resulted in the dose-dependent secretion of IFNG and GM-CSF PMID:21765015, PMID:22869907 CSF2 signaling can have both positive and negative influence on angiogenesis in tumors. First, CSF2 upregulates angiogenic factor VEGF expression via HIF1a, specific inhibition of PHD2 increases VEGF production. Second, CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. ( PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. 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. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="11946.25" y="5405.0"/> </glyph> <glyph class="macromolecule" id="s1712_sa219" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end </body> </html> </notes> <label text="GZMH"/> <bbox w="80.0" h="40.0" x="8555.0" y="7390.0"/> </glyph> <glyph class="macromolecule" id="s1713_sa223" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end </body> </html> </notes> <label text="GZMM"/> <bbox w="80.0" h="40.0" x="8645.0" y="7420.0"/> </glyph> <glyph class="macromolecule" id="s1714_sa222" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:14499265 Granulysin is a member of the saposin-like protein family that includes amoebapores and NK lysin. It is a cytolytic protein present in the granules of human CTLs and NK cells and is lytic against both microbes and tumors. http://dx.doi.org/10.5402/2012/876203 References_end </body> </html> </notes> <label text="GNLY"/> <bbox w="80.0" h="40.0" x="8800.0" y="7510.0"/> </glyph> <glyph class="macromolecule" id="s1721_sa483" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, probaby via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="PTK2B"/> <bbox w="80.0" h="40.0" x="8547.5" y="2175.0"/> <glyph class="state variable" id="_29499ec0-9494-495e-8b49-f09215d06af8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8542.5" y="2190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1751_sa435" 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: 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="90.0" h="50.0" x="14020.0" y="1355.0"/> <glyph class="state variable" id="_aa8e5506-9c9f-4535-b57c-9aa78ad630bc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14015.0" y="1375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1777_sa455" 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:PTPRC Identifiers_end Maps_Modules_begin: MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SLAMF7 MAP:NATURAL_KILLER INPUT_ACTIVATORS PMID:25312647 CD45 is required for the activating function of SLAMF7 but not of 2B4 in NK cells. References_end </body> </html> </notes> <label text="PTPRC"/> <bbox w="80.0" h="40.0" x="14075.0" y="1940.0"/> </glyph> <glyph class="macromolecule" id="s1778_sa481" 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: HUGO:ITGAM Identifiers_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_MACROPHAGE MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MDSC CASCADE:CR3 PMID:18633355 The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="9442.5" y="1305.0"/> <glyph class="unit of information" id="_149af0c7-9715-4bda-8489-2a73f18d875d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9460.0" y="1300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1788_sa520" 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:LYN 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:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. FN adhesion-induced activity of the PTKs pl2SFAK, Fyn, Lyn, and Zap-70. Lyn activity was induced by cross-linking of a4pI integrins, but not by cross-linking of asp, either with a-specific mAbs. PMID:21910624 The ITAM can be part of the same polypeptidic chain that engages the ligand, as in the case of FcγRIIA and FcγRIIC, or of a separate γ subunit that associates noncovalently with the ligand-binding subunit of the receptor, as in the case of FcγRI and FcγRIIIA. Upon receptor clustering, the ITAM associates with and becomes phosphorylated by Hck, Lyn (33, 34), and/or Fgr (35). PMID:8132624 Hck, Lyn binds to Fc_gamma_RII (CD32) and phosphorylates it in monocytes. PMID:8064233, PMID:12524384, PMID:24445665 Hck, Lyn binds to Fc_gamma_RI (cd64) in monocytes and probably phosphorylate ignal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. Probably these kinases activate also IgE receptors directly and FCAR and Fc_gamma_RIII complexes with Fc epsilon RI gamma. PMID:19909365 Lyn is adaptor protein of IgE receptor signaling in mast cells References_end </body> </html> </notes> <label text="LYN"/> <bbox w="80.0" h="40.0" x="9657.5" y="2260.0"/> <glyph class="state variable" id="_40d287ff-cd84-482a-b4f2-5bbc6f8e47c2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9652.5" y="2275.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1789_sa480" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 PMID:10679059, PMID:12626562 PTK2B, PYK2. Binding of NK cells to sensitive target cells or ligation of β2 integrins results in a rapid induction of Pyk2 phosphorylation and activation. y contrast, no detectable Pyk2 tyrosine phosphorylation is found upon CD16 stimulation. Pyk2 activation is a crucial event for natural but not Ab-dependent cytotoxicity. Ligation of Beta2 integrins on NK cells resulted in Pyk2-dependent Erk activation, probaby via VAV1/RAC1 pathway. Pyk-2-mediated control of integrin-triggered Rac-1 activation involves the regulation of Vav tyrosine phosphorylation. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="PTK2B"/> <bbox w="80.0" h="40.0" x="8537.5" y="2305.0"/> <glyph class="state variable" id="_eb8dc9c7-5254-4b4c-ae04-3bd927581c6a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="8530.0" y="2320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1794_sa351" 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:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 GENECARDS:HDAC1 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 GENECARDS:HDAC2 HUGO:HDAC3 HGNC:4854 ENTREZ:8841 UNIPROT:O15379 GENECARDS:HDAC3 HUGO:HDAC4 HGNC:14063 ENTREZ:9759 UNIPROT:P56524 GENECARDS:HDAC4 HUGO:HDAC5 HGNC:14068 ENTREZ:10014 UNIPROT:Q9UQL6 GENECARDS:HDAC5 HUGO:HDAC6 HGNC:14064 ENTREZ:10013 UNIPROT:Q9UBN7 GENECARDS:HDAC6 HUGO:HDAC7 HGNC:14067 ENTREZ:51564 UNIPROT:Q8WUI4 GENECARDS:HDAC7 HUGO:HDAC8 HGNC:13315 ENTREZ:55869 UNIPROT:Q9BY41 GENECARDS:HDAC8 HUGO:HDAC10 HGNC:18128 ENTREZ:83933 UNIPROT:Q969S8 GENECARDS:HDAC10 HUGO:HDAC11 HGNC:19086 ENTREZ:79885 UNIPROT:Q96DB2 GENECARDS:HDAC11 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: histone deacetylase 1 REACTOME:56408 KEGG:3065 ATLASONC:GC_HDAC1 WIKI:HDAC1 histone deacetylase 2 REACTOME:56410 KEGG:3066 ATLASONC:HDAC2ID40803ch6q22 WIKI:HDAC2 histone deacetylase 3 REACTOME:401336 KEGG:8841 ATLASONC:HDAC3ID40804ch5q31 WIKI:HDAC3 histone deacetylase 4 REACTOME:56414 KEGG:9759 ATLASONC:GC_HDAC4 WIKI:HDAC4 histone deacetylase 5 REACTOME:415622 KEGG:10014 ATLASONC:GC_HDAC5 WIKI:HDAC5 histone deacetylase 6 REACTOME:56418 KEGG:10013 ATLASONC:GC_HDAC6 WIKI:HDAC6 histone deacetylase 7 REACTOME:412089 KEGG:9734 ATLASONC:GC_HDAC7 WIKI:HDAC7 histone deacetylase 8 REACTOME:148335 KEGG:55869 ATLASONC:GC_HDAC8 WIKI:HDAC8 histone deacetylase 10 0 0 REACTOME:412605 KEGG:83933 ATLASONC:GC_HDAC10 WIKI:HDAC10 histone deacetylase 11 1 1 REACTOME:56406 KEGG:79885 ATLASONC:GC_HDAC11 WIKI:HDAC11 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:23801635 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. References_end </body> </html> </notes> <label text="HDAC*"/> <bbox w="80.0" h="40.0" x="10560.0" y="565.0"/> </glyph> <glyph class="macromolecule" id="s1816_sa39" 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:IRAP Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22790179, PMID:19498108 Proteasome-generated polypeptides need to be trimmed by amino-terminal peptidases to be loaded on MHC class I molecules, and both ER-associated aminopeptidase 1 (ERAP1)6 and endosomal insulin-responsive aminopeptidase (IRAP; also known as cystinyl aminopeptidase)7 have been shown to be involved in cross-presentation. References_end </body> </html> </notes> <label text="IRAP"/> <bbox w="80.0" h="40.0" x="13900.0" y="6100.0"/> </glyph> <glyph class="macromolecule" id="s1827_sa54" 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: 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="12750.0" y="6200.0"/> </glyph> <glyph class="macromolecule" id="s1829_sa578" 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:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 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 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="NFAT*"/> <bbox w="80.0" h="40.0" x="12415.0" y="4863.75"/> <glyph class="state variable" id="_0b22962c-000b-4e1e-a48a-87286b851890"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12410.0" y="4878.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s1831_sa567" 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:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 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 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="NFAT*"/> <bbox w="80.0" h="40.0" x="12250.0" y="4863.75"/> <glyph class="state variable" id="_de7e8f1f-edb8-4531-955b-f6a64edc4d03"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="12242.5" y="4878.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s1843_sa1355" 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:IL4 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="3717.745" y="5355.75"/> </glyph> <glyph class="macromolecule" id="s1851_sa49" 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: 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="11893.125" y="6507.5"/> </glyph> <glyph class="macromolecule" id="s1852_sa48" 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: HUGO:CTSD Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16237087 CTSD (aspartic cathepsin D) and CTSG (cathepsin G) participate in antigen processing in DC. PMID:12776207 Cathepsins B,D,L, S and AEP (LGMN) are the lysosomal proteases implicated in antigen presentation in DC. References_end </body> </html> </notes> <label text="CTSD"/> <bbox w="80.0" h="40.0" x="12113.125" y="6507.5"/> </glyph> <glyph class="macromolecule" id="s1855_sa35" 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: HUGO:HLA-DMA HUGO:HLA-DMB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:10716924, PMID:10611337, PMID:22138314 Dendritic cells carry functional HLA-DM on the surface, which is down-regulated upon maturation. CLIP which blocks peptide binding until HLA-DM binds to MHC II, releasing CLIP and allowing other (antigen) peptides to bind. References_end </body> </html> </notes> <label text="HLA-DM* "/> <bbox w="80.0" h="50.0" x="12213.125" y="6612.5"/> <glyph class="unit of information" id="_e915f427-8490-4d5f-9d75-5628053d2a13"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12230.625" y="6607.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1856_sa475" 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:RAF1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15516985, PMID:12566895 HRAS activates MEK/ERK pathway via RAF phosphorylation in NK cells. Ras functions asan adapter that binds to Raf kinases. Raf can activate both MEK1 and MEK2 (also called MKK1 and MKK2) References_end </body> </html> </notes> <label text="RAF1"/> <bbox w="80.0" h="40.0" x="9770.0" y="3750.0"/> <glyph class="state variable" id="_a6e38da2-bf16-4163-aa3f-8f3c69e6a57d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9762.5" y="3765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1867_sa536" 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:PLA2G4A 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:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end </body> </html> </notes> <label text="PLA2G4A"/> <bbox w="80.0" h="40.0" x="10210.0" y="4290.0"/> <glyph class="state variable" id="_732788d1-2bc1-4d19-8c24-859fef15f484"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10205.0" y="4305.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1868_sa534" 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:PLA2G2A 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:9973479 BETA1 integrin cross-linking inhibits CD16-induced sPLA2, but not cPLA2 nor PI-PLC, activity in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PMID:9120268 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end </body> </html> </notes> <label text="PLA2G2A"/> <bbox w="80.0" h="40.0" x="10080.0" y="4290.0"/> <glyph class="state variable" id="_24cdb33a-2ede-48d9-a523-437f5679ac1f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10075.0" y="4305.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1869_sa535" 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:PLA2G4A 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:9120268, PMID:9973479 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end </body> </html> </notes> <label text="PLA2G4A"/> <bbox w="80.0" h="40.0" x="10210.0" y="4390.0"/> <glyph class="state variable" id="_86930f09-3903-4de3-80be-2e20e9009296"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10202.5" y="4405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1870_sa533" 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:PLA2G2A 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:9973479 BETA1 integrin cross-linking inhibits CD16-induced sPLA2, but not cPLA2 nor PI-PLC, activity in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PMID:9120268 ERK2 activates Phospholipase A2 group IIA (sPLA2 and cPLA2) by phosphorylation downstream of CD16 activation, but CDl6-induced degranulation in human NK cells is dependent on ERK activation, but not on sPLA, or cPLA. PMID:8388321 Arachidonic acid (AA) release via phospholipase A2 (PLA2) activation has positive influence on both NK and ADCC activities of natural killers. References_end </body> </html> </notes> <label text="PLA2G2A"/> <bbox w="80.0" h="40.0" x="10080.0" y="4390.0"/> <glyph class="state variable" id="_326bce95-905b-4285-b042-84523f2a1916"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10072.5" y="4405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1872_sa23" 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: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="13180.0" y="7210.0"/> </glyph> <glyph class="macromolecule" id="s1875_sa33" 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: HUGO:ARL8B Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:25637027 MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b Arl8b-silenced cells show reduced formation of MHC II–peptide complexes in lysosomes. References_end </body> </html> </notes> <label text="ARL8B"/> <bbox w="80.0" h="40.0" x="11973.125" y="6637.5"/> </glyph> <glyph class="macromolecule" id="s1892_sa28" 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: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="13180.0" y="7150.0"/> </glyph> <glyph class="macromolecule" id="s1895_sa26" 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:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 GENECARDS:ACTA1 HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 GENECARDS:ACTA2 HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 GENECARDS:ACTB HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 GENECARDS:ACTC1 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 GENECARDS:ACTG1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:18802007 Disruption of actin polymerization inhibits the up-regulation of surface MHCII in a dose-dependent manner in DC. MAP:MAST_CELL CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:IL2 PMID:11766992 Fractalkine via CX3CR1 induces chemotaxis and migration associated actin polymerization in immature as well as in mature DCs. PMID:9314552, PMID:8570922 , PMID:19741094 Actin is likely to play an important role in phagocytosis since it is concentrated in the macrophage cytoplasm surrounding the particle being engulfed, and since cytochalasin D treatment, which blocks actin polymerization, abrogates phagocytosis without affecting particle binding 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:19909365 The Ca2+ influx is an essential trigger for fusion of the Mast Cell granules to the membrane and the breakdown of the actin cytoskeleton. References_end </body> </html> </notes> <label text="Actin cytoskeletal*"/> <clone/> <bbox w="130.0" h="50.0" x="12605.0" y="7545.0"/> </glyph> <glyph class="macromolecule" id="s1895_sa216" 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:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 GENECARDS:ACTA1 HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 GENECARDS:ACTA2 HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 GENECARDS:ACTB HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 GENECARDS:ACTC1 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 GENECARDS:ACTG1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:18802007 Disruption of actin polymerization inhibits the up-regulation of surface MHCII in a dose-dependent manner in DC. MAP:MAST_CELL CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:IL2 PMID:11766992 Fractalkine via CX3CR1 induces chemotaxis and migration associated actin polymerization in immature as well as in mature DCs. PMID:9314552, PMID:8570922 , PMID:19741094 Actin is likely to play an important role in phagocytosis since it is concentrated in the macrophage cytoplasm surrounding the particle being engulfed, and since cytochalasin D treatment, which blocks actin polymerization, abrogates phagocytosis without affecting particle binding 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:19909365 The Ca2+ influx is an essential trigger for fusion of the Mast Cell granules to the membrane and the breakdown of the actin cytoskeleton. References_end </body> </html> </notes> <label text="Actin cytoskeletal*"/> <clone/> <bbox w="130.0" h="50.0" x="9475.0" y="7125.0"/> </glyph> <glyph class="macromolecule" id="s1899_sa407" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCAM1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:11698225, NCAM1 (CD56) is a marker of NK cells References_end </body> </html> </notes> <label text="NCAM1"/> <bbox w="80.0" h="50.0" x="1323.75" y="267.5"/> <glyph class="unit of information" id="_57a163ae-78e6-4a89-aeed-9e7bb449adcf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1341.25" y="262.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s1918_sa16" 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:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 GENECARDS:ACTA1 HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 GENECARDS:ACTA2 HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 GENECARDS:ACTB HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 GENECARDS:ACTC1 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 GENECARDS:ACTG1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:18802007 Disruption of actin polymerization inhibits the up-regulation of surface MHCII in a dose-dependent manner in DC. MAP:MAST_CELL CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:IL2 PMID:11766992 Fractalkine via CX3CR1 induces chemotaxis and migration associated actin polymerization in immature as well as in mature DCs. PMID:9314552, PMID:8570922 , PMID:19741094 Actin is likely to play an important role in phagocytosis since it is concentrated in the macrophage cytoplasm surrounding the particle being engulfed, and since cytochalasin D treatment, which blocks actin polymerization, abrogates phagocytosis without affecting particle binding 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:19909365 The Ca2+ influx is an essential trigger for fusion of the Mast Cell granules to the membrane and the breakdown of the actin cytoskeleton. References_end </body> </html> </notes> <label text="Actin cytoskeletal*"/> <clone/> <bbox w="136.0" h="56.0" x="12602.0" y="7642.0"/> <glyph class="unit of information" id="_8c1888cc-2f15-4990-8a0b-1a8d8403ba41"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="12660.0" y="7637.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s1918_sa215" 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:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 GENECARDS:ACTA1 HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 GENECARDS:ACTA2 HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 GENECARDS:ACTB HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 GENECARDS:ACTC1 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 GENECARDS:ACTG1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:18802007 Disruption of actin polymerization inhibits the up-regulation of surface MHCII in a dose-dependent manner in DC. MAP:MAST_CELL CASCADE:CR3 CASCADE:Fc_gamma_RII CASCADE:IL2 PMID:11766992 Fractalkine via CX3CR1 induces chemotaxis and migration associated actin polymerization in immature as well as in mature DCs. PMID:9314552, PMID:8570922 , PMID:19741094 Actin is likely to play an important role in phagocytosis since it is concentrated in the macrophage cytoplasm surrounding the particle being engulfed, and since cytochalasin D treatment, which blocks actin polymerization, abrogates phagocytosis without affecting particle binding 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:19909365 The Ca2+ influx is an essential trigger for fusion of the Mast Cell granules to the membrane and the breakdown of the actin cytoskeleton. References_end </body> </html> </notes> <label text="Actin cytoskeletal*"/> <clone/> <bbox w="136.0" h="56.0" x="9462.0" y="7212.0"/> <glyph class="unit of information" id="_3d1c8560-ba24-4ca0-8749-f56a92d4af68"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="9520.0" y="7207.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1935_sa32" 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:PSMA1 HUGO:PSMA2 HUGO:PSMA3 HUGO:PSMA4 HUGO:PSMA5 HUGO:PSMA6 HUGO:PSMA7 HUGO:PSMA8 HUGO:PSMB1 HUGO:PSMB2 HUGO:PSMB3 HUGO:PSMB4 HUGO:PSMB5 HUGO:PSMB6 HUGO:PSMB7 HUGO:PSMB8 HUGO:PSMB9 HUGO:PSMB10 HUGO:PSMC1 HUGO:PSMC2 HUGO:PSMC3 HUGO:PSMC4 HUGO:PSMC5 HUGO:PSMC6 HUGO:PSMD1 HUGO:PSMD2 HUGO:PSMD3 HUGO:PSMD4 HUGO:PSMD5 HUGO:PSMD6 HUGO:PSMD7 HUGO:PSMD8 HUGO:PSMD9 HUGO:PSMD10 HUGO:PSMD11 HUGO:PSMD12 HUGO:PSMD13 HUGO:PSMD14 HUGO:PSME1 HUGO:PSME2 HUGO:PSME3 HUGO:PSME4 HUGO:PSMF1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11717192 The IFN-gamma-responsive immunoproteasome subunits LMP2, LMP7 and MECL1 are up-regulated in immature DC, whereas the other components of the MHC class I presentation machinery, such as PA28, TAP, tapasin, and HLA heavy and light chains, were found to be more abundant in mature DC. References_end </body> </html> </notes> <label text="proteasome*"/> <bbox w="80.0" h="40.0" x="13900.0" y="5960.0"/> </glyph> <glyph class="macromolecule" id="s1961_sa1828" 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: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="13973.75" y="5395.0"/> </glyph> <glyph class="macromolecule" id="s1972_sa2608" 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: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="5090.0" y="4756.875"/> <glyph class="state variable" id="_b3482843-39e7-4a50-8d12-286509b2f512"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5085.0" y="4771.875"/> </glyph> </glyph> <glyph class="macromolecule" id="s2013_sa4" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:CR4 CASCADE:FLT3LG CASCADE:IFNAB PMID:15573129 CD11c is a maker of myeloid DCs. PMID:8920882 FLT3 ligand upregulates surface expression of CD11c 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, CD206, CD23 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="CD11c*"/> <bbox w="80.0" h="50.0" x="2053.75" y="317.5"/> <glyph class="unit of information" id="_894c8c4c-4fc2-4f7e-b0fe-ddfab639f33f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2071.25" y="312.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2017_sa1068"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IL6 CASCADE:TLR2_4 CASCADE:STING CASCADE:FCAR CASCADE:IL15 PMID:7590867 Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation PMID:15573129, PMID:8837607, PMID:9845545 Macrophage colony-stimulating factor (M-CSF) and IL-6 have also been reported to be involved in the tumour-mediated regulation of DC differentiation. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation PMID:11306493 The presence of high (>400 pg/ml) concentrations of IL-6 and M-CSF in tumor cell supernatant was strongly correlated with the inhibitory capacity of tumor cell medium on MO-DC differentiation 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. The IFN-γ, TNFα and IL-6 transcripts were consistently expressed at higher levels at 330-, 14- and 20-folds, respectively, in donor-matched mIL-15 DCs than mIL-4 DCs 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo 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="IL6"/> <bbox w="80.0" h="40.0" x="238.5" y="3135.0"/> </glyph> <glyph class="macromolecule" id="s2019_sa1906"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="16600.0" y="5680.0"/> </glyph> <glyph class="macromolecule" id="s2025_sa789" 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:LTB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:11823516 Human immature dendritic cells express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or R:Fc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. References_end </body> </html> </notes> <label text="LTB"/> <bbox w="80.0" h="40.0" x="7496.25" y="7665.0"/> </glyph> <glyph class="macromolecule" id="s2029_sa3" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CLEC4C Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22437871 CLEC4C (CD303), CD1C and THBD (CD141) are the markers of human DC. References_end </body> </html> </notes> <label text="CLEC4C"/> <bbox w="80.0" h="50.0" x="1663.75" y="357.5"/> <glyph class="unit of information" id="_b8781bd8-f50c-46d6-bb84-ae5ec7697a40"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1681.25" y="352.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2031_sa7" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD1C Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22437871 CLEC4C (CD303), CD1C and THBD (CD141) are the markers of human DC. References_end </body> </html> </notes> <label text="CD1C"/> <bbox w="80.0" h="50.0" x="1663.75" y="287.5"/> <glyph class="unit of information" id="_1f1cb3c0-2087-4462-8cb9-00134af0a1a5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1681.25" y="282.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2034_sa2606" 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: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="5090.0" y="4846.875"/> <glyph class="state variable" id="_4c6ba82e-33b5-48e6-a86c-a9d116f0d076"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5082.5" y="4861.875"/> </glyph> </glyph> <glyph class="macromolecule" id="s2041_sa2610" 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: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="2550.0" y="3550.0"/> </glyph> <glyph class="macromolecule" id="s2061_sa1366" 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:INHBA Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 CASCADE:IL13 PMID:24204259 IL-4Rα-deficient DCs produced reduced IL-12, and IL18 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses. probably via STAT6 References_end </body> </html> </notes> <label text="INHBA"/> <bbox w="80.0" h="40.0" x="3620.0" y="5688.75"/> </glyph> <glyph class="macromolecule multimer" id="s2062_sa1368" 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:INHBA Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 CASCADE:IL13 PMID:24204259 IL-4Rα-deficient DCs produced reduced IL-12, and IL18 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses. probably via STAT6 References_end </body> </html> </notes> <label text="INHBA"/> <bbox w="86.0" h="46.0" x="3617.0" y="5797.0"/> <glyph class="unit of information" id="_11d83006-ce65-4013-ae25-0b16741de01d"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3650.0" y="5792.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2072_sa1069" 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: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="1055.0" y="2855.0"/> <glyph class="state variable" id="_37506a3b-cadb-4fe4-8f9a-241c82dfde9a"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="1117.5" y="2852.541"/> </glyph> <glyph class="unit of information" id="_d30f58cc-2a26-4914-a19a-1d1407955848"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1072.5" y="2850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2073_sa1070" 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: HUGO:IL6R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="885.0" y="2775.0"/> <glyph class="unit of information" id="_350dd96f-1879-4038-9123-00e93cf605a3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="902.5" y="2770.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2080_sa1361" 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:CSF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:GSF1 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling blocks CSF (M-CSF) production in DC induced by tumor cells. PMID:24669294 SCF1 (M-CSF) is assosiated with M2 phenotype of macrophages References_end </body> </html> </notes> <label text="CSF1"/> <bbox w="80.0" h="40.0" x="2782.5" y="5297.5"/> </glyph> <glyph class="macromolecule" id="s2081_sa76"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="13940.0" y="8610.0"/> </glyph> <glyph class="macromolecule" id="s2085_sa1839" 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: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="15395.0" y="3495.0"/> <glyph class="state variable" id="_7f2720c4-3189-4837-b5ed-adddfe780217"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15390.0" y="3515.0"/> </glyph> <glyph class="unit of information" id="_db81ca77-11e6-47c6-a536-46cdcd4b2abf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15412.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2097_sa1" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD209 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_MACROPHAGE Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL4 PMID:25582338 DC-specific marker DC-SIGN (CD209) was expressed significantly less on IL-15 DCs compared with IL-4 DCs References_end </body> </html> </notes> <label text="CD209"/> <bbox w="80.0" h="50.0" x="1663.75" y="147.5"/> <glyph class="unit of information" id="_dee669de-b8e8-43d1-8396-1278cfa7be52"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1681.25" y="142.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2112_sa5" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD8A Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:21930769 PMID:21930765 CD8a is a marker of DC supset which activates T cells References_end </body> </html> </notes> <label text="CD8A"/> <bbox w="80.0" h="50.0" x="1783.75" y="147.5"/> <glyph class="unit of information" id="_4e489a23-a011-4539-9932-ce5a576f53ca"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1801.25" y="142.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2113_sa2711" 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:SOCS2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 PMID:14764699 SOCS1 and SOCS3 are upregulated in mature DC. SOCS2 in immature DC. SOCS1 and SOCS2 expression is induced by IL4 signaling, and SOCS3 expression is upregulated more by GM-CSF (CSF2). SOCS proteins are characterized by the presence of an Src homology 2 domain and a C-terminal conserved domain called the SOCS box, and their inhibitory effects derive from direct interaction with cytokine receptors and/or Janus kinases (JAKs), thereby preventing recruitment of STATs to the signaling complex References_end </body> </html> </notes> <label text="SOCS2"/> <bbox w="80.0" h="40.0" x="14785.0" y="2410.0"/> </glyph> <glyph class="macromolecule" id="s2123_sa90" 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:CIITA Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL4 CASCADE:CSF2 CASCADE:IFNG PMID: 19224634 STAT5 promotes expression of MHC class II transactivator protein (CIITA) and upregulates MHC class II expression downstream of CSF2 ( PMID:8624807 CIITA is required for both constitutive and IFNγ-inducible expression of MHC class II genes CIITA-deficient (−/−) mice do not express conventional MHC class II molecules on the surface of splenic B cells and dendritic cells. PMID:11514596 Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (Ciita) Expression and down regulation of MHCII expression. PMID:22076556 CIITA expression is controlled in immature dendritic cells (DCs) by an activating transcriptional complex that contains PU.1, SP1, IRF8 and NF-κB, whereas it is inhibited in mature DCs by PR domain zinc finger protein 1 (PRDM1). Consequently, CIITA (with other factors) induces transcription of the MHC class II genes in immature DCs but not in mature DCs. References_end </body> </html> </notes> <label text="CIITA"/> <bbox w="80.0" h="40.0" x="14720.0" y="6007.5"/> </glyph> <glyph class="macromolecule" id="s2162_sa12" 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: HUGO:MSR1 Identifiers_end References_begin: MAP:DENDRITIC_CELL CASCADE:MSR1 PMID:12594251 Dendritic cells can capture the antigens through the ‘nibbling’ of live tumour cells, Class A Scavenger Receptor (MSR1) regulates the process. Internalized membrane colocalized with SR ligand and entered the endosomal pathway. DC very efficiently acquired and internalized gp100 tumor Ag expressed at the surface of viable adenocarcinoma cells via recombinant adenoviral infection. Cross-presentation of gp100 by DC to MHC class I-restricted T cells was inhibited by polyanionic SR ligand and an Ab to type A SR (SR-A), whereas Ab to the class B SR CD36, which mediates uptake of apoptotic cells, induced no inhibition. References_end </body> </html> </notes> <label text="MSR1"/> <bbox w="80.0" h="50.0" x="7282.5" y="1295.0"/> <glyph class="unit of information" id="_6e9b32b9-0f7d-4c97-941d-9ccc176481bb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7300.0" y="1290.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2169_sa1432"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="6832.5" y="1130.0"/> </glyph> <glyph class="macromolecule" id="s2175_sa1414" 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: 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="7012.5" y="1355.0"/> <glyph class="unit of information" id="_4944cd33-c14a-4d9d-a5b6-aa592981018e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7030.0" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2182_sa1421" 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: 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="7152.5" y="1355.0"/> <glyph class="unit of information" id="_807a8968-d584-4a9b-92c5-9f3bbf4e6ba3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7170.0" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2189_sa1409" 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: 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="6782.5" y="1355.0"/> <glyph class="unit of information" id="_25bad82d-c884-407a-8da0-408e220b445c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6800.0" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2193_sa1413" 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: 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="6652.5" y="1355.0"/> <glyph class="unit of information" id="_4d37d3cb-300a-416f-a361-a1a96d6a0afe"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6670.0" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2208_sa84" 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:MARCH1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL10 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. T regulatory cells impair dendritic cell function via an IL-10/MARCH1-dependent mechanism. Both the enhanced expression of MARCH1 and the decreased expression of CD83 were mediated by IL-10 produced by the iTregs. References_end </body> </html> </notes> <label text="MARCH1"/> <bbox w="80.0" h="40.0" x="13530.0" y="7880.0"/> </glyph> <glyph class="macromolecule" id="s2240_sa1427"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:THBS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:IL10 CASCADE:TGFB CASCADE:PGE2 PMID:14996710 Thrombospondin-1 is associated with tumor microenvironment. PMID:10657674 CD47 engagement by Thrombospondin-1 peptide inhibits cytokine production and maturation of human dendritic cells. PMID:14568985 Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47. IL-10, TGF-β, and PGE2 enhance TSP secretion by Dcs References_end </body> </html> </notes> <label text="THBS1"/> <bbox w="80.0" h="40.0" x="238.5" y="5505.0"/> </glyph> <glyph class="macromolecule" id="s2247_sa776" 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:CD274 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:24076050, PMID:12538684 PDL1 and PDL2 are expressed in DCs. blockade of PD-L2 on dendritic cells results in enhanced T cell proliferation and cytokine production, including that of IFN-gamma and IL-10, while blockade of PD-L1 results in similar, more modest, effects. Blockade of both PD-L1 and PD-L2 showed an additive effect. Both whole mAb and Fab enhanced T cell activation, showing that PD-L1 and PD-L2 function to inhibit T cell activation. References_end </body> </html> </notes> <label text="PDL1*"/> <bbox w="80.0" h="40.0" x="1310.0" y="6660.0"/> </glyph> <glyph class="macromolecule" id="s2248_sa775" 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:PDCD1LG2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:24076050, PMID:12538684 PDL1 and PDL2 are expressed in DCs. blockade of PD-L2 on dendritic cells results in enhanced T cell proliferation and cytokine production, including that of IFN-gamma and IL-10, while blockade of PD-L1 results in similar, more modest, effects. Blockade of both PD-L1 and PD-L2 showed an additive effect. Both whole mAb and Fab enhanced T cell activation, showing that PD-L1 and PD-L2 function to inhibit T cell activation. References_end </body> </html> </notes> <label text="PDL2*"/> <bbox w="80.0" h="40.0" x="1400.0" y="6600.0"/> </glyph> <glyph class="macromolecule" id="s2249_sa71" 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: HUGO:ICOSLG Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11007762 ICOSLG (B7RP1) is expressed on PB B cells and monocytes, and on PB monocyte-derived DC. It is the ligand to the co-stimulatory protein ICOS of T cells. References_end </body> </html> </notes> <label text="ICOSLG"/> <bbox w="80.0" h="40.0" x="14880.0" y="8060.0"/> </glyph> <glyph class="macromolecule" id="s2250_sa774" 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:CD276 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:17615586, PMID:15294965 After contact to Treg, DC up-regulate the inhibitory B7-H3 molecule and display reduced numbers of MHC–peptide complexes, leading to impaired T cell stimulatory function. B7-H3 plays a significant role in suppressing T cell activation by Treg-exposed DC. References_end </body> </html> </notes> <label text="B7H3*"/> <bbox w="80.0" h="40.0" x="1520.0" y="6660.0"/> </glyph> <glyph class="macromolecule" id="s2251_sa778" 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:VTCN1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:MACROPHAGE PMID:12818165 Freshly isolated human T cells, B cells, monocytes, and DC do not express B7-H4 on cell surface in FACS analysis. In contrast, B7-H4 expression can be induced on T cells, B cells, monocytes, and DC after in vitro stimulation B7H4 inhibits T-cell response. References_end </body> </html> </notes> <label text="B7H4*"/> <bbox w="80.0" h="40.0" x="1600.0" y="6600.0"/> </glyph> <glyph class="macromolecule" id="s2252_sa779" 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:TNFRSF14 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:18097025 HVEM is expressed in DCs. PMID:18193050 Binding of HVEM to BTLA or CD160 inhibited T cell activation. References_end </body> </html> </notes> <label text="HVEM*"/> <bbox w="80.0" h="40.0" x="1790.0" y="6600.0"/> </glyph> <glyph class="macromolecule" id="s2253_sa70" 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: HUGO:TNFSF9 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NEUTROPHIL PMID:8992967, PMID:16288496 TNFSF9 (CD137L, 4-1BBL) is expressed in DCs and induces T-cell activation adn inhibits tumor growth. PMID:25384214 TANs enhance T cell proliferation by direct cell-cell signaling, likely due to the OX40L/OX40 and 4-1BBL/4-1BB pathways. References_end </body> </html> </notes> <label text="TNFSF9"/> <bbox w="80.0" h="40.0" x="14690.0" y="8050.0"/> </glyph> <glyph class="macromolecule" id="s2267_sa100" 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: 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="13853.125" y="6657.5"/> </glyph> <glyph class="macromolecule" id="s2289_sa6" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LY75 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:10784619 LY75 (DEC-205) it is a a marker of dendritic cells with regulatory effects on CD8 T cell responses. PMID:8920882 FLT3 ligand upregulates surface expression of LY75 (DEC-205) in DCs. References_end </body> </html> </notes> <label text="LY75"/> <bbox w="80.0" h="50.0" x="2053.75" y="187.5"/> <glyph class="unit of information" id="_540acb32-1067-4a50-bd41-00703f95c0d7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2071.25" y="182.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2312_sa1194"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CCL5 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:CCR5 CASCADE:TGFB PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:11790543, PMID:15356122 CCR5 as a critical NK-cell homing receptor, CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="80.0" h="40.0" x="5830.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s2365_sa41" 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> 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="13740.0" y="6200.0"/> <glyph class="unit of information" id="_4451b69e-d7d0-48f5-8e80-2e91f9e9d432"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="13755.0" y="6195.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2368_sa95" 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: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="45.0" x="14810.0" y="6187.5"/> <glyph class="unit of information" id="_1e99167c-11bf-446c-b0d7-e397746ec1f8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14827.5" y="6182.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2370_sa94" 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: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="14630.0" y="6187.5"/> <glyph class="state variable" id="_68140221-5d6c-42bc-b855-fef7bc7a38eb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14625.0" y="6202.5"/> </glyph> <glyph class="unit of information" id="_f993b67f-4e4d-4ec6-9b63-d2129d1f237c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14647.5" y="6182.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2371_sa96" 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: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="14520.0" y="6190.0"/> <glyph class="unit of information" id="_a18e383e-9f41-4602-89f2-d0af35d5d4e7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14537.5" y="6185.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2402_sa38" 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: 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="11420.0" y="6640.0"/> </glyph> <glyph class="macromolecule" id="s2416_sa2146" 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:TMEM173 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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="cGAS*"/> <bbox w="80.0" h="40.0" x="7027.5" y="1960.0"/> </glyph> <glyph class="macromolecule" id="s2419_sa229" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:NKG2D CASCADE:2B4 CASCADE:IL15 MAP:NATURAL_KILLER PMID:16106370, PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:20189481 NKG2D, 2B4 signalings induces Granzyme B release probaly via VAV1/ERK pathway PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. PMID:24248158 Hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. PMID:18287025 JNK pathway plays important role in NK activation.JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. Inhibition of JNK activity by D-JNK-1, SP600125, or JNK-1-specific siRNA blocked polarization of granzyme B References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="80.0" h="40.0" x="8700.0" y="7510.0"/> </glyph> <glyph class="macromolecule" id="s2420_sa240" compartmentRef="c37_ca37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMA Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 PMID:16106370, PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11413196, PMID:11413196 VAV1 induces granule exocytosis of granzyme A probably via RAC1-ERK pathway. The absence of Vav1 results in defective granule exocytosis and reduced ability to lyse tumor targets. References_end </body> </html> </notes> <label text="GZMA"/> <bbox w="80.0" h="40.0" x="8760.0" y="7580.0"/> </glyph> <glyph class="macromolecule" id="s2422_sa314"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end </body> </html> </notes> <label text="GZMH"/> <bbox w="80.0" h="40.0" x="8470.0" y="8210.0"/> </glyph> <glyph class="macromolecule" id="s2423_sa315"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end </body> </html> </notes> <label text="GZMM"/> <bbox w="80.0" h="40.0" x="8580.0" y="8210.0"/> </glyph> <glyph class="macromolecule" id="s2424_sa316"> <notes> <html xmlns="http://www.w3.org/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:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:14499265 Granulysin is a member of the saposin-like protein family that includes amoebapores and NK lysin. It is a cytolytic protein present in the granules of human CTLs and NK cells and is lytic against both microbes and tumors. http://dx.doi.org/10.5402/2012/876203 References_end </body> </html> </notes> <label text="GNLY"/> <bbox w="80.0" h="40.0" x="8780.0" y="8210.0"/> </glyph> <glyph class="macromolecule" id="s2425_sa317"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMK Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:16106370, PMID:15607806, PMID:7734049 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. References_end </body> </html> </notes> <label text="GZMK"/> <bbox w="80.0" h="40.0" x="8360.0" y="8220.0"/> </glyph> <glyph class="macromolecule" id="s2428_sa320"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMA Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 PMID:16106370, PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11413196, PMID:11413196 VAV1 induces granule exocytosis of granzyme A probably via RAC1-ERK pathway. The absence of Vav1 results in defective granule exocytosis and reduced ability to lyse tumor targets. References_end </body> </html> </notes> <label text="GZMA"/> <bbox w="80.0" h="40.0" x="8890.0" y="8210.0"/> </glyph> <glyph class="macromolecule" id="s2431_sa410" 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: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="10585.0" y="2095.0"/> <glyph class="state variable" id="_c2e89a36-7a1c-4a19-88dc-4ca287e532f0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10580.0" y="2115.0"/> </glyph> <glyph class="unit of information" id="_20ec7c49-fa3b-470c-99df-dfe2e51844c4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10602.5" y="2090.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2436_sa449" 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: 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="13595.0" y="1570.0"/> <glyph class="state variable" id="_a5c717ec-ffbf-45b5-8e3e-29fe9f698c1e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="13587.5" y="1585.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2437_sa452" 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: 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="13465.0" y="1570.0"/> <glyph class="state variable" id="_f39e30bc-490f-43b0-a7ce-0f53d1b1230e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13460.0" y="1585.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2440_sa476" 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:RAF1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15516985, PMID:12566895 HRAS activates MEK/ERK pathway via RAF phosphorylation in NK cells. Ras functions asan adapter that binds to Raf kinases. Raf can activate both MEK1 and MEK2 (also called MKK1 and MKK2) References_end </body> </html> </notes> <label text="RAF1"/> <bbox w="80.0" h="40.0" x="9770.0" y="3650.0"/> <glyph class="state variable" id="_6784a0f0-cf03-4fd7-bdf1-4067ee0feb75"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9765.0" y="3665.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2445_sa495" 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:LIMK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. FcR-initiated LIMK1 phosphorylation was absent in the NK clones that had been treated with p160ROCK kinase inhibitor. Inhibition of the RhoA/p160ROCK/LIMK1 signaling pathway abrogates lipid raft polarization to the effector-target interface References_end </body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="6945.0" y="3720.0"/> <glyph class="state variable" id="_79aa78c1-6497-41a1-a7d3-831fef87be61"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6937.5" y="3735.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2447_sa497" 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:LIMK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:11698448 LIMK1 is a serine/threonine kinase that phosphorylates and inactivates the actin-depolymerization factor cofilin, thereby regulating actin cytoskeletal reorganization. FcR-initiated LIMK1 phosphorylation was absent in the NK clones that had been treated with p160ROCK kinase inhibitor. Inhibition of the RhoA/p160ROCK/LIMK1 signaling pathway abrogates lipid raft polarization to the effector-target interface References_end </body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="6930.0" y="3475.0"/> <glyph class="state variable" id="_7c7d169e-7d7c-4525-939f-eeba7b589967"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6925.0" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2450_sa521" 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:LYN 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:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII CASCADE:INTEGRIN_A4B1 PMID:8892616 Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. FN adhesion-induced activity of the PTKs pl2SFAK, Fyn, Lyn, and Zap-70. Lyn activity was induced by cross-linking of a4pI integrins, but not by cross-linking of asp, either with a-specific mAbs. PMID:21910624 The ITAM can be part of the same polypeptidic chain that engages the ligand, as in the case of FcγRIIA and FcγRIIC, or of a separate γ subunit that associates noncovalently with the ligand-binding subunit of the receptor, as in the case of FcγRI and FcγRIIIA. Upon receptor clustering, the ITAM associates with and becomes phosphorylated by Hck, Lyn (33, 34), and/or Fgr (35). PMID:8132624 Hck, Lyn binds to Fc_gamma_RII (CD32) and phosphorylates it in monocytes. PMID:8064233, PMID:12524384, PMID:24445665 Hck, Lyn binds to Fc_gamma_RI (cd64) in monocytes and probably phosphorylate ignal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. Probably these kinases activate also IgE receptors directly and FCAR and Fc_gamma_RIII complexes with Fc epsilon RI gamma. PMID:19909365 Lyn is adaptor protein of IgE receptor signaling in mast cells References_end </body> </html> </notes> <label text="LYN"/> <bbox w="80.0" h="40.0" x="9657.5" y="2360.0"/> <glyph class="state variable" id="_50ae0043-3eae-4f84-9446-4823ae2bbbe8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9650.0" y="2375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2451_sa553" 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: 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="9222.5" y="1305.0"/> <glyph class="state variable" id="_7b9b55bb-7c6a-41f2-bbf8-c0f1d05e2487"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9217.5" y="1307.2045"/> </glyph> <glyph class="state variable" id="_1fc1057e-27d5-4180-8b32-b827283ad04c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9217.5" y="1333.554"/> </glyph> <glyph class="unit of information" id="_440340c1-2f64-4dd4-835f-1785340e501e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9240.0" y="1300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2452_sa1976" 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: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="3660.0"/> </glyph> <glyph class="macromolecule" id="s2453_sa1973" 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: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="12955.0" y="3570.0"/> <glyph class="state variable" id="_e8828d9b-2f34-452b-a66a-760489ce9a3b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12950.0" y="3585.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2455_sa568" 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: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="6000.0" y="4190.0"/> </glyph> <glyph class="macromolecule" id="s2502_sa745" 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> 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="11445.0" y="1355.0"/> <glyph class="unit of information" id="_94b779b1-e71c-4df8-a92f-44b51d482d77"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11462.5" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2521_sa766" 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: 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="12275.0" y="1305.0"/> <glyph class="unit of information" id="_2f95246d-942d-47eb-91db-cba4c89eea17"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12292.5" y="1300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2522_sa767" 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: CHEBI:16238 KEGGCOMPOUND:C00016 CAS:146-14-5 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end ----- 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="12505.0" y="1305.0"/> <glyph class="unit of information" id="_50119f2b-e81d-4514-95dd-9fea3aa0c081"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12522.5" y="1300.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2640_sa777" 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:LGALS9 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22505239, PMID:16286920 Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. There are different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs References_end </body> </html> </notes> <label text="LGALS9"/> <bbox w="80.0" h="40.0" x="1700.0" y="6660.0"/> </glyph> <glyph class="macromolecule" id="s2654_sa816" 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: HUGO:LILRB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:LILRB1 MAP:NATURAL_KILLER PMID:15771571, PMID:10591185, PMID:9933109 LILRB1 binds with low afﬁnity to a conserved region in the α3 domain of essentially all HLA class I glycoproteins, including HLA-A, -B, -C, -E, -F, and -G. LILRB1 receptors on NK cells can suppress their activation (cytotoxicity) upon encountering HLA classI–bearing targets (demonstrated for HLA-G, only). References_end </body> </html> </notes> <label text="LILRB1"/> <bbox w="80.0" h="50.0" x="3965.0" y="1355.0"/> <glyph class="unit of information" id="_cb68b026-1654-48bd-b63c-f76b55766654"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3982.5" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2660_sa815" 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: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:IL2 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 PMID:17100877 KIR2DL4 both contains a cytoplasmic ITIM and encodes a transmembrane arginine residue, through which it can associate with the FcɛRγ-chain KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells References_end </body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="3660.0" y="1485.0"/> <glyph class="state variable" id="_764383f4-7bbf-4aaa-ab2d-c4bd831029f5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3655.0" y="1505.0"/> </glyph> <glyph class="unit of information" id="_d8478647-eb3d-4d9b-9541-c5769e7d7584"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3677.5" y="1480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2661_sa832" 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: HUGO:KIR3DS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:MARKERS_NK Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end </body> </html> </notes> <label text="KLRG1*"/> <bbox w="80.0" h="50.0" x="2395.0" y="1345.0"/> <glyph class="state variable" id="_e6f409bb-5b91-4d3d-a334-763df882be7f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2390.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_2f9d1dbe-58e6-4b0d-b174-394c1a4a1f28"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2412.5" y="1340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2662_sa834" 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: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="2697.5" y="3210.0"/> <glyph class="state variable" id="_93d99d04-8718-4079-b9b6-2207572db2f5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2690.0" y="3225.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2706_sa934" 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:RUNX1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15084276 Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. PMID:18003603 RUNX1 down-regulates IFNG expression in NK cells and upregulates expression of CD122 (IL-2/IL-15 common receptor beta subunit) via direct binding to its promoter in development. NK cells in Runx dominant negative form Tg mice have immature surface phenotype. References_end </body> </html> </notes> <label text="RUNX1"/> <bbox w="80.0" h="40.0" x="3440.0" y="4500.625"/> </glyph> <glyph class="macromolecule" id="s2747_sa963" 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:MAF Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 Maps_Modules_end References_begin: PMID:15749884 IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="MAF"/> <bbox w="80.0" h="40.0" x="4410.0" y="4496.875"/> </glyph> <glyph class="macromolecule" id="s2753_sa976" 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:KLF4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 Maps_Modules_end References_begin: PMID:21670502 KLF4 together with STAT6 upregulates expression of PPARG and ARG1 downstream of IL4. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. KLF4 inhibits PTGS2 (COX2) expression. Probably via prevention of NFkB activaiton. References_end </body> </html> </notes> <label text="KLF4"/> <bbox w="80.0" h="40.0" x="4420.0" y="4800.0"/> </glyph> <glyph class="macromolecule" id="s2769_sa967" 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:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL10 CASCADE:TGFB CASCADE:MIF CASCADE:CSF1 CASCADE:IL12 CASCADE:STING CASCADE:TLR2_4 CASCADE:IFNAB CASCADE:FLT3LG CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. 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:16713974 Production of IL10 is partially ERK dependent. PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. At the same tyme IL10 siglaning also participates in ID3 upregulation via PI3K/AKT pathway PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages PMID:9834059 NK cells stimulated by IL12 induces IL10 production. PMID:11207245 IFNA induces IL10 production in Dcs (negative loop) PMID:21220452 that IL-10 increased March1 mRNA by approximately six fold PMID:15579430 Metastatic Melanoma Secreted IL-10 Down-Regulates CD1(CD1a, CD1b, CD1c, and CD1d) protein Molecules on Dendritic Cells in Metastatic Tumor Lesions ( PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC References_end </body> </html> </notes> <label text="IL10"/> <bbox w="126.25" h="72.25" x="2149.375" y="5461.375"/> </glyph> <glyph class="macromolecule" id="s2770_sa1056" 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: 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="900.0" y="3660.0"/> <glyph class="unit of information" id="_1d494b57-3dea-4e88-a1bd-06caa14b5995"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="917.5" y="3655.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2796_sa1059"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GSF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter PMID:24091328 G-CSF–induced IRF-8 downregulation via STAT3 in MDSC References_end </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="238.5" y="2720.0"/> </glyph> <glyph class="macromolecule" id="s2797_sa1078"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL3 PMID:15549123 IL3 signaling is important for plasmacytoid DC which are expressing IL3RA. PMID:23762788 Tumor-infiltrating plasmacytoid dendritic cells (pDCs) have been associated with poor patient prognosis. PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce expression ICOS-L and OX40L. PMID:24778133, PMID:23026134 Expression ot ICOS-L and OX40L ligands by pDC promotes tumor progression by Promoting Th2 and Regulatory Immunity. References_end </body> </html> </notes> <label text="IL3"/> <bbox w="80.0" h="40.0" x="240.0" y="1240.0"/> </glyph> <glyph class="macromolecule" id="s2806_sa1095" 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: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="6003.5938" y="6355.9375"/> </glyph> <glyph class="macromolecule" id="s2832_sa1094" 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: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="6003.5938" y="6295.9375"/> </glyph> <glyph class="macromolecule" id="s2833_sa1102" 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: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="6003.5938" y="6245.9375"/> </glyph> <glyph class="macromolecule" id="s2850_sa829" 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:PTPN11 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL3 CASCADE:KIR2DL2 CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:KIR3DL1 CASCADE:KIR2DL4 CASCADE:2B4 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:19833085, PMID:15699106, PMID:12138178 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 PMID:10358138, PMID:15713798 Human 2B4 is phosphorylated following activation and recruits PTPN11 (SHP-2). Association of SAP with h2B4 prevents recruitment of SHP-2. PMID:12707331 There is direct correlation between SHP-2 recruitment and functional inhibition of target cell conjugation and cytotoxicity downstream of KIR3DL. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) . References_end </body> </html> </notes> <label text="PTPN11"/> <clone/> <bbox w="80.0" h="40.0" x="3217.5" y="2870.0"/> </glyph> <glyph class="macromolecule" id="s2850_sa830" 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:PTPN11 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL3 CASCADE:KIR2DL2 CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:KIR3DL1 CASCADE:KIR2DL4 CASCADE:2B4 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:19833085, PMID:15699106, PMID:12138178 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 PMID:10358138, PMID:15713798 Human 2B4 is phosphorylated following activation and recruits PTPN11 (SHP-2). Association of SAP with h2B4 prevents recruitment of SHP-2. PMID:12707331 There is direct correlation between SHP-2 recruitment and functional inhibition of target cell conjugation and cytotoxicity downstream of KIR3DL. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) . References_end </body> </html> </notes> <label text="PTPN11"/> <clone/> <bbox w="80.0" h="40.0" x="3217.5" y="3100.0"/> </glyph> <glyph class="macromolecule" id="s2850_sa1515" 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:PTPN11 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL3 CASCADE:KIR2DL2 CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:KIR3DL1 CASCADE:KIR2DL4 CASCADE:2B4 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:19833085, PMID:15699106, PMID:12138178 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 PMID:10358138, PMID:15713798 Human 2B4 is phosphorylated following activation and recruits PTPN11 (SHP-2). Association of SAP with h2B4 prevents recruitment of SHP-2. PMID:12707331 There is direct correlation between SHP-2 recruitment and functional inhibition of target cell conjugation and cytotoxicity downstream of KIR3DL. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK (directly demonstrated for KIR2DL3 only). (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) . References_end </body> </html> </notes> <label text="PTPN11"/> <clone/> <bbox w="80.0" h="40.0" x="14645.0" y="3030.0"/> </glyph> <glyph class="macromolecule" id="s2854_sa1847" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="15335.0" y="5020.0"/> <glyph class="state variable" id="_291d15ad-1000-427a-ad69-9340df81906d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15330.0" y="5035.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2854_sa2341" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="1510.0" y="4315.0"/> <glyph class="state variable" id="_c516ae96-8631-42b1-abfd-dd28b3cb8cd4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1505.0" y="4330.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2864_sa2" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL3RA Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:MARKERS_DC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL PMID:18633355 (CD123)The surface markers of myeloid cells CASCADE:IL3 PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3RA"/> <bbox w="80.0" h="50.0" x="1773.75" y="217.5"/> <glyph class="unit of information" id="_69cc1930-3fa0-41f3-bd65-0271a059dbc4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1791.25" y="212.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2872_sa1145" 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> 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="7630.0"/> </glyph> <glyph class="macromolecule" id="s2875_sa1148" 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> 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="7620.0"/> </glyph> <glyph class="macromolecule" id="s2879_sa1092" 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: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="5823.5938" y="6385.9375"/> </glyph> <glyph class="macromolecule" id="s2882_sa1160" 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> 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="5020.0" y="1590.0"/> <glyph class="unit of information" id="_7d0cd003-49f8-4ff6-befb-b15a5e692b19"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5037.5" y="1585.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2883_sa1166" 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:CCR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TNF Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. TNF inhibit CCR2 expression in tumor associated macrophages. PMID:15032599 CCR2 is a recptor for CLL2 References_end </body> </html> </notes> <label text="CCR2"/> <bbox w="80.0" h="50.0" x="5650.0" y="1850.0"/> <glyph class="unit of information" id="_2a75b779-1c33-4e6e-8cd8-07a9f7643116"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5667.5" y="1845.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2918_sa1285" 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:GSF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL CASCADE:GSF3 PMID:22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter PMID:24091328 G-CSF–induced IRF-8 downregulation via STAT3 in MDSC References_end </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="4570.0" y="5410.0"/> </glyph> <glyph class="macromolecule" id="s2923_sa1296" 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:IL23A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: 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. PMID:16688182 IL-23 promotes tumour incidence and growth References_end </body> </html> </notes> <label text="IL23A"/> <bbox w="80.0" h="40.0" x="2980.0" y="5560.0"/> </glyph> <glyph class="macromolecule" id="s2945_sa1339" 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: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="11806.25" y="5405.0"/> </glyph> <glyph class="macromolecule" id="s2948_sa1352" 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:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <bbox w="80.0" h="40.0" x="3930.0" y="5360.0"/> </glyph> <glyph class="macromolecule" id="s2955_sa2519" 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:MPP6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:IL4 Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="MPP6"/> <bbox w="80.0" h="40.0" x="3170.0" y="6570.0"/> </glyph> <glyph class="macromolecule" id="s2956_sa1394" 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:CCL24 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IL4 Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="CCL24"/> <bbox w="80.0" h="40.0" x="6410.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s2963_sa1412" 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: HUGO:SIRPA Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:SIRPA MAP:NATURAL_KILLER PMID:11509594 CD47 binds SIRP-α on DC. SIRP-α engagement down-regulates DC function CD47-Fc potently suppressed IL-12 and TNF-α release by monocyte-derived DC stimulated by SAC. The inhibitory effect was dose dependent, and significant suppression was seen with as little as 10 ng/ml CD47-Fc (Fig. 5⇓B). Other cytokines, including IL-6 and IL-10, were also suppressed, CD47-Fc not only suppressed cytokine release by maturing DC, but also largely prevented DC phenotypic maturation. As indicated in Fig. 6⇓, CD83 and CD86 up-regulation were strongly reduced regardless of the stimulus used. For CD80, the inhibition was almost complete in response to CD40 signaling, moderate in response to SAC, and modest, but significant in response to LPS. CD40 expression was weakly up-regulated during DC maturation. In all three conditions, SIRP-α ligation by CD47-Fc abrogated the CD40 increase. Note only a slight reduction in HLA-DR expression. All together, these results demonstrate that engagement of SIRP-α largely inhibits DC maturation References_end </body> </html> </notes> <label text="SIRPA"/> <bbox w="80.0" h="50.0" x="4490.0" y="1315.0"/> <glyph class="unit of information" id="_008584b3-5577-4c06-8345-f69ecbfd4925"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4507.5" y="1310.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2987_sa1440" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD47 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: CASCADE:CD47 MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:SIRPA PMID:11509594 CD47 binds SIRP-α on DC. SIRP-α engagement down-regulates DC function CD47-Fc potently suppressed IL-12 and TNF-α release by monocyte-derived DC stimulated by SAC. The inhibitory effect was dose dependent, and significant suppression was seen with as little as 10 ng/ml CD47-Fc (Fig. 5⇓B). Other cytokines, including IL-6 and IL-10, were also suppressed, CD47-Fc not only suppressed cytokine release by maturing DC, but also largely prevented DC phenotypic maturation. As indicated in Fig. 6⇓, CD83 and CD86 up-regulation were strongly reduced regardless of the stimulus used. For CD80, the inhibition was almost complete in response to CD40 signaling, moderate in response to SAC, and modest, but significant in response to LPS. CD40 expression was weakly up-regulated during DC maturation. In all three conditions, SIRP-α ligation by CD47-Fc abrogated the CD40 increase. Note only a slight reduction in HLA-DR expression. All together, these results demonstrate that engagement of SIRP-α largely inhibits DC maturation. PMID:10657674, PMID:10657674 CD47 is expresed on dendritic cells PMID:10657674, PMID:14568985 CD47 engagement by Thrombospondin-1 inhibits cytokine production and maturation of human dendritic cells. PMID:22310103 CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s [20]. Since then, CD47 has been found to be expressed on multiple human tumor types CD47 functions as an inhibitor of phagocytosis through ligation of SIRPα expressed on phagocytes, leading to tyrosine phosphatase activation and inhibition of myosin accumulation at the submembrane assembly site of the phagocytic synapse [14]. In this way, CD47 serves as a ‘don’t eat me signal’ and a marker of self, as loss of CD47 leads to homeostatic phagocytosis of aged or damaged cells References_end </body> </html> </notes> <label text="CD47"/> <bbox w="80.0" h="50.0" x="4300.0" y="935.0"/> <glyph class="unit of information" id="_55ff7da7-0921-4351-8fb2-4cb71a415723"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4317.5" y="930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2991_sa1423" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="8150.0" y="920.0"/> </glyph> <glyph class="macromolecule" id="s2993_sa1444" 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:LGALS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:LGALS1 PMID:21191065 Cancer-derived galectin-1 mediates dendritic cell anergy through inhibitor of DNA binding 3/IL-10 signaling pathway. LGALS1 upregulates ID3 expression, then ID3 upregulates expression of IL10 in DC. References_end </body> </html> </notes> <label text="LGALS1"/> <bbox w="80.0" h="40.0" x="780.0" y="820.0"/> </glyph> <glyph class="macromolecule" id="s2994_sa1429"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="7390.0" y="1070.0"/> </glyph> <glyph class="macromolecule" id="s3003_sa1411" 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: HUGO:CD47 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: CASCADE:CD47 MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:SIRPA PMID:11509594 CD47 binds SIRP-α on DC. SIRP-α engagement down-regulates DC function CD47-Fc potently suppressed IL-12 and TNF-α release by monocyte-derived DC stimulated by SAC. The inhibitory effect was dose dependent, and significant suppression was seen with as little as 10 ng/ml CD47-Fc (Fig. 5⇓B). Other cytokines, including IL-6 and IL-10, were also suppressed, CD47-Fc not only suppressed cytokine release by maturing DC, but also largely prevented DC phenotypic maturation. As indicated in Fig. 6⇓, CD83 and CD86 up-regulation were strongly reduced regardless of the stimulus used. For CD80, the inhibition was almost complete in response to CD40 signaling, moderate in response to SAC, and modest, but significant in response to LPS. CD40 expression was weakly up-regulated during DC maturation. In all three conditions, SIRP-α ligation by CD47-Fc abrogated the CD40 increase. Note only a slight reduction in HLA-DR expression. All together, these results demonstrate that engagement of SIRP-α largely inhibits DC maturation. PMID:10657674, PMID:10657674 CD47 is expresed on dendritic cells PMID:10657674, PMID:14568985 CD47 engagement by Thrombospondin-1 inhibits cytokine production and maturation of human dendritic cells. PMID:22310103 CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s [20]. Since then, CD47 has been found to be expressed on multiple human tumor types CD47 functions as an inhibitor of phagocytosis through ligation of SIRPα expressed on phagocytes, leading to tyrosine phosphatase activation and inhibition of myosin accumulation at the submembrane assembly site of the phagocytic synapse [14]. In this way, CD47 serves as a ‘don’t eat me signal’ and a marker of self, as loss of CD47 leads to homeostatic phagocytosis of aged or damaged cells References_end </body> </html> </notes> <label text="CD47"/> <bbox w="80.0" h="50.0" x="760.0" y="5630.0"/> <glyph class="unit of information" id="_854b4588-cf6e-4989-9f5b-da354b8700d8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="777.5" y="5625.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3025_sa1165" 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:FN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end </body> </html> </notes> <label text="FN1"/> <bbox w="80.0" h="40.0" x="6170.0" y="2175.0"/> </glyph> <glyph class="macromolecule" id="s3027_sa1195"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="6100.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s3030_sa1200" 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> 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="6010.0" y="1560.0"/> <glyph class="unit of information" id="_9b58af0f-fe8e-4360-a4dd-9ec5d3892e96"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6027.5" y="1555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3036_sa1193"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CCL4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CCR5 CASCADE:TLR2_4 CASCADE:NKG2D PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). References_end </body> </html> </notes> <label text="CCL4"/> <bbox w="80.0" h="40.0" x="6010.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s3061_sa1196"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CCL3 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:CCR5 CASCADE:TLR2_4 PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:16410834 T-bet upregulates the production of proinflammatory cytokine IL-1α and chemokines macrophage inflammatory protein-1α (MIP-1α) and downregulatesthymus- and activation-related chemokine (TARC) by DCs. References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="80.0" h="40.0" x="5920.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s3073_sa1520" 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: 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="16080.0" y="3130.0"/> </glyph> <glyph class="macromolecule" id="s3076_sa1523" 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:IRAK3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:TGFB Maps_Modules_end References_begin: PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. References_end </body> </html> </notes> <label text="IRAK3"/> <bbox w="80.0" h="40.0" x="10705.0" y="2840.0"/> </glyph> <glyph class="macromolecule" id="s3082_sa1551" 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: 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="15945.0" y="3130.0"/> <glyph class="state variable" id="_bb1c4e0c-9f0f-43b8-ba4a-091fa606de12"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16020.0" y="3145.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s3084_sa1554" 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:BIRC2 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: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. References_end </body> </html> </notes> <label text="BIRC2"/> <bbox w="80.0" h="40.0" x="15375.0" y="3380.0"/> </glyph> <glyph class="macromolecule" id="s3085_sa1555" 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:BIRC2 HUGO:BIRC3 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: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. References_end </body> </html> </notes> <label text="cIAP*"/> <bbox w="80.0" h="40.0" x="15315.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s3095_sa1566" 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:BIRC3 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: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. References_end </body> </html> </notes> <label text="BIRC3"/> <bbox w="80.0" h="40.0" x="15245.0" y="3380.0"/> </glyph> <glyph class="macromolecule" id="s3098_sa1570" 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: 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="16205.0" y="3510.0"/> </glyph> <glyph class="macromolecule" id="s3151_sa1487"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ILB1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:P2RX7 CASCADE:TLR2_4 CASCADE:IL15 CASCADE:IL1 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) PMID: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. PMID:24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. References_end </body> </html> </notes> <label text="trILB1"/> <bbox w="80.0" h="40.0" x="6250.0" y="1105.0"/> <glyph class="unit of information" id="_86b377f8-0e68-4a71-a402-975d06ca8b33"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="6265.0" y="1100.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3294_sa1857"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="16600.0" y="4105.0"/> </glyph> <glyph class="macromolecule" id="s3295_sa1858"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="16600.0" y="4790.0"/> </glyph> <glyph class="macromolecule" id="s3325_sa998" 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: 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="700.0" y="4420.0"/> <glyph class="state variable" id="_b22ebd7b-067f-48c7-8657-e145fc32394e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="775.0" y="4453.757"/> </glyph> <glyph class="unit of information" id="_1048ad59-a7c7-4d38-abbf-ed15b98964d8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="717.5" y="4415.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3325_sa1852" 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: 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="16205.0" y="5135.0"/> <glyph class="state variable" id="_65541749-8b94-4b8d-823a-b5d9951d771f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="16280.0" y="5168.757"/> </glyph> <glyph class="unit of information" id="_c54de62b-9f9d-47f8-b7b5-0c3724633f61"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16222.5" y="5130.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3337_sa1954"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="16600.0" y="4350.0"/> </glyph> <glyph class="macromolecule" id="s3350_sa1150"> <notes> <html xmlns="http://www.w3.org/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 PMID:20414655, PMID:18792398 Trx is one of the main intracellular oxido-reductases TXN expression is upregulated in activated macrophages, DC and probably macrophages secrete thioredoxin which reduces extracellular cystine to cysteine, which is then available for the uptake by T cells through their ASC transporter References_end </body> </html> </notes> <label text="TXN"/> <bbox w="80.0" h="40.0" x="15200.0" y="8300.0"/> </glyph> <glyph class="macromolecule" id="s3376_sa24" 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: 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="14750.176" y="6793.972"/> </glyph> <glyph class="macromolecule" id="s3377_sa25" 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> 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="14245.176" y="6800.222"/> <glyph class="unit of information" id="_da53145b-17e0-4ec7-8b12-a154f5c6ca7d"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="14260.176" y="6795.222"/> </glyph> </glyph> <glyph class="macromolecule" id="s3378_sa30" 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: 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="14551.176" y="6658.972"/> </glyph> <glyph class="macromolecule" id="s3379_sa31" 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: 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="14750.176" y="6703.972"/> <glyph class="unit of information" id="_397bcb80-1d32-489b-bd69-6ff795450384"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14767.676" y="6698.972"/> </glyph> </glyph> <glyph class="macromolecule" id="s3380_sa99" 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: 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="13913.125" y="6757.5"/> <glyph class="state variable" id="_5d93d819-775e-47d3-90b2-a0cf4b0ae34b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13908.125" y="6772.5"/> </glyph> <glyph class="unit of information" id="_bd894833-bca2-4f12-95a3-0fb33bd987fd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13930.625" y="6752.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3396_sa36" 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: 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="12093.125" y="6627.5"/> <glyph class="state variable" id="_4dae6fb0-b882-46b8-b3c0-8e6f680c86b5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="12088.125" y="6642.5"/> </glyph> <glyph class="unit of information" id="_984bbe83-f190-4426-8639-e7c64046ed59"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12110.625" y="6622.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3397_sa46" 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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:MCR1 CASCADE:INTEGRIN_AVB3 CASCADE:INTEGRIN_AVB5 CASCADE:CD36 PMID:9510252 Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs PMID:17948027, PMID:22437871, PMID:17204652 Dendritic Cells are critical Antigen-Presenting Cells in tumor Immunity. They present processed protein and lipid antigens to T cells via both classical (major histocompatibility complex (MHC) class I and class II) and non-classical (CD1 family) antigen-presenting molecules. 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). Additionally, after antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecules. PMID:10837075 Immature DCs are very efficient in Ag capture and can use several pathways, such as (a) macropinocytosis; (b) receptor-mediated endocytosis via C-type lectin receptors (mannose receptor, DEC-205) or Fcγ receptor types I (CD64) and II (CD32) [uptake of immune complexes or opsonized particles ]; and (c) phagocytosis of particles such as latex beads , apoptotic and necrotic cell fragments (involving CD36 and αvβ3 or αvβ5 integrins), viruses, and bacteria including mycobacteria, as well as intracellular parasites such as Leishmania major. DCs can also internalize the peptide loaded heat shock proteins gp96 and Hsp70 through presently unknown mechanisms References_end </body> </html> </notes> <label text="Tumor_antigen"/> <bbox w="80.0" h="40.0" x="11690.0" y="6350.0"/> </glyph> <glyph class="macromolecule" id="s3399_sa50" 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: 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="11520.0" y="6560.0"/> <glyph class="unit of information" id="_69d4d9b2-b088-4a67-a628-a2f653ff4911"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11537.5" y="6555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3400_sa57" 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> 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="12080.0" y="6140.0"/> <glyph class="unit of information" id="_8aa9a530-95ba-4c9d-95a0-7b6841450794"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12095.0" y="6135.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3415_sa1235" 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:ILB1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:P2RX7 CASCADE:TLR2_4 CASCADE:IL15 CASCADE:IL1 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) PMID: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. PMID:24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. References_end </body> </html> </notes> <label text="trILB1"/> <bbox w="80.0" h="40.0" x="4700.0" y="6680.0"/> <glyph class="unit of information" id="_946894dc-a78f-451a-bd57-e9646483e778"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4715.0" y="6675.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3428_sa8" 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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:MCR1 CASCADE:INTEGRIN_AVB3 CASCADE:INTEGRIN_AVB5 CASCADE:CD36 PMID:9510252 Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs PMID:17948027, PMID:22437871, PMID:17204652 Dendritic Cells are critical Antigen-Presenting Cells in tumor Immunity. They present processed protein and lipid antigens to T cells via both classical (major histocompatibility complex (MHC) class I and class II) and non-classical (CD1 family) antigen-presenting molecules. 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). Additionally, after antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecules. PMID:10837075 Immature DCs are very efficient in Ag capture and can use several pathways, such as (a) macropinocytosis; (b) receptor-mediated endocytosis via C-type lectin receptors (mannose receptor, DEC-205) or Fcγ receptor types I (CD64) and II (CD32) [uptake of immune complexes or opsonized particles ]; and (c) phagocytosis of particles such as latex beads , apoptotic and necrotic cell fragments (involving CD36 and αvβ3 or αvβ5 integrins), viruses, and bacteria including mycobacteria, as well as intracellular parasites such as Leishmania major. DCs can also internalize the peptide loaded heat shock proteins gp96 and Hsp70 through presently unknown mechanisms References_end </body> </html> </notes> <label text="Tumor_antigen"/> <bbox w="80.0" h="40.0" x="11120.0" y="8850.0"/> </glyph> <glyph class="macromolecule" id="s3431_sa21" 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: CHEBI:17552 KEGGCOMPOUND:C00035 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGA5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A5B1 PMID:24202395, PMID:22067905 References_end </body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="40.0" x="13590.0" y="7310.0"/> <glyph class="unit of information" id="_936a84d2-dd6a-4feb-a13b-5bcac9daabb3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13607.5" y="7305.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3441_sa1831" 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:STAT5A HUGO:STAT5B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 CASCADE:CSF2 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. PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. 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 (.) References_end </body> </html> </notes> <label text="STAT5*"/> <bbox w="80.0" h="40.0" x="14525.0" y="5300.0"/> <glyph class="state variable" id="_781f34d0-366e-4c81-8211-f4100a5dd694"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14520.0" y="5315.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3463_sa1971" 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: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="12605.0" y="3210.0"/> </glyph> <glyph class="macromolecule" id="s3464_sa1974" 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: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="12715.0" y="3650.0"/> </glyph> <glyph class="macromolecule" id="s3465_sa1975" 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: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="13215.0" y="3630.0"/> </glyph> <glyph class="macromolecule" id="s3466_sa1977" 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: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="13205.0" y="3020.0"/> <glyph class="state variable" id="_3716cafb-f4ba-4557-b63d-eb806d3423c3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13280.0" y="3035.4336"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s3468_sa1981" 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: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="86.0" h="46.0" x="11922.0" y="3107.0"/> <glyph class="unit of information" id="_81a6bfca-0739-4be3-bd12-47a177717912"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="11955.0" y="3102.0"/> </glyph> <glyph class="state variable" id="_8a4fe3db-cf70-4655-9e38-5d30e0bfd93a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11914.5" y="3125.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s3469_sa1982" 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: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="86.0" h="46.0" x="11912.0" y="2997.0"/> <glyph class="unit of information" id="_0a9bdcfc-6a98-49b6-9c7c-2b633bc5367c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="11945.0" y="2992.0"/> </glyph> <glyph class="state variable" id="_043c586f-1d45-4681-9209-7cce4b14b5fa"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11907.0" y="3015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3473_sa1994" 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: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="140.0" h="90.0" x="11685.0" y="3485.0"/> <glyph class="unit of information" id="_5ee420b6-bff5-4b0c-b3f5-05d3ded68d95"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="11730.0" y="3480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3474_sa1995" 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:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 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="NFKB1_p105*"/> <bbox w="130.0" h="80.0" x="11690.0" y="3180.0"/> <glyph class="state variable" id="_da506f56-756b-409c-8085-31386c44476e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11685.0" y="3215.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3477_sa1998" 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:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 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="NFKB1_p105*"/> <bbox w="130.0" h="80.0" x="10930.0" y="3610.0"/> <glyph class="state variable" id="_c4e215ff-84d9-4a4f-bf96-8c5c21377942"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10922.5" y="3645.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3540_sa2615"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MAP:NATURAL_KILLER CASCADE:CXCR3 CASCADE:IFNAB CASCADE:TLR2_4 MAP:DENDRITIC_CELL Maps_Modules_end References_begin: PMID:18922917 Significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3−/− mice, and the capacity of adoptively transferred CXCR3−/− NK cells to accumulate in the tumor was severely impaired. Ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell–dependent survival. References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="80.0" h="40.0" x="5250.0" y="1125.0"/> </glyph> <glyph class="macromolecule" id="s3541_sa1335" 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:CCL18 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:IFNAB MAP:DENDRITIC_CELL PMID:11698286 IFNA upregulates chemokine mRNA expression CCL18 (DC-DK1), CXCL10 (IP10) , References_end </body> </html> </notes> <label text="CCL18"/> <bbox w="80.0" h="40.0" x="6210.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s3550_sa845" 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: 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="4125.0" y="1695.0"/> <glyph class="state variable" id="_b36ca01b-0f9f-45ad-a60f-088ea7f6e897"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4117.5" y="1715.0"/> </glyph> <glyph class="unit of information" id="_f7bee90b-4f10-463f-b6dc-b77392a92557"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4142.5" y="1690.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3559_sa1164" 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> 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="5130.0" y="1540.0"/> <glyph class="unit of information" id="_ce6aa8e5-5535-427b-8ccc-df4c0e181e57"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5147.5" y="1535.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3563_sa2072" 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: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="4280.0" y="4500.625"/> </glyph> <glyph class="macromolecule" id="s3573_sa2086" 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:IRF5 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:MIF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as IRF5 PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IRF5"/> <bbox w="80.0" h="40.0" x="10275.0" y="4625.0"/> </glyph> <glyph class="macromolecule" id="s3574_sa1547" 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:IRF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:IL2 CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 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. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="80.0" h="40.0" x="10445.0" y="4685.0"/> <glyph class="state variable" id="_7f25357f-e1df-4ec1-94cc-c19493841d87"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10440.0" y="4700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3577_sa1543" 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:IRF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:IL2 CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 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. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="80.0" h="40.0" x="10445.0" y="4795.0"/> <glyph class="state variable" id="_4d61d8c0-9389-40a7-a49e-f7fdf59c82ad"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="10435.0" y="4810.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3578_sa1985" 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:IRF3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TGFB CASCADE:STING 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:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages.. References_end </body> </html> </notes> <label text="IRF3"/> <bbox w="80.0" h="40.0" x="10782.5" y="4718.75"/> <glyph class="state variable" id="_2a0671ac-a136-49e5-b564-b2f4c5de48d6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10777.5" y="4733.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s3579_sa1984" 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:IRF3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TGFB CASCADE:STING 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:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages.. References_end </body> </html> </notes> <label text="IRF3"/> <bbox w="80.0" h="40.0" x="10782.5" y="4798.75"/> <glyph class="state variable" id="_a6318998-4579-46f3-81c3-f70e205e6bdb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10775.0" y="4813.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s3580_sa2093" 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: 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="760.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s3585_sa2098" 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:PTGS2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MIF CASCADE:TLR2_4 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:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="80.0" h="40.0" x="4140.0" y="5920.0"/> </glyph> <glyph class="macromolecule" id="s3597_sa2116" 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:MAP2K4 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. PMID:17379190 MEK4/JNK/AP-1 path way is active in mactophages downstream of TLR4, and induces iNOS expression. PMID:15170913, PMID:9582321, PMID:11668179 MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway upregulates COX2 expression and PGE2 production in macrophages, via activation of transcription factor C/EBP beta. References_end </body> </html> </notes> <label text="MAP2K4"/> <bbox w="80.0" h="40.0" x="10691.0" y="3280.0"/> <glyph class="state variable" id="_34499f22-7798-47a5-b357-09aa2a0f8618"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10686.0" y="3295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3598_sa2117" 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:MAP2K4 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. PMID:17379190 MEK4/JNK/AP-1 path way is active in mactophages downstream of TLR4, and induces iNOS expression. PMID:15170913, PMID:9582321, PMID:11668179 MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway upregulates COX2 expression and PGE2 production in macrophages, via activation of transcription factor C/EBP beta. References_end </body> </html> </notes> <label text="MAP2K4"/> <bbox w="80.0" h="40.0" x="10691.0" y="3380.0"/> <glyph class="state variable" id="_6a83eb60-8148-4f86-b783-112a24423c9c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10683.5" y="3395.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3599_sa2123" 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:MAP2K3 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:TLR2_4 PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. PMID:9379049 MKK3 and MKK4 are capable of phosphorylating p38mapk in macrophages, downstream of TNF/Tnf receptor signaling. References_end </body> </html> </notes> <label text="MAP2K3"/> <bbox w="80.0" h="40.0" x="10361.0" y="3330.0"/> <glyph class="state variable" id="_8b1eb481-17fa-4d11-88b8-6bbbdeb6d8bc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10356.0" y="3345.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3600_sa2124" 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:MAP2K3 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:TLR2_4 PMID:10661401 MKK3 is activated by β1 Integrin Cross-Linking on Human NK Cells, It activates p38MAPK regulated IL8 production by NK cells downstream of integrin signaling. PMID:9379049 MKK3 and MKK4 are capable of phosphorylating p38mapk in macrophages, downstream of TNF/Tnf receptor signaling. References_end </body> </html> </notes> <label text="MAP2K3"/> <bbox w="80.0" h="40.0" x="10361.0" y="3410.0"/> <glyph class="state variable" id="_beda2f8e-4a40-4416-9a0d-b3d297970dff"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10353.5" y="3425.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3602_sa2131" 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:MYC Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:GSF3 CASCADE:IL4 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="MYC"/> <bbox w="80.0" h="40.0" x="5190.0" y="4636.875"/> </glyph> <glyph class="macromolecule" id="s3603_sa2132" 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:CEBPB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MDSC CASCADE:GSF3 PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. References_end </body> </html> </notes> <label text="CEBPB"/> <bbox w="80.0" h="40.0" x="4970.0" y="4516.875"/> <glyph class="state variable" id="_6792abaa-cd3c-4f0d-8b14-c0fda0cd2fb9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4962.5" y="4531.8433"/> </glyph> </glyph> <glyph class="macromolecule" id="s3604_sa2133" 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:CEBPD Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:11668179 CEBPD syntesis and activity are induced downstream of TLR4/p38 signaling. It regulates COX2 expression. References_end </body> </html> </notes> <label text="CEBPD"/> <bbox w="80.0" h="40.0" x="4151.0" y="4500.625"/> </glyph> <glyph class="macromolecule" id="s3615_sa2008" 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:FOS Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:21385848, PMID:22634314 c-Fos downregulates mRNA expression of TNF, IL6, IL1B, IL12p40. IL12p35, IL23a Additionally Fos downregulates CD86, CD40 surface expression, IL2 secretion and Tcell activation. PMID:22634314 Expression of IL-10 was enhanced in DC overexpressed Fos. PMID:16394015 PMID:19667062 TPL-2 ERK pathway induces Fos expression in macrophages () PMID:16394015 , PMID:19667062, PMID:15067049 Fos inhibits the expression of IL-12 p40 and IFNB and upregulates IL10 production downstream of FOS in macrophages and DCs PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 References_end </body> </html> </notes> <label text="FOS"/> <bbox w="80.0" h="40.0" x="2755.625" y="4568.125"/> <glyph class="state variable" id="_999febae-f294-4aa4-997c-3206b9036171"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2750.625" y="4583.125"/> </glyph> </glyph> <glyph class="macromolecule" id="s3616_sa2138" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CRP Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII PMID:3489521, PMID:11801683, PMID:15531769 Macrophage tumoricidal activity induced by human C-reactive protein. Probably through Fc gamma RIIa and FcγRI receptors and PI3K, PLCG pathways. This pathway is involeved also in neutrophil activity regulation. References_end </body> </html> </notes> <label text="CRP"/> <bbox w="80.0" h="40.0" x="10172.5" y="1000.0"/> </glyph> <glyph class="macromolecule" id="s3617_sa2139" 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: HUGO:C5AR1 HUGO:C5AR2 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:C5 MAP:MDSC PMID:18820683 C5a via C5AR regulates the accumulation and migration of MDSCs in tumor References_end </body> </html> </notes> <label text="C5AR*"/> <bbox w="80.0" h="50.0" x="5650.0" y="1380.0"/> <glyph class="unit of information" id="_5e6ea991-ec92-4b7b-a6b6-6bf8d02890cb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5667.5" y="1375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3624_sa2148" 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:TMEM173 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING 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: 23986532 STING ablation abolished hallmark TGF-β and IL-10 regulatory cytokine induction (mRNA)by apoptotic cells, and proinflammatory IL-6 mRNA was expressed instead in DCs References_end </body> </html> </notes> <label text="STING*"/> <bbox w="80.0" h="40.0" x="6897.5" y="2210.0"/> </glyph> <glyph class="macromolecule" id="s3625_sa1987" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING PMID:25517615, PMID:25517609, PMID:24766893 Activated STING then recruits TBK1 to phosphorylate IRF3 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. References_end </body> </html> </notes> <label text="TBK1"/> <clone/> <bbox w="80.0" h="40.0" x="10675.0" y="4705.0"/> </glyph> <glyph class="macromolecule" id="s3625_sa2149" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING PMID:25517615, PMID:25517609, PMID:24766893 Activated STING then recruits TBK1 to phosphorylate IRF3 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. References_end </body> </html> </notes> <label text="TBK1"/> <clone/> <bbox w="80.0" h="40.0" x="7017.5" y="2240.0"/> </glyph> <glyph class="macromolecule" id="s3625_sa2635" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING PMID:25517615, PMID:25517609, PMID:24766893 Activated STING then recruits TBK1 to phosphorylate IRF3 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. References_end </body> </html> </notes> <label text="TBK1"/> <clone/> <bbox w="80.0" h="40.0" x="10675.0" y="4635.0"/> </glyph> <glyph class="macromolecule" id="s3651_sa2168" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PECAM1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:PECAM1 MAP:NEUTROPHIL MAP:MACROPHAGE PMID:12110892 CD31 (also known as platelet-endothelial cell adhesion molecule-1, PECAM-1) is an example of a cell-surface molecule that prevents phagocyte ingestion of closely apposed viable cells by transmitting 'detachment' signals, and which changes function on apoptosis, promoting tethering of dying cells to phagocytes. References_end </body> </html> </notes> <label text="PECAM1"/> <bbox w="80.0" h="50.0" x="4440.0" y="945.0"/> <glyph class="unit of information" id="_a7360ea1-7021-4e8c-8299-1878f647d7f8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4457.5" y="940.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3683_sa2169" 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: HUGO:STAB2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:STAB2 PMID:17962816 The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-beta. Furthermore, the results of time-lapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. References_end </body> </html> </notes> <label text="STAB2"/> <bbox w="80.0" h="50.0" x="7252.5" y="1395.0"/> <glyph class="unit of information" id="_5176f83b-132f-4dcb-9043-ed04e1d69a9f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7270.0" y="1390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3687_sa2172" 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: HUGO:ADGRB1 Identifiers_end References_begin: PMID:17960134 ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment. phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells by macrophages. References_end </body> </html> </notes> <label text="ADGRB1"/> <bbox w="80.0" h="50.0" x="7362.5" y="1395.0"/> <glyph class="unit of information" id="_8696ddb0-e3b7-4050-ba7d-31a76d69a752"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7380.0" y="1390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3691_sa2175" 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: HUGO:TIMD4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TIMD4 PMID:18082433 TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. References_end </body> </html> </notes> <label text="TIMD4"/> <bbox w="80.0" h="50.0" x="7652.5" y="1395.0"/> <glyph class="unit of information" id="_bef34bec-5b4a-4e93-9a4d-65e415bd5f93"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7670.0" y="1390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3692_sa2176" 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: HUGO:HAVCR1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:HAVCR1 PMID:18082433 TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1(HAVCR1) specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. References_end </body> </html> </notes> <label text="HAVCR1"/> <bbox w="80.0" h="50.0" x="7532.5" y="1385.0"/> <glyph class="unit of information" id="_31a9b409-9efb-4989-935a-e20521d7b125"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7550.0" y="1380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3694_sa2179" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PROS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK PMID:12447359 Purified protein S was equivalent to serum in its ability to stimulate macrophage phagocytosis of apoptotic lymphoma cells, and immunodepletion of protein S eliminated the prophagocytic activity of serum. Protein S acted by binding to phosphatidylserine expressed on the apoptotic cell surface. PMID:25695599 Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells downstream of PROS1 and Gas6 References_end </body> </html> </notes> <label text="PROS1"/> <bbox w="80.0" h="40.0" x="7770.0" y="920.0"/> </glyph> <glyph class="macromolecule" id="s3709_sa2188" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GAS6 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK PMID:19631584 The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. PMID:25695599 Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells downstream of PROS1 and Gas6 References_end </body> </html> </notes> <label text="GAS6"/> <bbox w="80.0" h="40.0" x="7900.0" y="920.0"/> </glyph> <glyph class="macromolecule" id="s3722_sa2196" 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: HUGO:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:CR4 CASCADE:FLT3LG CASCADE:IFNAB PMID:15573129 CD11c is a maker of myeloid DCs. PMID:8920882 FLT3 ligand upregulates surface expression of CD11c 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, CD206, CD23 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="CD11c*"/> <bbox w="80.0" h="50.0" x="9462.5" y="1495.0"/> <glyph class="unit of information" id="_9ff5d30b-592b-4231-9200-6144d0d739a3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9480.0" y="1490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3726_sa2199" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C1QA HUGO:C1QB HUGO:C1QC Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR1 PMID:11120776 CR1 is a receptor for all the primary opsonins of complement, namely, MBL, C1q, References_end </body> </html> </notes> <label text="C1q*"/> <bbox w="80.0" h="40.0" x="9960.0" y="1000.0"/> </glyph> <glyph class="macromolecule" id="s3727_sa2200" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C4B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: CASCADE:CR1 PMID:2972794 CR1 is a receptor for all the primary opsonins of complement, namely C4b, and C3b. References_end </body> </html> </notes> <label text="C4B"/> <bbox w="80.0" h="40.0" x="9850.0" y="1000.0"/> </glyph> <glyph class="macromolecule" id="s3728_sa2201" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR1 CASCADE:CR4 CASCADE:CR3 References_end </body> </html> </notes> <label text="C3"/> <bbox w="80.0" h="40.0" x="9537.5" y="1000.0"/> </glyph> <glyph class="macromolecule" id="s3729_sa2202"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR1 CASCADE:CR4 CASCADE:CR3 PMID:1358992 Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized cells. References_end </body> </html> </notes> <label text="iC3b*"/> <bbox w="80.0" h="40.0" x="9542.5" y="1180.0"/> <glyph class="unit of information" id="_f6843099-b2da-49df-87f6-0dae2d000777"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="9557.5" y="1175.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3730_sa2203"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:C3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR1 CASCADE:CR4 CASCADE:CR3 PMID:2972794 CR1 is a receptor for all the primary opsonins of complement, namely C4b, and C3b. References_end </body> </html> </notes> <label text="C3B*"/> <bbox w="80.0" h="40.0" x="9537.5" y="1090.0"/> <glyph class="unit of information" id="_970810ba-d6b2-457e-bac3-3e64ad7d4239"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="9552.5" y="1085.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3731_sa2204" 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: HUGO:FCGR2A HUGO:FCGR2C Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:Fc_gamma_RII 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. 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:8132624 Hck, Lyn binds to Fc_gamma_RII (CD32) and phosphorylates it in monocytes. References_end </body> </html> </notes> <label text="FcγRII_activating*"/> <bbox w="80.0" h="50.0" x="10227.5" y="1475.0"/> <glyph class="state variable" id="_854e25b3-468b-4217-91d4-7c902672b0d9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10222.5" y="1495.0"/> </glyph> <glyph class="unit of information" id="_9afa68c4-aab0-4330-8fae-4992aca78f4c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10245.0" y="1470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3732_sa2205" 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: HUGO:FCGR1A HUGO:FCGR1B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:Fc_gamma_RI 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 PMID:8064233 Hck, Lyn binds to Fc_gamma_RI (cd64) in monocytes and probably phosphorylate ignal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. PMID:26819959 Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy. References_end </body> </html> </notes> <label text="FcγRI*"/> <bbox w="80.0" h="50.0" x="10117.5" y="1475.0"/> <glyph class="unit of information" id="_535e1ff9-3959-4bf2-8284-ee5573ca1f2e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10135.0" y="1470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3733_sa2206" 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: HUGO:FCER1A HUGO:FCER1G HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL CASCADE:FCER PMID:8283051 FCE RI and FcyRlll trigger phagocytosis in mast cells PMID:9000133 Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. PMID:1534410 Two forms of the low-affinity Fc receptor for IgE (Fc epsilon RIIa and Fc epsilon RIIb)differentially mediate endocytosis and phagocytosis PMID:6401249 Fc receptor for IgE provides phagocytosis in macrophages. 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="FcεR*"/> <bbox w="80.0" h="50.0" x="9937.5" y="1475.0"/> <glyph class="state variable" id="_f154fc0a-dc88-470c-840d-e5f41f9b3c2a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9932.5" y="1495.0"/> </glyph> <glyph class="unit of information" id="_9951f524-907b-4e6e-a531-ece66244edd5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9955.0" y="1470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3735_sa2209" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MBL2 Identifiers_end Maps_Modules_begin: MODULE:DANGER_SIGNAL_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: CASCADE:CR1 PMID:11120776 CR1 is a receptor for all the primary opsonins of complement, namely, MBL, C1q, References_end </body> </html> </notes> <label text="MBL2"/> <bbox w="80.0" h="40.0" x="9710.0" y="1000.0"/> </glyph> <glyph class="macromolecule" id="s3744_sa2216" 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: HUGO:FCGR2B Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL CASCADE:FCGR2B PMID:24445665 The activation of macrophages by immune complexes is determined by the balance between the triggering of activating ITAM-bearing FcγRs and the triggering of inhibitory ITIM-bearing FcγRIIB. PMID:18759918, PMID:8805703, PMID:1238444 Inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors. 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:12176909, PMID:12773515 In macrophages SHP-1 inhibits Fcgamma receptor-mediated phagocytosis and the activation of RAC. Probably downstream of FcgammaRII(b) and other receptors. References_end </body> </html> </notes> <label text="FcγRII_inhibiting*"/> <bbox w="80.0" h="50.0" x="2265.0" y="1445.0"/> <glyph class="unit of information" id="_ebd09e87-ed96-41af-9c25-22e6b7d31a99"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2282.5" y="1440.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3754_sa2223" 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: 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="10247.5" y="1805.0"/> <glyph class="unit of information" id="_1120509c-cf9d-4df5-8c3f-73ec6ae86f7e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10265.0" y="1800.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3755_sa2224" 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: HUGO:FCAR Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:FCAR PMID:9952373, PMID:2451784 FcαRI provides phagocytosis in neurophiles. GM-CSF and G-CSF both activates gA-mediated phagocytosis in neutrophiles PMID:7590867 Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation. References_end </body> </html> </notes> <label text="FCAR"/> <bbox w="80.0" h="50.0" x="10027.5" y="1475.0"/> <glyph class="unit of information" id="_7b8c2e23-152a-4e23-a25f-3d0803cd81a0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10045.0" y="1470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3766_sa2235" 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: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="9445.0" y="3025.0"/> <glyph class="state variable" id="_9aaa728b-2ce2-493d-916c-8a46aa2c18c8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9437.5" y="3045.0"/> </glyph> <glyph class="unit of information" id="_775d2536-455f-4920-9d24-9e2f2c535783"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9462.5" y="3020.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3773_sa2242" 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> Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:19741094, 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. WASP was required for actin polymerization, whereas N-WASP was required for pseudopod protrusion. Cdc42 Is Required for Activation and Tyrosine Phosphorylation of WASP/N-WASP References_end </body> </html> </notes> <label text="WASL"/> <bbox w="80.0" h="40.0" x="10670.0" y="6750.0"/> <glyph class="state variable" id="_6a556721-dbb0-4b23-9149-a29a837c2d1a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10665.0" y="6765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3774_sa2243" 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> Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: PMID:19741094, 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. WASP was required for actin polymerization, whereas N-WASP was required for pseudopod protrusion. Cdc42 Is Required for Activation and Tyrosine Phosphorylation of WASP/N-WASP References_end </body> </html> </notes> <label text="WASL"/> <bbox w="80.0" h="40.0" x="10670.0" y="6860.0"/> <glyph class="state variable" id="_249f4c1f-d029-417b-a20c-2bc5893ec912"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10662.5" y="6875.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3775_sa2244" 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:MYL6 HUGO:MYL6B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10710.0" y="5890.0"/> </glyph> <glyph class="macromolecule" id="s3776_sa2245" 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:MYL9 HUGO:MYL12A HUGO:MYL12B Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:CR3 PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="10720.0" y="5980.0"/> <glyph class="state variable" id="_e2a062f2-f086-4959-8c20-c22682c45b71"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10715.0" y="5995.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s3777_sa2246" 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:MYH9 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 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. References_end </body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="10617.0" y="6107.0"/> <glyph class="unit of information" id="_e2529514-e386-48ba-89cf-aae1e5562d96"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="10650.0" y="6102.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3786_sa2253" 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:MYLK HUGO:MYLK2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:25712372, PMID:12194823 MLCK and ROCK phosphorylares RLC 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. MLCK caused a significant reduction of both myosin-IIA localization and particle uptake, while it did not affect actin or Arp2/3 complex recruitment, suggesting a role for MLCK and myosin-IIA in later steps of phagosome formation PMID:10733514 ERK2 activated MLCK, resulting in phosphorylation of the MLCK substrate or of the myosin light chain itself. And induces phagocytosis. References_end </body> </html> </notes> <label text="MLCK*"/> <bbox w="80.0" h="40.0" x="10840.0" y="6240.0"/> <glyph class="state variable" id="_0e762b0d-a67f-497c-a504-80ad781f7177"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10832.5" y="6255.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3794_sa2259" 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:MYLK HUGO:MYLK2 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:25712372, PMID:12194823 MLCK and ROCK phosphorylares RLC 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. MLCK caused a significant reduction of both myosin-IIA localization and particle uptake, while it did not affect actin or Arp2/3 complex recruitment, suggesting a role for MLCK and myosin-IIA in later steps of phagosome formation PMID:10733514 ERK2 activated MLCK, resulting in phosphorylation of the MLCK substrate or of the myosin light chain itself. And induces phagocytosis. References_end </body> </html> </notes> <label text="MLCK*"/> <bbox w="80.0" h="40.0" x="10839.0" y="6150.0"/> <glyph class="state variable" id="_e58b3315-a324-4eed-8687-154f9f6dff11"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10834.0" y="6165.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3795_sa2260" 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:DOC1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_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="DOCK1"/> <bbox w="80.0" h="40.0" x="8010.0" y="3310.0"/> </glyph> <glyph class="macromolecule" id="s3809_sa2266" 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:WNT7B Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MDSC PMID:24638982 we found tumor progression relied upon WNT7B produced by myeloid cells in the microenvironment. Wnt7b deletion in myeloid cells reduced the mass and volume of tumors due to a failure in the angiogenic switch. References_end </body> </html> </notes> <label text="WNT7B"/> <bbox w="80.0" h="40.0" x="4030.0" y="7510.0"/> </glyph> <glyph class="macromolecule" id="s3810_sa2267" 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:ADM Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:21994414 ADM was expressed by infiltrating TAMs in human melanoma, and its secretion from macrophages was upregulated upon coculture with melanoma cells, or with melanoma cells conditioned media. Meanwhile, TAMs enhanced endothelial cell migration and tubule formation and also increased B16/F10 tumor growth. Neutralizing ADM antibody and ADM receptor antagonist, AMA, attenuated TAM-induced angiogenesis in vitro and melanoma growth in vivo, respectively. References_end </body> </html> </notes> <label text="ADM"/> <bbox w="80.0" h="40.0" x="4210.0" y="7170.0"/> </glyph> <glyph class="macromolecule" id="s3811_sa2268" 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:MMP1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. References_end </body> </html> </notes> <label text="MMP1"/> <bbox w="80.0" h="40.0" x="3370.0" y="6740.0"/> </glyph> <glyph class="macromolecule" id="s3813_sa2270" 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:MMP3 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. References_end </body> </html> </notes> <label text="MMP3"/> <bbox w="80.0" h="40.0" x="3360.0" y="6900.0"/> </glyph> <glyph class="macromolecule" id="s3814_sa2271" 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:MMP7 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:18633355 MMP7, MMP9 and MMP12 drives angiogenesis References_end </body> </html> </notes> <label text="MMP7"/> <bbox w="80.0" h="40.0" x="3360.0" y="6990.0"/> </glyph> <glyph class="macromolecule" id="s3815_sa2272" 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:MMP10 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:23691065 Macrophage migration and invasion is regulated by MMP10 expression. References_end </body> </html> </notes> <label text="MMP10"/> <clone/> <bbox w="80.0" h="40.0" x="3090.0" y="6830.0"/> </glyph> <glyph class="macromolecule" id="s3815_sa2284" 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:MMP10 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:23691065 Macrophage migration and invasion is regulated by MMP10 expression. References_end </body> </html> </notes> <label text="MMP10"/> <clone/> <bbox w="80.0" h="40.0" x="6160.0" y="2075.0"/> </glyph> <glyph class="macromolecule" id="s3816_sa2273" 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:MMP12 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:18633355 MMP7, MMP9 and MMP12 drives angiogenesis References_end </body> </html> </notes> <label text="MMP12"/> <bbox w="80.0" h="40.0" x="3090.0" y="6990.0"/> </glyph> <glyph class="macromolecule" id="s3817_sa2274" 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:MMP14 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:18633355 MDSC isolated from murine tumours express higher levels of various MMPs (MMP2, MMP9, MMP13 and MMP14 than MDSC from healthy mice References_end </body> </html> </notes> <label text="MMP14"/> <bbox w="80.0" h="40.0" x="2790.0" y="6840.0"/> </glyph> <glyph class="macromolecule" id="s3818_sa2275" 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:MMP25 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. References_end </body> </html> </notes> <label text="MMP25"/> <bbox w="80.0" h="40.0" x="2790.0" y="7010.0"/> </glyph> <glyph class="macromolecule" id="s3819_sa2276" 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:TIMP3 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:IL4 PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:25171061, PMID:26707830 TIMP3 is a dominant negative regulator of angiogenesis TIMP-3 expression in tumor microenvironment suggests a favorable prognosis for HCC patients. PMID:25807548 Among the TIMP family, TIMP3 is unique in that it is tightly bound to the extracellular matrix via heparan sulfate and it has the most broad protease-inhibition profile which in addition to MMPs includes many ADAMs (a disintegrin and metalloproteinase). Specifically, TIMP3 is the sole inhibitor of ADAM17, also known as tumor necrosis factor alpha (TNF) converting enzyme (TACE) References_end </body> </html> </notes> <label text="TIMP3"/> <bbox w="80.0" h="40.0" x="3330.0" y="6580.0"/> </glyph> <glyph class="macromolecule" id="s3820_sa2277" 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:MMP2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:24526468 Pancreatic cancer cells (Panc-1, MiaPaca-2, HPAF, and ASPC, data pooled) upregulated MMP2 expression in macrophages . PMID:18633355 MDSC isolated from murine tumours express higher levels of various MMPs (MMP2, MMP9, MMP13 and MMP14 than MDSC from healthy mice References_end </body> </html> </notes> <label text="MMP2"/> <bbox w="80.0" h="40.0" x="3370.0" y="6820.0"/> </glyph> <glyph class="macromolecule" id="s3821_sa2278" 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:MMP8 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. PMID:26819959 Neutrophils produce MMP8 References_end </body> </html> </notes> <label text="MMP8"/> <bbox w="80.0" h="40.0" x="3090.0" y="6740.0"/> </glyph> <glyph class="macromolecule" id="s3822_sa2279" 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:MMP19 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. References_end </body> </html> </notes> <label text="MMP19"/> <bbox w="80.0" h="40.0" x="2790.0" y="6930.0"/> </glyph> <glyph class="macromolecule" id="s3823_sa2280" 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:MMP11 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22880008 Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. References_end </body> </html> </notes> <label text="MMP11"/> <bbox w="80.0" h="40.0" x="3090.0" y="6900.0"/> </glyph> <glyph class="macromolecule" id="s3839_sa2287" 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:PLAU Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. References_end </body> </html> </notes> <label text="PLAU"/> <bbox w="80.0" h="40.0" x="4380.0" y="7290.0"/> </glyph> <glyph class="macromolecule" id="s3840_sa2288" 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:PDGFB Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. PMID:24359404 PDGF signaling drives tumor growth PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, histamine, which is an immunosuppressant, mitogenic factors, such as platelet-derived growth factor (PDGF), nerve GF (NGF), stem-cell factor (SCF), and proteases, which disrupt the surrounding matrix and facilitate metastases. References_end </body> </html> </notes> <label text="PDGFB"/> <bbox w="80.0" h="40.0" x="4380.0" y="7170.0"/> </glyph> <glyph class="macromolecule" id="s3842_sa2290" 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:HGF Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL PMID:18633355 Hypoxia induces a distinct pro-angiogenic phenotype in human macrophages in vitro42, 43 including the upregulation of VEGF, bFGF, CXCL8, COX2, hepatocyte growth factor (HGF), VEGFR1, tissue factor (F3) and MMP12. PMID:16212809 HGF drives tumor growth PMID:26819959, PMID:12649206 Neutrophiles produce HGF and induce tumor growth High HGF levels in BALF supernatants were significantly associated with poorer outcome in patients with BAC References_end </body> </html> </notes> <label text="HGF"/> <bbox w="80.0" h="40.0" x="4190.0" y="7500.0"/> </glyph> <glyph class="macromolecule" id="s3844_sa2292" 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:MMP13 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MDSC PMID:18633355 MDSC isolated from murine tumours express higher levels of various MMPs (MMP2, MMP9, MMP13 and MMP14 than MDSC from healthy mice References_end </body> </html> </notes> <label text="MMP13"/> <bbox w="80.0" h="40.0" x="2790.0" y="6750.0"/> </glyph> <glyph class="macromolecule" id="s3845_sa2293" 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:OSM Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:NEUTROPHIL PMID:16204061 Upon contact with breast carcinoma cell lines in vitro neutrophils secrete oncostatin M. This pleiotropic cytokine induces breast cancer cells to secrete VEGF and thus promote angiogenesis References_end </body> </html> </notes> <label text="OSM"/> <bbox w="80.0" h="40.0" x="4220.0" y="7280.0"/> </glyph> <glyph class="macromolecule" id="s3847_sa2295" 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:ANGPT1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MAST_CELL PMID:15520864 Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors. References_end </body> </html> </notes> <label text="ANGPT1"/> <bbox w="80.0" h="40.0" x="3600.0" y="7505.0"/> </glyph> <glyph class="macromolecule" id="s3855_sa2310" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="12746.25" y="5655.0"/> </glyph> <glyph class="macromolecule" id="s3855_sa2725" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="7855.0" y="7665.0"/> </glyph> <glyph class="macromolecule" id="s3858_sa2314" 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:EGF Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:8101258 In cell populations derived from primary breast carcinoma, epidermal growth factor (EGF) is secreted by cells with the characteristic morphological and immunophenotypic profile of activated macrophages PMID:15958574, PMID:15466195 Macrophages express epidermal growth factor (EGF), which promotes the formation of elongated protrusions and cell invasion by carcinoma cells. Colony stimulating factor 1 (CSF-1) produced by carcinoma cells promotes the expression of EGF by macrophages. In addition, EGF promotes the expression of CSF-1 by carcinoma cells thereby generating a positive feedback loop. Disruption of this loop by blockade of either EGF receptor or CSF-1 receptor signaling is sufficient to inhibit both macrophage and tumor cell migration and invasion. References_end </body> </html> </notes> <label text="EGF"/> <bbox w="80.0" h="40.0" x="3710.0" y="7505.0"/> </glyph> <glyph class="macromolecule" id="s3860_sa2317" 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:TYMP Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:12543812, PMID:11011118 Monocytes are expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration in tumors and drive angiogenesis. References_end </body> </html> </notes> <label text="TYMP"/> <bbox w="80.0" h="40.0" x="4690.0" y="7280.0"/> </glyph> <glyph class="macromolecule" id="s3861_sa2318" 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:IDO1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IFNG CASCADE:TLR2_4 CASCADE:TNF PMID:15459668 Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan.Cells expressing IDO can suppress T-cell responses and promote tolerance IDO could be expressed by Macrophages and DCs. he mouse and human IDO gene promoters contain multiple sequence elements that confer responsiveness to type I (IFN-/) and, more potently, type II (IFN-) interferon. IDO-expressing host APCs (whatever their subtype) might contribute to a state of local immunosuppression in tumour-draining lymph nodes, and might help to induce systemic tolerance to tumour antigens as well. PMID:8663541 IFNG induces IDO expression via STAT1 and IRF-1 in DC PMID:11477543 TLR4 -induced systemic IDO is largely dependent on TNF-alpha rather than IFN-gamma in macrophages. References_end </body> </html> </notes> <label text="IDO1"/> <bbox w="80.0" h="40.0" x="4520.0" y="5930.0"/> </glyph> <glyph class="macromolecule" id="s3866_sa2323" 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: HUGO:KDR Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:VEGFA PMID:17086423 Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2 (KDR) VEGF treatment enhanced the phospho-Erk 1 and 2 via KDR. References_end </body> </html> </notes> <label text="KDR"/> <bbox w="80.0" h="50.0" x="710.0" y="5980.0"/> <glyph class="unit of information" id="_b2a9ddc5-ea32-4e98-abed-1873d423cd3c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="727.5" y="5975.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3901_sa984" 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: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. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. 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"/> <clone/> <bbox w="80.0" h="40.0" x="1640.0" y="3915.0"/> <glyph class="state variable" id="_8f419522-dd22-4a37-967e-a122ffc2c483"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1635.0" y="3930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3901_sa1851" 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: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. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. 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"/> <clone/> <bbox w="80.0" h="40.0" x="14945.0" y="5310.0"/> <glyph class="state variable" id="_e4750e7e-55b8-4db8-87b5-c7224bff2b77"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14940.0" y="5325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3903_sa989" 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: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. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. 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"/> <clone/> <bbox w="80.0" h="40.0" x="1870.0" y="3915.0"/> <glyph class="state variable" id="_636434ab-7151-43cd-8004-cc975d62ccf4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1862.5" y="3930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3903_sa1850" 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: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. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. 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"/> <clone/> <bbox w="80.0" h="40.0" x="14945.0" y="5400.0"/> <glyph class="state variable" id="_4c1f9296-b5b6-426d-8ee6-5fec9efc2113"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14937.5" y="5415.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3906_sa994" 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:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <clone/> <bbox w="80.0" h="40.0" x="1840.0" y="4615.0"/> <glyph class="state variable" id="_975fcc05-f26f-4e71-8782-2890308939e6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1914.8059" y="4650.0"/> </glyph> <glyph class="state variable" id="_935df301-de99-4ca7-abdc-d284a4b2e8ab"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1832.5" y="4628.7124"/> </glyph> </glyph> <glyph class="macromolecule" id="s3906_sa1510" 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:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <clone/> <bbox w="120.0" h="80.0" x="14500.0" y="3250.0"/> <glyph class="state variable" id="_c008badf-dfd6-4f90-9ed3-93582fd4791c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14614.709" y="3325.0"/> </glyph> <glyph class="state variable" id="_f63c7a03-6045-47e2-9eae-53c7a34c405c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14492.5" y="3282.4246"/> </glyph> </glyph> <glyph class="macromolecule" id="s3907_sa996" 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:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <clone/> <bbox w="80.0" h="40.0" x="1691.25" y="4607.0"/> <glyph class="state variable" id="_bfca34af-85e5-4e48-9727-5ff92ef29b66"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1766.0559" y="4642.0"/> </glyph> <glyph class="state variable" id="_2b5b8273-2f97-4377-ad96-fc6f33af17b9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1686.25" y="4620.7124"/> </glyph> </glyph> <glyph class="macromolecule" id="s3907_sa1496" 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:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <clone/> <bbox w="80.0" h="40.0" x="14685.0" y="3210.0"/> <glyph class="state variable" id="_50145618-1a2e-406c-b9e8-9fbe73fd96ed"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14759.806" y="3245.0"/> </glyph> <glyph class="state variable" id="_8bc94f8d-0d10-441b-8dde-9313e88b71f1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14680.0" y="3223.7124"/> </glyph> </glyph> <glyph class="macromolecule" id="s3912_sa2327" 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: HUGO:SLC16A1 HUGO:SLC16A3 HUGO:SLC16A7 HUGO:SLC16A8 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE: CASCADE:LACTIC MAP:DENDRITIC_CELL MAP:MACROPHAGE PMID:16278308, PMID:23506875 Lactate is transported into the cell probably by the monocarboxylate transporters (MCTs) and this process is strictly pH dependent References_end </body> </html> </notes> <label text="MCT*"/> <bbox w="80.0" h="40.0" x="820.0" y="5840.0"/> </glyph> <glyph class="macromolecule" id="s3913_sa2329" 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: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MDSC CASCADE:VEGFA PMID:16002046, PMID:9570538 Inhibitory function of VEGF on DC function is most likely mediated by Flt-1. PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="FLT1"/> <bbox w="80.0" h="50.0" x="820.0" y="6005.0"/> <glyph class="unit of information" id="_953075da-14b7-4c49-b4fe-6fde0b016c11"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="837.5" y="6000.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3921_sa2336" 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: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="1510.0" y="4245.0"/> <glyph class="state variable" id="_c3d1d800-3bf4-40be-a695-5f3c26aec0fd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1502.5" y="4260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3922_sa2337" 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: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="1520.0" y="4055.0"/> <glyph class="state variable" id="_44cbf3b6-5ed6-48b6-a7e3-7348604603e4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1512.5" y="4070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3923_sa2338" 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: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="1530.0" y="4445.0"/> <glyph class="state variable" id="_8ac7b74e-758c-465a-9590-d4b73e002cf6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1522.5" y="4460.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3940_sa2355" 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:ID3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:LGALS1 CASCADE:IL10 PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. significantly increased IL-10 promoter activity was noted in CD14+ monocytes in the presence of A459-CM, NCI-H460-CM, or galectin-1. Increased IL-10 promoter activity was also found in cells overexpressing Id3 References_end </body> </html> </notes> <label text="ID3"/> <bbox w="80.0" h="40.0" x="4031.0" y="4500.625"/> </glyph> <glyph class="macromolecule" id="s3945_sa14" 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: HUGO:CD36 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL13 CASCADE:IL4 CASCADE:THBS1 CASCADE:CD36 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. PMID:17101731 Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. PMID:14568985 The exogenous and endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47 and probably CD36 References_end </body> </html> </notes> <label text="CD36"/> <clone/> <bbox w="80.0" h="50.0" x="7882.5" y="1295.0"/> <glyph class="unit of information" id="_398212be-dbf9-4c78-a38b-874bc95fb9a2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7900.0" y="1290.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3945_sa2362" 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: HUGO:CD36 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL13 CASCADE:IL4 CASCADE:THBS1 CASCADE:CD36 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. PMID:17101731 Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. PMID:14568985 The exogenous and endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47 and probably CD36 References_end </body> </html> </notes> <label text="CD36"/> <clone/> <bbox w="80.0" h="50.0" x="740.0" y="5470.0"/> <glyph class="unit of information" id="_71ff7e10-2e18-4c5d-a1d5-bb5805042f07"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="757.5" y="5465.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3949_sa2365" 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:THBS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:THBS1 CASCADE:IL10 CASCADE:TGFB CASCADE:PGE2 PMID:14996710 Thrombospondin-1 is associated with tumor microenvironment. PMID:10657674 CD47 engagement by Thrombospondin-1 peptide inhibits cytokine production and maturation of human dendritic cells. PMID:14568985 Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, and IL-10 release through its interactions with CD47. IL-10, TGF-β, and PGE2 enhance TSP secretion by Dcs References_end </body> </html> </notes> <label text="THBS1"/> <bbox w="80.0" h="40.0" x="2612.5" y="5297.5"/> </glyph> <glyph class="macromolecule" id="s3953_sa2368" 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: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="12372.5" y="5470.0"/> </glyph> <glyph class="macromolecule" id="s3956_sa2374" 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:LGALS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:LGALS3 CASCADE:TGFB CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. 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 CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="3830.0" y="5710.0"/> </glyph> <glyph class="macromolecule" id="s3962_sa2406" 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:MIF Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:MIF CASCADE:TNF CASCADE:IFNG CASCADE:IL4 CASCADE:IL13 CASCADE:TLR2_4 PMID:9637476, PMID:10878343 MIF prevented the release of perforin granules by NK cells but not CTLs. Tumor cells produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells. PMID:18490733 MIF inhibits NK cell activity through a transcriptional down-regulation of NKG2D PMID:16283355, PMID:12803886 MIF upregulates expression of TLR4 in macrothages via PU.1 (SPI1) activation PMID:12782713 MIF signal transduction initiated by binding to CD74. PMID:23390297 MIF deficiency or small-molecule inhibition reduces splenic MDSC immune suppression in tumor-bearing mice PMID:8195715 TNF and INFG induce MIF secretion in macrophages, TLR4 signaling induces MIF expression. 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 References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="2612.5" y="5457.5"/> </glyph> <glyph class="macromolecule" id="s3965_sa2410" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAB1 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:MIF PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="STAB1"/> <bbox w="80.0" h="50.0" x="2188.75" y="645.625"/> <glyph class="unit of information" id="_824a52d1-a5ed-47d5-adc1-a9f91e9930ef"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2206.25" y="640.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s3966_sa2416"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:MIF CASCADE:LFA1 CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 CASCADE:IFNAB PMID:21350056, PMID:23906377 Human perforin is expressed in natural killer cells.NK cytotoxicity is mediated by the directed exocytosis of cytolytic granules to release perforins and granzymes, which perforate the target cell plasma cell membrane and trigger apoptosis, respectively. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:16204312 Calcium influx is an early event during perforin-mediated cytotoxicity. PLC-γ2 is absolutely required to regulate degranulation of cytotoxic perforin granules. PMID:15356110 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:15113754 LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. PMID:9637476, PMID:10878343 MIF prevented the release of perforin granules by NK cells but not CTLs. Tumor cells produce Macrophage Migration-Inhibitory Factor to Prevent Lysis by NK Cells. References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="80.0" h="40.0" x="8990.0" y="8210.0"/> </glyph> <glyph class="macromolecule" id="s3967_sa2417"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:NKG2D CASCADE:2B4 CASCADE:IL15 MAP:NATURAL_KILLER PMID:16106370, PMID:15607806 Five granzymes are expressed in human NK cells (Grz A, B, H, K and M) GrzA and GrzK are trypsins (cleaving at basic residues arginine and lysine) GrzB is an aspase, cleaving after aspartic acid residues, and GrzH is a chymase, cleaving after hydrophobic residues such as phenylalanine. GrzM has a unique enzyme specificity, preferring cleavage after methionine, leucine, or isoleucine. PMID:11062502, PMID:15536084 ERK1/2 activation induces perforin and granzyme B movement towards target tumor cells downstream of PI3K signaling in NK cells. PMID:20189481 NKG2D, 2B4 signalings induces Granzyme B release probaly via VAV1/ERK pathway PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15. PMID:24248158 Hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. PMID:18287025 JNK pathway plays important role in NK activation.JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. Inhibition of JNK activity by D-JNK-1, SP600125, or JNK-1-specific siRNA blocked polarization of granzyme B References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="80.0" h="40.0" x="8680.0" y="8210.0"/> </glyph> <glyph class="macromolecule" id="s3977_sa2426" 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: HUGO:GST3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL6 PMID:16286017 Cystatin C is an inhibitor of cathepsin S. IL-6-Mediated STAT3 Activation Reduced Cystatin C mRNA Level in DCs and upregulates cathepsin S activity References_end </body> </html> </notes> <label text="CST3"/> <bbox w="80.0" h="40.0" x="12370.0" y="6240.0"/> </glyph> <glyph class="macromolecule" id="s3993_sa2445" 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:SOCS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:TLR2_4 CASCADE:IL6 CASCADE:TNF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12754507 IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="80.0" h="40.0" x="14625.0" y="2420.0"/> </glyph> <glyph class="macromolecule" id="s3998_sa2453" 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:BCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL10 Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="3580.0" y="4490.625"/> </glyph> <glyph class="macromolecule" id="s4000_sa2455" 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:HDAC1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:15465827 BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. References_end </body> </html> </notes> <label text="HDAC1"/> <bbox w="80.0" h="40.0" x="13016.25" y="5305.0"/> </glyph> <glyph class="macromolecule" id="s4007_sa2460" 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:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MAST_CELL MAP:NEUTROPHIL CASCADE:TGFB CASCADE:STING CASCADE:STAB2 CASCADE:TLR2_4 CASCADE:IFNG PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:17070508, PMID:18490733 TGFB downregulates NKG2D expression. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-β in NK cells via the c-Jun N-terminal kinase (JNK) pathway PMID:2871107 Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. PMID:20538542 TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. The roles of TGFβ in the tumour microenvironment. PMID:20616810 The polarization of immune cells in the tumour environment by TGFbeta. PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. PMID:21372296 HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms. PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC 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:26966341 tudies have shown that, analogously to the M1 and M2 dichotomy, TANs develop a protumorigenic (N2) phenotype in untreated tumors, largely driven by the presence of TGF-β References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3232.5" y="5647.5"/> </glyph> <glyph class="macromolecule" id="s4008_sa2465" 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: 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="16025.0" y="1560.0"/> </glyph> <glyph class="macromolecule" id="s4015_sa2488" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD209 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_MACROPHAGE Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL4 PMID:25582338 DC-specific marker DC-SIGN (CD209) was expressed significantly less on IL-15 DCs compared with IL-4 DCs References_end </body> </html> </notes> <label text="CD209"/> <bbox w="80.0" h="50.0" x="2382.25" y="645.625"/> <glyph class="unit of information" id="_f2ec813b-8d26-48dd-b35e-46ecfeb815e2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2399.75" y="640.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s4033_sa2525" 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:SUMO1 HUGO:SUMO2 HUGO:SUMO3 HUGO:SUMO4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE 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="SUMO*"/> <bbox w="80.0" h="40.0" x="2852.25" y="3850.0"/> </glyph> <glyph class="macromolecule" id="s4036_sa2546" 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:IL5 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL4 PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end </body> </html> </notes> <label text="IL5"/> <bbox w="80.0" h="40.0" x="4050.0" y="5360.0"/> </glyph> <glyph class="macromolecule" id="s4039_sa2571" 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:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL13 CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 CASCADE:IL18 CASCADE:TNF Maps_Modules_end References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. PMID:9743347 IL13 inhibits JNK phosphorylation and AP1 activation (provavly via dusp1) PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 ( 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: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. PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. References_end </body> </html> </notes> <label text="AP1*"/> <bbox w="80.0" h="40.0" x="10735.0" y="3900.0"/> <glyph class="state variable" id="_b4e89036-256a-45a0-91c4-fc39696907a8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="10730.0" y="3915.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4042_sa2578" 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:GSK3A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. References_end </body> </html> </notes> <label text="GSK3α*"/> <bbox w="80.0" h="40.0" x="9470.0" y="3980.0"/> <glyph class="state variable" id="_79bc5f5a-19f5-41fb-8429-648a0af36465"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="9462.5" y="3995.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4043_sa2579" 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:GSK3A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. References_end </body> </html> </notes> <label text="GSK3α*"/> <bbox w="80.0" h="40.0" x="9470.0" y="4060.0"/> <glyph class="state variable" id="_ad4ef1c7-79ff-4d8e-addd-1cb9c7f5a5c5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9465.0" y="4075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4083_sa2614" 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: HUGO:CXCR3 Identifiers_end References_begin: MAP:NATURAL_KILLER CASCADE:CXCR3 PMID:18922917 Significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3−/− mice, and the capacity of adoptively transferred CXCR3−/− NK cells to accumulate in the tumor was severely impaired. Ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell–dependent survival. References_end </body> </html> </notes> <label text="CXCR3"/> <bbox w="80.0" h="50.0" x="5280.0" y="1530.0"/> <glyph class="unit of information" id="_9abfce2c-4eec-4943-92b9-41c71732264f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5297.5" y="1525.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4087_sa2618" 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: HUGO:CXCR1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 PMID:18633355 The surface markers of myeloid cells PMID:21328342, PMID:18980965 Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils, downstream of IL8. References_end </body> </html> </notes> <label text="CXCR1"/> <bbox w="80.0" h="50.0" x="5360.0" y="1320.0"/> <glyph class="unit of information" id="_c3ba7434-a5f3-47d3-a991-c9440cecafd4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5377.5" y="1315.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4088_sa2619" 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: HUGO:CXCR2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 PMID:18633355 The surface markers of myeloid cells PMID:21328342, PMID:18980965 Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils, downstream of IL8. References_end </body> </html> </notes> <label text="CXCR2"/> <bbox w="80.0" h="50.0" x="5450.0" y="1320.0"/> <glyph class="unit of information" id="_ec094c66-0809-4591-8f01-7ea60610c7cf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5467.5" y="1315.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4102_sa2007" 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:FOS Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:21385848, PMID:22634314 c-Fos downregulates mRNA expression of TNF, IL6, IL1B, IL12p40. IL12p35, IL23a Additionally Fos downregulates CD86, CD40 surface expression, IL2 secretion and Tcell activation. PMID:22634314 Expression of IL-10 was enhanced in DC overexpressed Fos. PMID:16394015 PMID:19667062 TPL-2 ERK pathway induces Fos expression in macrophages () PMID:16394015 , PMID:19667062, PMID:15067049 Fos inhibits the expression of IL-12 p40 and IFNB and upregulates IL10 production downstream of FOS in macrophages and DCs PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 References_end </body> </html> </notes> <label text="FOS"/> <bbox w="80.0" h="40.0" x="2760.0" y="4640.625"/> <glyph class="state variable" id="_a2c465c7-6180-4216-8d4b-e6f4c3d7ee3b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2752.5" y="4655.625"/> </glyph> </glyph> <glyph class="macromolecule" id="s4103_sa2572" 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:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL13 CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 CASCADE:IL18 CASCADE:TNF Maps_Modules_end References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. PMID:9743347 IL13 inhibits JNK phosphorylation and AP1 activation (provavly via dusp1) PMID:9064320 CD16-induced ERK activation provides TNFA expression in NK cells. MEK/ERK cascade induces AP1(c-fos) phosphorylation downstream of CD16 ( 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: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. PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. References_end </body> </html> </notes> <label text="AP1*"/> <bbox w="80.0" h="40.0" x="10735.0" y="4000.0"/> <glyph class="state variable" id="_545cc17d-209d-4d61-a72d-b8cfcc909560"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10727.5" y="4015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4109_sa1830" 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:STAT5A HUGO:STAT5B Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL21 CASCADE:IL2 CASCADE:CSF2 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. PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. 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 (.) References_end </body> </html> </notes> <label text="STAT5*"/> <bbox w="80.0" h="40.0" x="14535.0" y="5400.0"/> <glyph class="state variable" id="_b82f9454-aec4-4c4a-ba79-f391391fe5f1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14527.5" y="5415.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4110_sa993" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 CASCADE:IL15 CASCADE:IL21 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IFNAB Maps_Modules_end References_begin: ‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:15573129 Constitutively active STAT3 inhibited the functional maturation of DCs in vitro. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation. 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter Stat3 activity is required for tumor factor–induced migration of ECs. PMID:14670306, PMID:16418395 FLT3 sidnaling in Dcs acts via STAT3 PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="80.0" h="40.0" x="1690.0" y="4425.0"/> <glyph class="state variable" id="_4898d9dd-3e71-4202-857f-ed4847667eef"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1685.0" y="4439.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s4110_sa1811" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 CASCADE:IL15 CASCADE:IL21 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IFNAB Maps_Modules_end References_begin: ‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:15573129 Constitutively active STAT3 inhibited the functional maturation of DCs in vitro. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation. 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter Stat3 activity is required for tumor factor–induced migration of ECs. PMID:14670306, PMID:16418395 FLT3 sidnaling in Dcs acts via STAT3 PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="80.0" h="40.0" x="14725.0" y="5310.0"/> <glyph class="state variable" id="_86b5ae9a-1982-4897-9184-2412a3e745dc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14720.0" y="5324.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s4111_sa992" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 CASCADE:IL15 CASCADE:IL21 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IFNAB Maps_Modules_end References_begin: ‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:15573129 Constitutively active STAT3 inhibited the functional maturation of DCs in vitro. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation. 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter Stat3 activity is required for tumor factor–induced migration of ECs. PMID:14670306, PMID:16418395 FLT3 sidnaling in Dcs acts via STAT3 PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="80.0" h="40.0" x="1820.0" y="4425.0"/> <glyph class="state variable" id="_50f13401-58f6-43dd-9a94-18cdeb183cf7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1812.5" y="4439.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s4111_sa1820" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:IL4 CASCADE:IL13 CASCADE:IL6 CASCADE:GSF3 CASCADE:IL15 CASCADE:IL21 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IFNAB Maps_Modules_end References_begin: ‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:15573129 Constitutively active STAT3 inhibited the functional maturation of DCs in vitro. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation. 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter Stat3 activity is required for tumor factor–induced migration of ECs. PMID:14670306, PMID:16418395 FLT3 sidnaling in Dcs acts via STAT3 PMID:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="80.0" h="40.0" x="14725.0" y="5410.0"/> <glyph class="state variable" id="_a4913987-4b66-46e6-8e10-a129206f5543"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="14717.5" y="5424.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s4114_sa1845" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="15335.0" y="4780.0"/> <glyph class="state variable" id="_d6a895c3-a63f-42aa-a855-87910ec8242e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15330.0" y="4795.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4114_sa2340" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="1520.0" y="4125.0"/> <glyph class="state variable" id="_3bb6997f-367f-477f-9ca7-f21dcabc8241"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1515.0" y="4140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4116_sa1846" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="15335.0" y="4860.0"/> <glyph class="state variable" id="_dc2d5bbf-2760-45db-8286-ff175ecc7208"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15330.0" y="4875.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4116_sa2342" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="1530.0" y="4515.0"/> <glyph class="state variable" id="_496afbe4-87d7-4c57-89a0-acb8e72fb6bb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1525.0" y="4530.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4146_sa1236" 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:IL1B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MAP:DENDRITIC_CELL MAP:MAST_CELL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:P2RX7 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:17043764 IL1 signaling has both antitumor effect (low dose of IL B and menbran associated IL1A) and protumor effect (high dose of IL1) in tumor microevironment, PMID:12598651 Microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. PMID:24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. 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:21826665 TANs produce TNF and IL1B, probably downstream of TLR4 References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="80.0" h="40.0" x="4696.25" y="6555.0"/> </glyph> <glyph class="macromolecule" id="s4148_sa2879" 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:FN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end </body> </html> </notes> <label text="FN1"/> <bbox w="80.0" h="40.0" x="8580.0" y="780.0"/> </glyph> <glyph class="macromolecule" id="s4150_sa1506" 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: 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"/> <clone/> <bbox w="80.0" h="40.0" x="15190.0" y="1545.0"/> </glyph> <glyph class="macromolecule" id="s4150_sa2588" 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: 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"/> <clone/> <bbox w="80.0" h="40.0" x="6320.0" y="1395.0"/> </glyph> <glyph class="macromolecule" id="s4153_sa2670" 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: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="11255.0" y="3070.0"/> </glyph> <glyph class="macromolecule" id="s4155_sa2673" 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: 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="14080.0" y="8075.0"/> <glyph class="state variable" id="_13832521-4158-4de0-9423-270a39f6b051"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="14070.0" y="8090.0"/> </glyph> <glyph class="unit of information" id="_6de36250-a035-4e38-b7bf-4292a05719e8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14097.5" y="8070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4167_sa2688" 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:IFNA1 HUGO:IFNA2 HUGO:IFNA4 HUGO:IFNA5 HUGO:IFNA6 HUGO:IFNA7 HUGO:IFNA8 HUGO:IFNA10 HUGO:IFNA13 HUGO:IFNA14 HUGO:IFNA16 HUGO:IFNA17 HUGO:IFNA21 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 MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IFNAB PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. PMID:11449378 IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. IFN-α and IL-12 induce tyrosine phosphorylation and DNA binding of Stat4 to IFN-γ promoter GAS element PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. http://www.tandfonline.com/doi/abs/10.4161/21624011.2014.948705#.VJLI5efuK2s IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells. PMID:11207245 IFNA induces IL10 production in Dcs 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="IFNA*"/> <bbox w="80.0" h="40.0" x="13516.25" y="5395.0"/> </glyph> <glyph class="macromolecule" id="s4168_sa2689" 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:IFNB1 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 MAP:NEUTROPHIL CASCADE:IFNAB CASCADE:IL15 PMID:15289500 Lytic function by NK cells and their ability to kill MHC-negative targets was regulated by type I IFNs produced by activated DCs. PMID: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:20237412 IFN-β regulates expression of homing and angiogenic factors in neutrophils. IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils additionally Stat3 and c-myc are downregulated by IFN-β. (STAT3 is known to be required for full activation of the Cxcr4 gene ) References_end </body> </html> </notes> <label text="IFNB*"/> <bbox w="80.0" h="40.0" x="13636.25" y="5395.0"/> </glyph> <glyph class="macromolecule" id="s4169_sa2692" 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> 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="15605.0" y="4145.0"/> <glyph class="unit of information" id="_79df2e54-b2c4-4a3b-bdec-d60b1c74d7f4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15622.5" y="4140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4174_sa2698"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="3705.0" y="8290.0"/> <glyph class="unit of information" id="_3cc63cdb-e130-48be-b21a-76cba333225a"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3720.0" y="8285.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4197_sa2729" 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:MAPK8 HGNC:6881 ENTREZ:5599 UNIPROT:P45983 GENECARDS:MAPK8 HUGO:MAPK9 HGNC:6886 ENTREZ:5601 UNIPROT:P45984 GENECARDS:MAPK9 HUGO:MAPK10 HGNC:6872 ENTREZ:5602 UNIPROT:P53779 GENECARDS:MAPK10 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:59293 KEGG:5599 ATLASONC:JNK1ID196 WIKI:MAPK8 mitogen-activated protein kinase 9 REACTOME:59295 KEGG:5601 ATLASONC:JNK2ID426 WIKI:MAPK9 mitogen-activated protein kinase 10 REACTOME:59297 KEGG:5602 ATLASONC:JNK3ID427 WIKI:MAPK10 MAP:MACROPHAGE MAP:NATURAL_KILLER CASCADE:IL10 CASCADE:TLR2_4 CASCADE:IL18 CASCADE:NKG2D CASCADE:TNF CASCADE:IFNG PMID:18287025 JNK is localized to the centrosome. JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. Inhibition of JNK activity by D-JNK-1, SP600125, Or JNK-1-specific siRNA blocked polarization of granzyme B, PMID:17070508 IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. PMID:17379190 MEK4/JNK/AP-1 path way is active in mactophages downstream of TLR4, and induces iNOS expression. PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:17073741 DUSP1 inhibits p38 and JNK pathways of innate innunity downstream of IL10. PMID:9743347 IL13 inhibits JNK phosphorylation and AP1 activation (provavly via dusp1) 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:23508573 HMGB1 induces activation (phosphorylation) of ERK, JNK and p38 via TLR4 in macrophages. 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. 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 References_end </body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="10585.0" y="3700.0"/> <glyph class="state variable" id="_e41dde01-5423-4632-8220-a3a8f9576a37"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="10577.5" y="3715.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4200_sa2734" 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:IRF9 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB PMID:25960930 INFA induced expression of IRF9 is PKC-θ-dependent in NK. References_end </body> </html> </notes> <label text="IRF9"/> <bbox w="80.0" h="40.0" x="10015.0" y="4635.0"/> </glyph> <glyph class="macromolecule" id="s4201_sa2737" 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:IL3RA Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:MARKERS_DC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL PMID:18633355 (CD123)The surface markers of myeloid cells CASCADE:IL3 PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3RA"/> <bbox w="80.0" h="50.0" x="1360.0" y="2135.0"/> <glyph class="unit of information" id="_59788935-7bfb-4af2-99e5-2837b613e174"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1377.5" y="2130.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4203_sa2741" 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:CREB1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. 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 References_end </body> </html> </notes> <label text="CREB1"/> <bbox w="80.0" h="40.0" x="11185.0" y="4505.0"/> <glyph class="state variable" id="_27c90b2c-1e1e-47d5-93eb-e47838556951"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11180.0" y="4520.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4204_sa2742" 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:CREB1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. 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 References_end </body> </html> </notes> <label text="CREB1"/> <bbox w="80.0" h="40.0" x="11185.0" y="4575.0"/> <glyph class="state variable" id="_6a3d76b6-4fe1-4f7b-8c59-d8dc37536784"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="11177.5" y="4590.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4226_sa1251" 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:IL6 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:IL6 CASCADE:TLR2_4 CASCADE:STING CASCADE:FCAR CASCADE:IL15 PMID:7590867 Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation PMID:15573129, PMID:8837607, PMID:9845545 Macrophage colony-stimulating factor (M-CSF) and IL-6 have also been reported to be involved in the tumour-mediated regulation of DC differentiation. PMID:15356132 The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation PMID:11306493 The presence of high (>400 pg/ml) concentrations of IL-6 and M-CSF in tumor cell supernatant was strongly correlated with the inhibitory capacity of tumor cell medium on MO-DC differentiation 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. The IFN-γ, TNFα and IL-6 transcripts were consistently expressed at higher levels at 330-, 14- and 20-folds, respectively, in donor-matched mIL-15 DCs than mIL-4 DCs 16286017 IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII αβ Dimer Level in DCs In Vivo 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="IL6"/> <bbox w="80.0" h="40.0" x="2422.5" y="5457.5"/> </glyph> <glyph class="macromolecule" id="s4241_sa102" 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: 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="14993.125" y="6737.5"/> </glyph> <glyph class="macromolecule" id="s4242_sa101" 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: 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="14983.125" y="6642.5"/> <glyph class="unit of information" id="_a7b92fd2-5ed6-4cd2-b968-98da049998ce"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15000.625" y="6637.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4256_sa2668" 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:HMGB1 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 MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL18 CASCADE:TLR2_4 CASCADE:IFNG CASCADE:TNF PMID:15802534 Activated NK cells release HMGB1, which promotes inflammation and induces DC maturation. IL-18 induces HMGB1 secretion by NK cells PMID:12646658 IFNG upregulates protein level and secretion of HMGB1 partially via TNF induction in macrophages References_end </body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="12176.25" y="5405.0"/> </glyph> <glyph class="macromolecule" id="s4257_sa2792" 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:CXCL16 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL PMID:11017100 CXCL16 is produced by DC and regulates Tcell and NKT migration. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. References_end </body> </html> </notes> <label text="CXCL16"/> <bbox w="80.0" h="40.0" x="5180.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s4262_sa2798" 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:HDC Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:MAST_CELL PMID:10353253, PMID:18347416 Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase in mast cells. It plays dual role in cancer. References_end </body> </html> </notes> <label text="HDC"/> <bbox w="80.0" h="40.0" x="3840.0" y="5950.0"/> </glyph> <glyph class="macromolecule" id="s4265_sa2801" 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:NGF Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, histamine, which is an immunosuppressant, mitogenic factors, such as platelet-derived growth factor (PDGF), nerve GF (NGF), stem-cell factor (SCF), and proteases, which disrupt the surrounding matrix and facilitate metastases. PMID:17764704 NGF is angiogenic factor References_end </body> </html> </notes> <label text="NGF"/> <bbox w="80.0" h="40.0" x="4180.0" y="7720.0"/> </glyph> <glyph class="macromolecule" id="s4266_sa2802"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KITLG Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, histamine, which is an immunosuppressant, mitogenic factors, such as platelet-derived growth factor (PDGF), nerve GF (NGF), stem-cell factor (SCF), and proteases, which disrupt the surrounding matrix and facilitate metastases. PMID:18524989 SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="KITLG"/> <bbox w="80.0" h="40.0" x="5550.0" y="1115.0"/> </glyph> <glyph class="macromolecule" id="s4267_sa2803" 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: HUGO:KIT Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:18633355 The surface markers of myeloid cells PMID:18524989 Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="KIT"/> <bbox w="80.0" h="50.0" x="5570.0" y="1300.0"/> <glyph class="unit of information" id="_e3d85b94-ca45-4b03-8dc0-7d38b8a892d6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5587.5" y="1295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4273_sa2807" 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:CCL17 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL PMID:26966341, PMID:24501019 TANs from established tumors produce CCL17 or CCL22, recruiting immunosuppressive regulatory T cells (Tregs) with defective cytotoxic functions into the tumor and leading to suppression of antitumoral immunity References_end </body> </html> </notes> <label text="CCL17"/> <bbox w="80.0" h="40.0" x="5150.0" y="2195.0"/> </glyph> <glyph class="macromolecule" id="s4274_sa2808" 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:CCL22 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL PMID:26966341, PMID:24501019 TANs from established tumors produce CCL17 or CCL22, recruiting immunosuppressive regulatory T cells (Tregs) with defective cytotoxic functions into the tumor and leading to suppression of antitumoral immunity References_end </body> </html> </notes> <label text="CCL22"/> <bbox w="80.0" h="40.0" x="5240.0" y="2195.0"/> </glyph> <glyph class="macromolecule" id="s4275_sa2809" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL6 Identifiers_end References_begin: MAP:NEUTROPHIL CASCADE:RECRUITMENT_OF_IMMUNE_CELLS PMID:21236563 Another chemokine recently shown to be important in the recruitment of neutrophils to melanoma tumors is GCP-2 (CXCL6). Specific anti-CXCL6 monoclonal antibodies not only reduced recruitment of neutrophils to tumor sites in mice but also caused reduction in tumor growth References_end </body> </html> </notes> <label text="CXCL6"/> <bbox w="80.0" h="40.0" x="5290.0" y="1055.0"/> </glyph> <glyph class="macromolecule" id="s4276_sa2810" 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:ELANE Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:NEUTROPHIL PMID:20081861 Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas References_end </body> </html> </notes> <label text="ELANE"/> <bbox w="80.0" h="40.0" x="3480.0" y="7505.0"/> </glyph> <glyph class="macromolecule" id="s4277_sa2811" 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:CTSG Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NEUTROPHIL PMID:16237087 CTSD (aspartic cathepsin D) and CTSG (cathepsin G) participate in antigen processing in DC. PMID:26819959 TANs-derived cathepsin G may induce ECM remodeling and promote tumor progression and metastasis References_end </body> </html> </notes> <label text="CTSG"/> <bbox w="80.0" h="40.0" x="2775.0" y="7360.0"/> </glyph> <glyph class="macromolecule" id="s4283_sa2813" 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:TGFB2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end </body> </html> </notes> <label text="TGFB2"/> <bbox w="80.0" h="40.0" x="3242.5" y="5757.5"/> </glyph> <glyph class="macromolecule" id="s4284_sa2814" 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:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end </body> </html> </notes> <label text="TGFB3"/> <bbox w="80.0" h="40.0" x="3342.5" y="5757.5"/> </glyph> <glyph class="macromolecule" id="s4291_sa2818" 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: 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="6010.0" y="3765.0"/> <glyph class="unit of information" id="_5d089b94-e972-4390-81c9-1758b6c16006"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6027.5" y="3760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4293_sa2820" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_MACROPHAGE MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MDSC CASCADE:CR3 PMID:18633355 The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="1998.75" y="732.875"/> <glyph class="unit of information" id="_82e83bf5-ebbb-44b9-8438-68aee2c89724"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2016.25" y="727.875"/> </glyph> </glyph> <glyph class="macromolecule" id="s4294_sa2821" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD68 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MACROPHAGE Maps_Modules_end References_begin: MAP:MACROPHAGE http://www.biolegend.com/essential_markers CD68 is a macrophage marker References_end </body> </html> </notes> <label text="CD68"/> <bbox w="80.0" h="50.0" x="2098.75" y="732.875"/> <glyph class="unit of information" id="_bfa64861-9559-4a3d-a854-eda1ac5e2174"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2116.25" y="727.875"/> </glyph> </glyph> <glyph class="macromolecule" id="s4295_sa2823" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:MARKERS_MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:LGALS3 CASCADE:TGFB CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. 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 CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="2198.75" y="737.875"/> </glyph> <glyph class="macromolecule" id="s4296_sa2824" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD33 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC Maps_Modules_end References_begin: MAP:MDSC http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="CD33"/> <bbox w="80.0" h="40.0" x="1121.1562" y="538.03125"/> </glyph> <glyph class="macromolecule" id="s4297_sa2825" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FUT4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:MDSC PMID:18633355 (CD15) The surface markers of myeloid cells References_end </body> </html> </notes> <label text="FUT4"/> <bbox w="80.0" h="40.0" x="1240.2188" y="538.03125"/> </glyph> <glyph class="macromolecule" id="s4298_sa2826" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FUT4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:MDSC PMID:18633355 (CD15) The surface markers of myeloid cells References_end </body> </html> </notes> <label text="FUT4"/> <bbox w="80.0" h="40.0" x="2313.75" y="322.5"/> </glyph> <glyph class="macromolecule" id="s4299_sa2827" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1121.2188" y="679.59375"/> <glyph class="unit of information" id="_bddd1e64-c45b-4717-9b18-aec06eca893f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1138.7188" y="674.59375"/> </glyph> </glyph> <glyph class="macromolecule" id="s4300_sa2828" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="2423.75" y="187.5"/> <glyph class="unit of information" id="_7d3bc8ec-889d-4e44-b8d4-a46d817c8f76"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2441.25" y="182.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4302_sa2830" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1240.2188" y="603.03125"/> </glyph> <glyph class="macromolecule" id="s4303_sa2831" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1898.75" y="737.875"/> </glyph> <glyph class="macromolecule" id="s4304_sa2832" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_MACROPHAGE MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MDSC CASCADE:CR3 PMID:18633355 The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="1240.2812" y="679.59375"/> <glyph class="unit of information" id="_f6c3d8e0-57cc-4748-a456-3c2babd67506"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1257.7812" y="674.59375"/> </glyph> </glyph> <glyph class="macromolecule" id="s4305_sa2833" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD34 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC Maps_Modules_end References_begin: MAP:MDSC http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="CD34"/> <bbox w="80.0" h="50.0" x="1121.2188" y="598.03125"/> <glyph class="unit of information" id="_b83bc7cf-74bd-4625-bb0b-42ac44ba9ddc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1138.7188" y="593.03125"/> </glyph> </glyph> <glyph class="macromolecule" id="s4306_sa2834" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1223.75" y="267.5"/> <glyph class="unit of information" id="_9b3ca6f0-c28f-4301-8461-af9df2d32a74"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1241.25" y="262.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4307_sa2835" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="CD1A"/> <bbox w="80.0" h="50.0" x="1663.75" y="217.5"/> <glyph class="unit of information" id="_8b8bad22-5faa-476d-b89b-283d448746fd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1681.25" y="212.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4308_sa2836" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1913.75" y="342.5"/> </glyph> <glyph class="macromolecule" id="s4309_sa2837" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LILRB4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="LILRB4"/> <bbox w="80.0" h="50.0" x="1773.75" y="287.5"/> <glyph class="unit of information" id="_686a7e5d-654e-498d-a856-235bfee5e929"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1791.25" y="282.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4310_sa2838" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="50.0" x="1913.75" y="217.5"/> <glyph class="unit of information" id="_ce52941a-013a-4667-8d19-ebc0fb859b9b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1931.25" y="212.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4311_sa2839" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="50.0" x="1913.75" y="147.5"/> <glyph class="unit of information" id="_c1b30778-b0c4-4071-8f8b-fa6ee47e8ebc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1931.25" y="142.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4312_sa2840" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> 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="50.0" x="1913.75" y="277.5"/> <glyph class="state variable" id="_4b0c4066-73fd-4e37-8631-bfdf3808def7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1908.75" y="297.5"/> </glyph> <glyph class="unit of information" id="_6c7ce0f2-0ae0-4fe8-b84d-d2747e7c1358"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1931.25" y="272.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4314_sa2842" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIT Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:18633355 The surface markers of myeloid cells PMID:18524989 Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="KIT"/> <bbox w="80.0" h="50.0" x="1644.75" y="537.5"/> <glyph class="unit of information" id="_67619ca4-cb94-4d78-a1de-156f3e5ada66"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1662.25" y="532.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4315_sa2843" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ENPP3 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST Maps_Modules_end References_begin: MAP:MAST_CELL http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="ENPP3"/> <bbox w="80.0" h="50.0" x="1644.75" y="597.5"/> <glyph class="unit of information" id="_b175c4ff-6592-4830-89cd-38445311f984"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1662.25" y="592.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4316_sa2844" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCER1A HUGO:FCER1G HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MAST_CELL CASCADE:FCER PMID:8283051 FCE RI and FcyRlll trigger phagocytosis in mast cells PMID:9000133 Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. PMID:1534410 Two forms of the low-affinity Fc receptor for IgE (Fc epsilon RIIa and Fc epsilon RIIb)differentially mediate endocytosis and phagocytosis PMID:6401249 Fc receptor for IgE provides phagocytosis in macrophages. 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="FcεR*"/> <bbox w="80.0" h="50.0" x="1551.25" y="597.5"/> <glyph class="state variable" id="_68fb9e64-bd6e-4d76-82e5-ae54706042f3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1543.75" y="617.5"/> </glyph> <glyph class="unit of information" id="_4b37cc71-2272-4a23-81c2-9a1e950fc653"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1568.75" y="592.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4317_sa2845" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CEACAM8 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:MDSC PMID:18633355 (CD66)The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CEACAM8"/> <bbox w="80.0" h="50.0" x="1362.7812" y="679.59375"/> <glyph class="unit of information" id="_94d3f979-5844-4ac1-9ffd-1c081d6dbcc6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1380.2812" y="674.59375"/> </glyph> </glyph> <glyph class="macromolecule" id="s4318_sa2846" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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). References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="1360.2188" y="533.03125"/> <glyph class="state variable" id="_7996db3e-2c65-4ce8-807c-f0877cf9ea53"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1435.2188" y="567.42053"/> </glyph> <glyph class="unit of information" id="_4cd4dfd5-5896-4b99-8e52-bda50f6b5db7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1377.7188" y="528.03125"/> </glyph> </glyph> <glyph class="macromolecule" id="s4320_sa2848" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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: MODULE:MARKERS_MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MDSC CASCADE:VEGFA PMID:16002046, PMID:9570538 Inhibitory function of VEGF on DC function is most likely mediated by Flt-1. PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="FLT1"/> <bbox w="80.0" h="50.0" x="1362.7812" y="598.03125"/> <glyph class="unit of information" id="_3c396fb5-c5eb-4442-b03d-2a3237c332ea"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1380.2812" y="593.03125"/> </glyph> </glyph> <glyph class="macromolecule" id="s4321_sa2849" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_MACROPHAGE MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MAP:MDSC CASCADE:CR3 PMID:18633355 The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="2423.75" y="257.5"/> <glyph class="unit of information" id="_4961fa3b-1b63-4208-9071-044d377f3f3d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2441.25" y="252.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4322_sa2850" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MME Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:NEUTROPHIL http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="MME"/> <bbox w="80.0" h="40.0" x="2313.75" y="192.5"/> </glyph> <glyph class="macromolecule" id="s4323_sa2851" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:CR4 CASCADE:FLT3LG CASCADE:IFNAB PMID:15573129 CD11c is a maker of myeloid DCs. PMID:8920882 FLT3 ligand upregulates surface expression of CD11c 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, CD206, CD23 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="CD11c*"/> <bbox w="80.0" h="50.0" x="2210.0" y="136.25"/> <glyph class="unit of information" id="_941806f7-bab0-4f5d-a354-599987701f17"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2227.5" y="131.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4324_sa2852" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ANPEP Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:NEUTROPHIL http://www.biolegend.com/cell_markers References_end </body> </html> </notes> <label text="ANPEP"/> <bbox w="80.0" h="40.0" x="2313.75" y="262.5"/> </glyph> <glyph class="macromolecule" id="s4325_sa2853" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="2313.75" y="132.5"/> </glyph> <glyph class="macromolecule" id="s4327_sa2855" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PECAM1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:PECAM1 MAP:NEUTROPHIL MAP:MACROPHAGE PMID:12110892 CD31 (also known as platelet-endothelial cell adhesion molecule-1, PECAM-1) is an example of a cell-surface molecule that prevents phagocyte ingestion of closely apposed viable cells by transmitting 'detachment' signals, and which changes function on apoptosis, promoting tethering of dying cells to phagocytes. References_end </body> </html> </notes> <label text="PECAM1"/> <bbox w="80.0" h="50.0" x="2423.75" y="127.5"/> <glyph class="unit of information" id="_5cbbc3a9-d97a-4db1-a0b6-34dac9e22f01"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2441.25" y="122.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4328_sa2856" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1223.75" y="137.5"/> <glyph class="unit of information" id="_19727328-4ea8-4a43-b775-5983b2ab7973"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1241.25" y="132.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4329_sa2857" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="1123.75" y="267.5"/> <glyph class="unit of information" id="_df8f0268-655f-4c77-bb32-1e4ccf4d14b0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1141.25" y="262.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4330_sa2858" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR3DL1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: KIR3DL1 MAP:NATURAL_KILLER PMID:11513144, PMID:8976179, PMID:8986721 KIR3DL1 is a receptor for HLA-B. Recognition of Inhibitory HLA-B Allotypes (Bw4+) by the KIR NKB1 Alters Stimulatory Signal Transduction Pathways in NK Cells via inhibition of PI3K pathway and Ca2+ mobilization. Probably it acts via LAT inhibition.KIR recognition of inhibitory class I molecules disrupted the ability of pp36 (LAT) to associate with Grb2 in vitro. PTP-1C (SHP-1) activated by KIR3DL1 binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2. PMID:11994457 Tyrosine-phosphorylated KIR3DL1 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2, SHP-1.3DL1-mediated inhibition of cytotoxicity was abolished upon overexpression of SHP-1. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end </body> </html> </notes> <label text="KIR3DL1"/> <bbox w="80.0" h="50.0" x="1223.75" y="197.5"/> <glyph class="state variable" id="_e239c24d-47be-460f-b099-062469c1f4dd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1218.75" y="217.5"/> </glyph> <glyph class="unit of information" id="_ba836a6e-dbcc-464f-a67e-a837c76ee6d8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1241.25" y="192.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4331_sa2859" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR2DL1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL1 MAP:NATURAL_KILLER PMID:11513144 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor PMID:12917349, PMID:18835194 Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). PMID:12515815 Coengagement of inhibitory receptor KIR2DL1 blocked 2B4 phosphorylation and downstream signaling. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end </body> </html> </notes> <label text="KIR2DL1"/> <bbox w="80.0" h="50.0" x="1323.75" y="197.5"/> <glyph class="state variable" id="_9e2a1898-0df4-4f1f-9fb3-a9058c599627"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1318.75" y="217.5"/> </glyph> <glyph class="unit of information" id="_69746830-10e6-4456-a067-dac9f75caf9b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1341.25" y="192.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4333_sa2861" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR2DL3 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL3 MAP:NATURAL_KILLER PMID:11513144, PMID:8574854 KIRs constitute a family of slightly polymorphic receptors with distinct MHC-I-binding profiles for classical HLA-A, HLA-B, and HLA-C molecules. Most KIRs with two Ig domains (KIR2DL) recognize subsets of the HLA-C allotypes. KIR2DL3 inhibits NK cells downstream of HLA-C via SHP-1 binding and activation. PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4) References_end </body> </html> </notes> <label text="KIR2DL3"/> <bbox w="80.0" h="50.0" x="1323.75" y="137.5"/> <glyph class="state variable" id="_6beec935-e4a1-4ed9-a700-4f645289f775"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1318.75" y="157.5"/> </glyph> <glyph class="unit of information" id="_69e5e1c1-5d75-4cde-832f-e3d4a2479c89"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1341.25" y="132.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4334_sa2862" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS MODULE:MARKERS_NK Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. PMID:11884419 KLRG1-signaling inhibits IFNG and TNFA production and NK cell-mediated cytotoxicity. References_end </body> </html> </notes> <label text="KLRG1*"/> <bbox w="80.0" h="50.0" x="1123.75" y="137.5"/> <glyph class="state variable" id="_88468aeb-8750-43fb-b645-d86dd8eede1a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1118.75" y="157.5"/> </glyph> <glyph class="unit of information" id="_91087aef-6788-4289-887f-53afc50e5e25"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1141.25" y="132.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4335_sa2860" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:IL2 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 PMID:17100877 KIR2DL4 both contains a cytoplasmic ITIM and encodes a transmembrane arginine residue, through which it can associate with the FcɛRγ-chain KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells References_end </body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="1123.75" y="197.5"/> <glyph class="state variable" id="_24046de3-ef73-4283-8484-a173a97cfc48"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1118.75" y="217.5"/> </glyph> <glyph class="unit of information" id="_c50c74de-fd15-4867-9ca2-beaa1d9af22f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1141.25" y="192.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4336_sa2864" compartmentRef="c44_ca45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:KLRB1 CASCADE:IL12 PMID:18159636 Transcription of the KLRB1 gene is suppressed in human cancer tissues PMID:16339513 CLEC2D (LLT1) is a ligand for the inhibitory human KLRB1 (NKR-P1A) receptor. LLT1 inhibits NK cytotoxicity induced by either the 2B4(CD48/CD244) pathway or the MICA/NKG2D pathway. PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. NKRP1A-induced inhibition of CD16 or p46 mediated cytolytic activity. PMID:22378844, PMID:24227772 miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. IL15 and KLRB1 (NK1.1) ligation also induce MIR155 expression. References_end </body> </html> </notes> <label text="KLRB1"/> <bbox w="80.0" h="50.0" x="1423.75" y="137.5"/> <glyph class="unit of information" id="_8baa5ae0-14d4-48d6-ae07-991d1732136f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1441.25" y="132.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4337_sa2865" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:THBD Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:22437871 CLEC4C (CD303), CD1C and THBD (CD141) are the markers of human DC. References_end </body> </html> </notes> <label text="THBD"/> <bbox w="80.0" h="50.0" x="1773.75" y="357.5"/> <glyph class="unit of information" id="_141f007b-b1fc-4dfb-8cd4-4f4d72272532"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1791.25" y="352.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4338_sa2866" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCR2 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 PMID:18633355 The surface markers of myeloid cells PMID:21328342, PMID:18980965 Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils, downstream of IL8. References_end </body> </html> </notes> <label text="CXCR2"/> <bbox w="80.0" h="50.0" x="2210.0" y="256.25"/> <glyph class="unit of information" id="_e78f9c5d-e11b-467e-bddd-74e656fcb9b9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2227.5" y="251.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4339_sa2867" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCR1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:IL8 PMID:18633355 The surface markers of myeloid cells PMID:21328342, PMID:18980965 Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils, downstream of IL8. References_end </body> </html> </notes> <label text="CXCR1"/> <bbox w="80.0" h="50.0" x="2210.0" y="326.25"/> <glyph class="unit of information" id="_31301a37-3c9e-484f-92fb-01e7f733e2eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2227.5" y="321.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4340_sa2868" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CEACAM8 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MDSC MODULE:MARKERS_NEUTROPHIL Maps_Modules_end References_begin: MAP:MDSC PMID:18633355 (CD66)The surface markers of myeloid cells References_end </body> </html> </notes> <label text="CEACAM8"/> <bbox w="80.0" h="50.0" x="2210.0" y="196.25"/> <glyph class="unit of information" id="_d4c4b7e0-8799-42eb-a427-c8629becf414"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2227.5" y="191.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4341_sa2869" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFSF8 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST Maps_Modules_end References_begin: MAP:MAST_CELL PMID:18633355 (CD66)The surface markers of myeloid cells References_end </body> </html> </notes> <label text="TNFSF8"/> <bbox w="80.0" h="50.0" x="1551.25" y="537.5"/> <glyph class="unit of information" id="_cac8055b-954f-4edf-8617-90ef4490c98c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1568.75" y="532.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4342_sa2870" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SPN Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST Maps_Modules_end References_begin: MAP:MAST_CELL PMID:18633355 (CD43)The surface markers of myeloid cells References_end </body> </html> </notes> <label text="SPN"/> <bbox w="80.0" h="40.0" x="1551.25" y="672.5"/> </glyph> <glyph class="macromolecule" id="s4343_sa2871" compartmentRef="c11_ca11"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL3RA Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:MARKERS_DC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL PMID:18633355 (CD123)The surface markers of myeloid cells CASCADE:IL3 PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3RA"/> <bbox w="80.0" h="50.0" x="1644.75" y="667.5"/> <glyph class="unit of information" id="_1f86a364-6a1d-483b-84dd-ff14e88a2e8c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1662.25" y="662.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4367_sa72" 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: HUGO:CD70 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19062317, PMID:17237405 CD70 is a costimulatory ligand acquired upon DC maturation. It stimulates T-cells and provides tumor regression. PMID:17237405 Surface expression of CD70 in DC is TLR and CD40 dependent. References_end </body> </html> </notes> <label text="CD70"/> <bbox w="80.0" h="40.0" x="14830.0" y="8000.0"/> </glyph> <glyph class="macromolecule" id="s4376_sa2666" 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: HUGO:CSF1R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:GSF1 CASCADE:IL4 Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="80.0" h="50.0" x="1140.0" y="2475.0"/> <glyph class="unit of information" id="_13b03cf0-49ed-421b-bea3-46e97f74c8fb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1157.5" y="2470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4384_sa1203" 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> 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"/> <clone/> <bbox w="80.0" h="40.0" x="6120.0" y="1915.0"/> </glyph> <glyph class="macromolecule" id="s4384_sa1205" 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> 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"/> <clone/> <bbox w="80.0" h="40.0" x="6120.0" y="2005.0"/> </glyph> <glyph class="macromolecule" id="s4384_sa1844" 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> 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"/> <clone/> <bbox w="80.0" h="40.0" x="15335.0" y="4940.0"/> </glyph> <glyph class="macromolecule" id="s4384_sa2339" 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> 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"/> <clone/> <bbox w="80.0" h="40.0" x="1530.0" y="4895.0"/> </glyph> <glyph class="macromolecule" id="s4461_sa1061" 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:CSF1R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:GSF1 CASCADE:IL4 Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="80.0" h="50.0" x="1390.0" y="2475.0"/> <glyph class="unit of information" id="_4b6b6bf6-923f-42f1-ac7e-76deae03f99f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1407.5" y="2470.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4462_sa1071" 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:IL6ST Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL6 CASCADE:IL4 Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="1360.0" y="2865.0"/> <glyph class="state variable" id="_7b70a2e3-2a45-4159-b578-546e00b6cfcc"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="1422.5" y="2862.541"/> </glyph> <glyph class="unit of information" id="_97f500d7-ef99-4c9d-b66c-6f6f756dd3a0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1377.5" y="2860.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4501_sa2722" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="16185.0" y="5485.0"/> <glyph class="unit of information" id="_a683c465-4e5c-42e2-818b-4e16b4f13b5c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16202.5" y="5480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4501_sa2736" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="650.0" y="1840.0"/> <glyph class="unit of information" id="_5f0837a2-2756-476f-88b7-13e30390ca9f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="667.5" y="1835.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4594_sa1582"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="16600.0" y="3450.0"/> </glyph> <glyph class="macromolecule" id="s4634_sa905"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MAST_CELL MAP:NEUTROPHIL CASCADE:TGFB CASCADE:STING CASCADE:STAB2 CASCADE:TLR2_4 CASCADE:IFNG PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:17070508, PMID:18490733 TGFB downregulates NKG2D expression. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-β in NK cells via the c-Jun N-terminal kinase (JNK) pathway PMID:2871107 Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. PMID:20538542 TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. The roles of TGFβ in the tumour microenvironment. PMID:20616810 The polarization of immune cells in the tumour environment by TGFbeta. PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. PMID:21372296 HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms. PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC 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:26966341 tudies have shown that, analogously to the M1 and M2 dichotomy, TANs develop a protumorigenic (N2) phenotype in untreated tumors, largely driven by the presence of TGF-β References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="1690.0" y="1100.0"/> </glyph> <glyph class="macromolecule" id="s4688_sa426" 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: 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="10905.0" y="1785.0"/> <glyph class="unit of information" id="_89903202-0d2c-4096-8e58-a0662ebc63df"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10922.5" y="1780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4694_sa1211" 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: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:IL10 CASCADE:IFNG CASCADE:IL18 CASCADE:LFA1 PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity PMID:14662834 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 via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:1673988 Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. PMID:23364881 Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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: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="ICAM1"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="1790.0"/> </glyph> <glyph class="macromolecule" id="s4694_sa2441" 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: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:IL10 CASCADE:IFNG CASCADE:IL18 CASCADE:LFA1 PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity PMID:14662834 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 via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:1673988 Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. PMID:23364881 Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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: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="ICAM1"/> <clone/> <bbox w="80.0" h="50.0" x="14320.0" y="7975.0"/> </glyph> <glyph class="macromolecule" id="s4700_sa1849" 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: 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="15575.0" y="3965.0"/> <glyph class="unit of information" id="_d2f29010-fa72-428d-9b27-ca296a656385"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15592.5" y="3960.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4730_sa69" 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: HUGO:TNFSF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NEUTROPHIL CASCADE:IL3 CASCADE:CD40LG PMID:9378971, PMID:10626891 OX40L is expressed on DCs surface after CD40 stimulation. Ox40L-deficient dendritic cells are defective in costimulating T cell cytokine production. PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce production ICOS-L and expression of OX40L. PMID:24778133 Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL . PMID:25384214 TANs enhance T cell proliferation by direct cell-cell signaling, likely due to the OX40L/OX40 and 4-1BBL/4-1BB pathways. References_end </body> </html> </notes> <label text="OX40L*"/> <bbox w="80.0" h="40.0" x="14690.625" y="7977.5"/> </glyph> <glyph class="macromolecule" id="s4738_sa1219" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="1630.0"/> <glyph class="unit of information" id="_68a27082-702a-47ca-953f-4cb47163d77f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6437.5" y="1625.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4738_sa2684" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="16055.0" y="2175.0"/> <glyph class="unit of information" id="_0dbfe701-347d-4a72-80b9-663b52db6a9d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16072.5" y="2170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4739_sa1222" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="1700.0"/> <glyph class="unit of information" id="_c3644622-ed72-4ada-bd45-72f2b479d244"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6437.5" y="1695.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4739_sa2685" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="16135.0" y="2175.0"/> <glyph class="unit of information" id="_5ffbb521-6fa9-453f-a9b0-7958300cab7c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16152.5" y="2170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4747_sa771" 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: CHEBI:17552 KEGGCOMPOUND:C00035 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGA5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A5B1 PMID:24202395, PMID:22067905 References_end </body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="50.0" x="8500.0" y="1735.0"/> <glyph class="unit of information" id="_98b5af02-ef72-4f95-a90a-2cef3465328b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8517.5" y="1730.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4757_sa2735" 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: HUGO:IL3RA Identifiers_end Maps_Modules_begin: MODULE:MARKERS_MAST MODULE:MARKERS_DC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MAST_CELL PMID:18633355 (CD123)The surface markers of myeloid cells CASCADE:IL3 PMID:15573129, PMID:11698286 IL3RA is a maker of plasmacytoid DCs (pDCs). For survival in vitro, myeloid DCs are dependent on GM-CSF, whereas pDCs are dependent on IL-3 and IFNA. References_end </body> </html> </notes> <label text="IL3RA"/> <bbox w="80.0" h="50.0" x="670.0" y="1960.0"/> <glyph class="unit of information" id="_cd44de63-737e-4301-b2bb-708bace7eb5a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="687.5" y="1955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4824_sa2311" 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: HUGO:TIMP1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:1629188 TIMP1 and TIMP2 are produced by macrophages. TIMP1 production is upregulated by TLR4 (LPS) TIMP2 production is inhibited by TLR4 signaling. PMID:24174628 Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9 References_end </body> </html> </notes> <label text="TIMP1"/> <bbox w="80.0" h="40.0" x="3380.0" y="8065.0"/> </glyph> <glyph class="macromolecule" id="s4825_sa2312" 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: HUGO:TIMP2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:TLR2_4 PMID:1629188 TIMP1 and TIMP2 are produced by macrophages. TIMP1 production is upregulated by TLR4 (LPS) TIMP2 production is inhibited by TLR4 signaling. PMID:22735808 TIMP-2 as a negative regulator of MDSCs in tumors PMID:24437600 TIMP2 drives "normalization" of the tumor microenvironment References_end </body> </html> </notes> <label text="TIMP2"/> <bbox w="80.0" h="40.0" x="3260.0" y="8065.0"/> </glyph> <glyph class="macromolecule" id="s4828_sa2748"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MAST_CELL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TLR2_4 CASCADE:IL15 Maps_Modules_end References_begin: PMID:17043764 IL1 signaling has both antitumor effect (low dose of IL B and menbran associated IL1A) and protumor effect (high dose of IL1) in tumor microevironment, PMID:12598651 Microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. 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. PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. PMID:16410834 T-bet upregulates the production of proinflammatory cytokine IL-1α and chemokines macrophage inflammatory protein-1α (MIP-1α) and downregulatesthymus- and activation-related chemokine (TARC) by DCs. 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="IL1A"/> <bbox w="80.0" h="40.0" x="4750.0" y="8190.0"/> </glyph> <glyph class="macromolecule" id="s4829_sa2788"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TNF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:18633355 Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="80.0" h="40.0" x="4400.0" y="8190.0"/> </glyph> <glyph class="macromolecule" id="s4894_sa2789" 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: HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:GROWTH_FACTORS_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MAST_CELL MAP:NEUTROPHIL CASCADE:TGFB CASCADE:STING CASCADE:STAB2 CASCADE:TLR2_4 CASCADE:IFNG PMID:24132110 TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGFβ will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells, for example, activation of antigen-presenting dendritic cells and inhibition of interferon-γ (IFNγ) secretion, which drives T helper 1 cell (TH1 cell) maturation TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:17070508, PMID:18490733 TGFB downregulates NKG2D expression. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-β in NK cells via the c-Jun N-terminal kinase (JNK) pathway PMID:2871107 Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. PMID:20538542 TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. The roles of TGFβ in the tumour microenvironment. PMID:20616810 The polarization of immune cells in the tumour environment by TGFbeta. PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. PMID:21372296 HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms. PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC 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:26966341 tudies have shown that, analogously to the M1 and M2 dichotomy, TANs develop a protumorigenic (N2) phenotype in untreated tumors, largely driven by the presence of TGF-β References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3105.0" y="8060.0"/> </glyph> <glyph class="macromolecule" id="s4904_sa2755" 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> References_begin: CASCADE:NKG2D PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins downstream of NKG2D. References_end </body> </html> </notes> <label text="PXN"/> <bbox w="80.0" h="40.0" x="7930.0" y="5170.0"/> </glyph> <glyph class="macromolecule" id="s4906_sa1907" 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: 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="15575.0" y="5685.0"/> <glyph class="unit of information" id="_50153179-c42c-4e5d-a624-8f83b0f17175"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15592.5" y="5680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4914_sa18" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PSD4 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. Probably downstream of PIP5K1A. References_end </body> </html> </notes> <label text="PSD4"/> <clone/> <bbox w="80.0" h="40.0" x="13610.0" y="7490.0"/> </glyph> <glyph class="macromolecule" id="s4914_sa22" 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:STAT3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PSD4 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. Probably downstream of PIP5K1A. References_end </body> </html> </notes> <label text="PSD4"/> <clone/> <bbox w="80.0" h="40.0" x="13470.0" y="7490.0"/> </glyph> <glyph class="macromolecule" id="s4917_sa42" 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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:MCR1 CASCADE:INTEGRIN_AVB3 CASCADE:INTEGRIN_AVB5 CASCADE:CD36 PMID:9510252 Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs PMID:17948027, PMID:22437871, PMID:17204652 Dendritic Cells are critical Antigen-Presenting Cells in tumor Immunity. They present processed protein and lipid antigens to T cells via both classical (major histocompatibility complex (MHC) class I and class II) and non-classical (CD1 family) antigen-presenting molecules. 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). Additionally, after antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecules. PMID:10837075 Immature DCs are very efficient in Ag capture and can use several pathways, such as (a) macropinocytosis; (b) receptor-mediated endocytosis via C-type lectin receptors (mannose receptor, DEC-205) or Fcγ receptor types I (CD64) and II (CD32) [uptake of immune complexes or opsonized particles ]; and (c) phagocytosis of particles such as latex beads , apoptotic and necrotic cell fragments (involving CD36 and αvβ3 or αvβ5 integrins), viruses, and bacteria including mycobacteria, as well as intracellular parasites such as Leishmania major. DCs can also internalize the peptide loaded heat shock proteins gp96 and Hsp70 through presently unknown mechanisms References_end </body> </html> </notes> <label text="Tumor_antigen"/> <bbox w="80.0" h="40.0" x="13740.0" y="6080.0"/> </glyph> <glyph class="macromolecule" id="s4919_sa67" 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:TNFSF4 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NEUTROPHIL CASCADE:IL3 CASCADE:CD40LG PMID:9378971, PMID:10626891 OX40L is expressed on DCs surface after CD40 stimulation. Ox40L-deficient dendritic cells are defective in costimulating T cell cytokine production. PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce production ICOS-L and expression of OX40L. PMID:24778133 Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL . PMID:25384214 TANs enhance T cell proliferation by direct cell-cell signaling, likely due to the OX40L/OX40 and 4-1BBL/4-1BB pathways. References_end </body> </html> </notes> <label text="OX40L*"/> <bbox w="80.0" h="40.0" x="14690.625" y="7747.5"/> </glyph> <glyph class="macromolecule" id="s4920_sa68" 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:CD70 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:19062317, PMID:17237405 CD70 is a costimulatory ligand acquired upon DC maturation. It stimulates T-cells and provides tumor regression. PMID:17237405 Surface expression of CD70 in DC is TLR and CD40 dependent. References_end </body> </html> </notes> <label text="CD70"/> <bbox w="80.0" h="40.0" x="14830.0" y="7750.0"/> </glyph> <glyph class="macromolecule" id="s4921_sa75" 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: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="14526.875" y="7751.5"/> <glyph class="unit of information" id="_def0e0f3-fdbc-4b98-a3c8-601ffca11dc0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14544.375" y="7746.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4922_sa78" 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: 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="14200.0" y="7975.0"/> <glyph class="unit of information" id="_4883d9ad-2750-4424-8f75-c8422f4654ae"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14217.5" y="7970.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4923_sa80" 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: 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="14070.0" y="7965.0"/> <glyph class="state variable" id="_4ad969a0-66ef-41d9-affe-5f33ff7bb5c8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14065.0" y="7980.0"/> </glyph> <glyph class="unit of information" id="_bec758d9-bd2b-45c6-8e0f-1229ebdcd98c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14087.5" y="7960.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4924_sa82" 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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:TLR2_4 CASCADE:TNF CASCADE:FLT3LG CASCADE:IFNAB PMID:22076556, PMID:21220452, PMID:24218453 In immature DCs, internalization of MHC class II molecules from the plasma membrane may require the ubiquitin ligase MARCH1, which is controlled by interleukin-10 (IL-10). CD83 on mature DCs prevents this ubiquitylation of MHC class II molecules and thus stabilizes MHC class II molecules on the cell surface. Addidionally it prevents CD86 ubiquitinqtion. 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. 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:25215878 FLT3 ligand upregulates surface expression of CD83 in DCs. PMID:21930769, PMID:21930765, PMID:11964292, PMID:11698286, 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. References_end </body> </html> </notes> <label text="CD83"/> <bbox w="80.0" h="50.0" x="13680.0" y="7810.0"/> <glyph class="unit of information" id="_cb1bac81-0769-43b9-81f2-1958cfe3b54e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13697.5" y="7805.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4926_sa414" 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: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="10905.0" y="1955.0"/> <glyph class="unit of information" id="_0787d5e1-f7e7-46e6-819c-c28e1f45d650"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="10922.5" y="1950.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4927_sa472" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:8892616 PTK2 (FAK) Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. References_end </body> </html> </notes> <label text="PTK2"/> <clone/> <bbox w="80.0" h="40.0" x="8867.5" y="2195.0"/> </glyph> <glyph class="macromolecule" id="s4927_sa515" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:8892616 PTK2 (FAK) Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells downstream of fibronectin. References_end </body> </html> </notes> <label text="PTK2"/> <clone/> <bbox w="80.0" h="40.0" x="8877.5" y="2325.0"/> </glyph> <glyph class="macromolecule" id="s4929_sa823" 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:KIR2DL4 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_NK MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:IL2 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995, PMID:12055234 KIR2DL4 (CD158d) is an NK cell-activating receptor with inhibitory potential. KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. PMID:11994457 Tyrosine-phosphorylated KIR2DL4 inhibits NK cytotoxixity. It inhibits the immunoreceptor tyrosine-based activation motif (ITAM)-dependent activation mediated by NKp46 or the ITAM-independent activation mediated by 2B4. via binding and activation of SHP-2 PMID:9751747 KIR2DL3, KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2, KIR2DL4 interact with SHP-2 in NK cells and probably are phosphorylated by LCK 5directly demonstrated for KIR2DL3 only. (CL6 = KIR2DL3,CL42 =KIR2DL1, CL39 = KIR2DS4, NKAT3= KIR3DL1, NKAT4 = KIR3DL2,KIR103AS=KIR2DL4). PMID:11489965, PMID:15778339 ‭KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production via p38 but not cytotoxicity in resting NK cells. PMID:15778339 IL2 stimulates surface expression of KIR2DL4 (2DL4.1)and NKp46 PMID:17100877 KIR2DL4 both contains a cytoplasmic ITIM and encodes a transmembrane arginine residue, through which it can associate with the FcɛRγ-chain KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. It induces IFNG production but not cytotoxicity in resting NK cells References_end </body> </html> </notes> <label text="KIR2DL4"/> <bbox w="80.0" h="50.0" x="3665.0" y="1915.0"/> <glyph class="state variable" id="_408a365d-3208-4eb2-9fe8-c2b6a07187f5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3660.0" y="1935.0"/> </glyph> <glyph class="unit of information" id="_bd363893-c6d6-492d-ad83-ce31e654508a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3682.5" y="1910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4934_sa1147" 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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:20414655, PMID:18792398 Trx is one of the main intracellular oxido-reductases TXN expression is upregulated in activated macrophages, DC and probably macrophages secrete thioredoxin which reduces extracellular cystine to cysteine, which is then available for the uptake by T cells through their ASC transporter References_end </body> </html> </notes> <label text="TXN"/> <bbox w="80.0" h="40.0" x="15190.0" y="7860.0"/> </glyph> <glyph class="macromolecule" id="s4936_sa1207" 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> Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:CCR5 CASCADE:IFNAB PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:11790543, PMID:15356122 CCR5 as a critical NK-cell homing receptor, CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. References_end </body> </html> </notes> <label text="CCR5"/> <bbox w="80.0" h="50.0" x="5770.0" y="1910.0"/> <glyph class="unit of information" id="_b7b2a01f-5ef0-4070-a937-e39b77cbc2bf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5787.5" y="1905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4937_sa1208" 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> 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="6000.0" y="1910.0"/> <glyph class="unit of information" id="_04c64656-cd6b-4cbd-ba21-75a29477a92a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6017.5" y="1905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4938_sa1209" 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: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="6310.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s4939_sa1210" 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:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:IL10 CASCADE:IFNG CASCADE:IL18 CASCADE:LFA1 PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity PMID:14662834 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 via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:1673988 Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. PMID:23364881 Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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: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="ICAM1"/> <clone/> <bbox w="80.0" h="50.0" x="6420.0" y="1910.0"/> </glyph> <glyph class="macromolecule" id="s4939_sa2440" 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:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:IL10 CASCADE:IFNG CASCADE:IL18 CASCADE:LFA1 PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity PMID:14662834 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 via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:1673988 Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. PMID:23364881 Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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: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="ICAM1"/> <clone/> <bbox w="80.0" h="50.0" x="14320.0" y="7755.0"/> </glyph> <glyph class="macromolecule" id="s4940_sa1255" 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:CCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TGFB CASCADE:CSF1 CASCADE:CCR2 CASCADE:TLR2_4 CASCADE:IFNG Maps_Modules_end References_begin: PMID:19915063 Phosphorylated STAT1 is critical for IFN-gamma-induced (CCL2)MCP-1 production PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="80.0" h="40.0" x="5660.0" y="2445.0"/> </glyph> <glyph class="macromolecule" id="s4941_sa1258" 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:CCL3 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:CCR5 CASCADE:TLR2_4 PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:16410834 T-bet upregulates the production of proinflammatory cytokine IL-1α and chemokines macrophage inflammatory protein-1α (MIP-1α) and downregulatesthymus- and activation-related chemokine (TARC) by DCs. References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="80.0" h="40.0" x="5760.0" y="2445.0"/> </glyph> <glyph class="macromolecule" id="s4942_sa1259" 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:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MAST_CELL CASCADE:TNF CASCADE:CSF2 MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 MAP:NATURAL_KILLER CASCADE:IL8 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself iDC in ovarian cancer ascites promote angiogenesis in vivo through production of TNF and CXCL8 PMID:18980965 Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="80.0" h="40.0" x="4270.0" y="6740.0"/> </glyph> <glyph class="macromolecule" id="s4943_sa1265" 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:CXCL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MAP:NATURAL_KILLER CASCADE:CXCR3 CASCADE:IFNAB CASCADE:TLR2_4 MAP:DENDRITIC_CELL Maps_Modules_end References_begin: PMID:18922917 Significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3−/− mice, and the capacity of adoptively transferred CXCR3−/− NK cells to accumulate in the tumor was severely impaired. Ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell–dependent survival. References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="80.0" h="40.0" x="5040.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s4944_sa1275" 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:CXCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="80.0" h="40.0" x="4940.0" y="2435.0"/> </glyph> <glyph class="macromolecule" id="s4945_sa1282" 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:CCL4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:CCR5 CASCADE:TLR2_4 CASCADE:NKG2D PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). References_end </body> </html> </notes> <label text="CCL4"/> <bbox w="80.0" h="40.0" x="5860.0" y="2445.0"/> </glyph> <glyph class="macromolecule" id="s4946_sa1380" 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: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="4130.0" y="6730.0"/> </glyph> <glyph class="macromolecule" id="s4947_sa1819" 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:IL1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MAST_CELL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TLR2_4 CASCADE:IL15 Maps_Modules_end References_begin: PMID:17043764 IL1 signaling has both antitumor effect (low dose of IL B and menbran associated IL1A) and protumor effect (high dose of IL1) in tumor microevironment, PMID:12598651 Microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. 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. PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. PMID:16410834 T-bet upregulates the production of proinflammatory cytokine IL-1α and chemokines macrophage inflammatory protein-1α (MIP-1α) and downregulatesthymus- and activation-related chemokine (TARC) by DCs. 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="IL1A"/> <bbox w="80.0" h="40.0" x="4420.0" y="6750.0"/> </glyph> <glyph class="macromolecule" id="s4948_sa1825" 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: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="15275.0" y="3495.0"/> <glyph class="unit of information" id="_b69d96e2-a262-428a-bd5b-eeb1346a16af"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15292.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4949_sa1908" 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: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="15245.0" y="5705.0"/> <glyph class="unit of information" id="_738b5a62-ca9f-46bc-8870-92b34549cfa4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15262.5" y="5700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4950_sa1920" 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: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"/> <clone/> <bbox w="80.0" h="50.0" x="15165.0" y="3575.0"/> <glyph class="unit of information" id="_91b358bd-fed5-4c0f-b26d-15b60747a24e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15182.5" y="3570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4950_sa2695" 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: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"/> <clone/> <bbox w="80.0" h="50.0" x="14975.0" y="3575.0"/> <glyph class="unit of information" id="_abc782d2-5a37-44f4-8042-82a311a04963"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14992.5" y="3570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4951_sa1921" 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: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"/> <clone/> <bbox w="80.0" h="50.0" x="15165.0" y="3485.0"/> <glyph class="unit of information" id="_42aed2c2-78e7-43fc-96d6-b424b455aec4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15182.5" y="3480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4951_sa2694" 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: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"/> <clone/> <bbox w="80.0" h="50.0" x="14975.0" y="3495.0"/> <glyph class="unit of information" id="_e1305ff6-2ab0-47e7-892d-3da3f3a6066a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14992.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4954_sa2229" 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:HCK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII PMID:21910624 The ITAM can be part of the same polypeptidic chain that engages the ligand, as in the case of FcγRIIA and FcγRIIC, or of a separate γ subunit that associates noncovalently with the ligand-binding subunit of the receptor, as in the case of FcγRI and FcγRIIIA. Upon receptor clustering, the ITAM associates with and becomes phosphorylated by Hck, Lyn (33, 34), and/or Fgr (35). PMID:8132624 Hck, Lyn binds to Fc_gamma_RII (CD32) and phosphorylates it in monocytes. PMID:8064233, PMID:12524384, PMID:24445665 Hck, Lyn binds to Fc_gamma_RI (cd64) in monocytes and probably phosphorylate ignal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. Probably these kinases activate also IgE receptors directly and FCAR and Fc_gamma_RIII complexes with Fc epsilon RI gamma. References_end </body> </html> </notes> <label text="HCK"/> <clone/> <bbox w="80.0" h="40.0" x="9867.5" y="2260.0"/> </glyph> <glyph class="macromolecule" id="s4954_sa2230" 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:HCK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:FCER CASCADE:FCAR CASCADE:Fc_gamma_RI CASCADE:Fc_gamma_RII CASCADE:Fc_gamma_RIII PMID:21910624 The ITAM can be part of the same polypeptidic chain that engages the ligand, as in the case of FcγRIIA and FcγRIIC, or of a separate γ subunit that associates noncovalently with the ligand-binding subunit of the receptor, as in the case of FcγRI and FcγRIIIA. Upon receptor clustering, the ITAM associates with and becomes phosphorylated by Hck, Lyn (33, 34), and/or Fgr (35). PMID:8132624 Hck, Lyn binds to Fc_gamma_RII (CD32) and phosphorylates it in monocytes. PMID:8064233, PMID:12524384, PMID:24445665 Hck, Lyn binds to Fc_gamma_RI (cd64) in monocytes and probably phosphorylate ignal transducing gamma subunit of the high-affinity IgE receptor (Fc epsilon RI gamma). Induction of cytoplasmic protein tyrosine phosphorylation by Fc gamma RI cross-linking is known to be important in mediating Fc gamma RI-coupled effector functions. Probably these kinases activate also IgE receptors directly and FCAR and Fc_gamma_RIII complexes with Fc epsilon RI gamma. References_end </body> </html> </notes> <label text="HCK"/> <clone/> <bbox w="80.0" h="40.0" x="9867.5" y="2360.0"/> </glyph> <glyph class="macromolecule" id="s4955_sa2231" 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:FGR Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:Fc_gamma_RII PMID:21910624 The ITAM can be part of the same polypeptidic chain that engages the ligand, as in the case of FcγRIIA and FcγRIIC, or of a separate γ subunit that associates noncovalently with the ligand-binding subunit of the receptor, as in the case of FcγRI and FcγRIIIA. Upon receptor clustering, the ITAM associates with and becomes phosphorylated by Hck, Lyn (33, 34), and/or Fgr (35). PMID:8327512 In neutrophiles Fgr is physically and functionally associated with Fc gamma RII and involved in Fc gamma RII-mediated signal transduction pathways. References_end </body> </html> </notes> <label text="FGR"/> <clone/> <bbox w="80.0" h="40.0" x="10048.5" y="2270.0"/> </glyph> <glyph class="macromolecule" id="s4955_sa2232" 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:FGR Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:FC_RECEPTORS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:Fc_gamma_RII PMID:21910624 The ITAM can be part of the same polypeptidic chain that engages the ligand, as in the case of FcγRIIA and FcγRIIC, or of a separate γ subunit that associates noncovalently with the ligand-binding subunit of the receptor, as in the case of FcγRI and FcγRIIIA. Upon receptor clustering, the ITAM associates with and becomes phosphorylated by Hck, Lyn (33, 34), and/or Fgr (35). PMID:8327512 In neutrophiles Fgr is physically and functionally associated with Fc gamma RII and involved in Fc gamma RII-mediated signal transduction pathways. References_end </body> </html> </notes> <label text="FGR"/> <clone/> <bbox w="80.0" h="40.0" x="10047.5" y="2370.0"/> </glyph> <glyph class="macromolecule" id="s4956_sa2294" 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:CXCL1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TNF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:18633355 Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="80.0" h="40.0" x="4530.0" y="7280.0"/> </glyph> <glyph class="macromolecule" id="s4957_sa2401" 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:CCL5 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:CCR5 CASCADE:TGFB PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:11790543, PMID:15356122 CCR5 as a critical NK-cell homing receptor, CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="80.0" h="40.0" x="5970.0" y="2445.0"/> </glyph> <glyph class="macromolecule" id="s4958_sa2415" 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:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC MODULE:MARKERS_NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:CR4 CASCADE:FLT3LG CASCADE:IFNAB PMID:15573129 CD11c is a maker of myeloid DCs. PMID:8920882 FLT3 ligand upregulates surface expression of CD11c 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, CD206, CD23 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="CD11c*"/> <bbox w="80.0" h="50.0" x="9472.5" y="1915.0"/> <glyph class="unit of information" id="_bbca9671-a2f5-4ac5-b480-976852feaa46"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9490.0" y="1910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4959_sa2436" 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:ICOSLG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL3 CASCADE:CD40LG PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce production ICOS-L and expression of OX40L. PMID:24778133 Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL. References_end </body> </html> </notes> <label text="B7H2*"/> <bbox w="80.0" h="40.0" x="1340.0" y="7140.0"/> </glyph> <glyph class="macromolecule" id="s4960_sa2461" 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:TRAF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TLR2_4 PMID:16306937 IL10 and IFNB expression is TRAF3 dependent on mRNA level downstream of TLR4 signaling.. References_end </body> </html> </notes> <label text="TRAF3"/> <clone/> <bbox w="80.0" h="40.0" x="15155.0" y="2110.0"/> </glyph> <glyph class="macromolecule" id="s4960_sa2462" 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:TRAF3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TLR2_4 PMID:16306937 IL10 and IFNB expression is TRAF3 dependent on mRNA level downstream of TLR4 signaling.. References_end </body> </html> </notes> <label text="TRAF3"/> <clone/> <bbox w="80.0" h="40.0" x="15155.0" y="2190.0"/> </glyph> <glyph class="macromolecule" id="s4961_sa2594" 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> 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="5240.0" y="1930.0"/> <glyph class="unit of information" id="_03ead2c1-5944-47af-a99b-4210ecd68040"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5257.5" y="1925.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4962_sa2628" 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: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="11525.0" y="1935.0"/> <glyph class="unit of information" id="_496b12ad-bf50-4d40-a1d4-e56364463e4c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="11542.5" y="1930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4963_sa2634" 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: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="9212.5" y="1955.0"/> <glyph class="state variable" id="_0e8c24b5-8727-43b5-9012-a4f3ed850204"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9207.5" y="1957.2045"/> </glyph> <glyph class="state variable" id="_0da8c496-733a-4412-a0ac-6fb3d3c42e7f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="9207.5" y="1983.554"/> </glyph> <glyph class="unit of information" id="_5578f0b9-0ee8-41fd-865d-93df6e35af83"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9230.0" y="1950.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4964_sa2690" 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: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="12875.0" y="1955.0"/> <glyph class="unit of information" id="_56213bb6-8630-4fbb-bcbc-9dc03fd72af6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="12892.5" y="1950.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4965_sa2747" 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: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="9382.5" y="1915.0"/> <glyph class="unit of information" id="_19e4e851-b9db-43e8-9b8d-3613ebcb889f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9400.0" y="1910.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4966_sa2790" 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:TIMP2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:TLR2_4 PMID:1629188 TIMP1 and TIMP2 are produced by macrophages. TIMP1 production is upregulated by TLR4 (LPS) TIMP2 production is inhibited by TLR4 signaling. PMID:22735808 TIMP-2 as a negative regulator of MDSCs in tumors PMID:24437600 TIMP2 drives "normalization" of the tumor microenvironment References_end </body> </html> </notes> <label text="TIMP2"/> <bbox w="80.0" h="40.0" x="3260.0" y="7395.0"/> </glyph> <glyph class="macromolecule" id="s4967_sa2791" 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:TIMP1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:1629188 TIMP1 and TIMP2 are produced by macrophages. TIMP1 production is upregulated by TLR4 (LPS) TIMP2 production is inhibited by TLR4 signaling. PMID:24174628 Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9 References_end </body> </html> </notes> <label text="TIMP1"/> <bbox w="80.0" h="40.0" x="3380.0" y="7395.0"/> </glyph> <glyph class="macromolecule" id="s4968_sa2806" 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:KITLG Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MAST_CELL PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, histamine, which is an immunosuppressant, mitogenic factors, such as platelet-derived growth factor (PDGF), nerve GF (NGF), stem-cell factor (SCF), and proteases, which disrupt the surrounding matrix and facilitate metastases. PMID:18524989 SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. tumor-derived SCF recruits MCs to the tumor environment and also activates them. References_end </body> </html> </notes> <label text="KITLG"/> <bbox w="80.0" h="40.0" x="5710.0" y="2365.0"/> </glyph> <glyph class="macromolecule" id="s4972_sa416" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="14175.0" y="1335.0"/> <glyph class="state variable" id="_77fa8b54-644a-4f9b-98f7-4633df18664e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14170.0" y="1355.0"/> </glyph> <glyph class="unit of information" id="_119fe4de-325f-4a4b-9464-212a573fdf53"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14192.5" y="1330.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4972_sa846" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="4260.0" y="1405.0"/> <glyph class="state variable" id="_d9e291fc-2b96-487e-8eba-357ec373879a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4255.0" y="1425.0"/> </glyph> <glyph class="unit of information" id="_730ca075-c897-4204-84c3-51b7b77aaa77"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4277.5" y="1400.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4973_sa1197" 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> Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:CCR5 CASCADE:IFNAB PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:11790543, PMID:15356122 CCR5 as a critical NK-cell homing receptor, CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. References_end </body> </html> </notes> <label text="CCR5"/> <clone/> <bbox w="80.0" h="50.0" x="5890.0" y="1750.0"/> <glyph class="unit of information" id="_7fbef48e-72b5-4f30-8e31-4e70fb018e04"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5907.5" y="1745.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4973_sa1199" 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> Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:CCR5 CASCADE:IFNAB PMID:11698286 IFNA induces surface expression of CCR5 in Dcs. This higher expression of CCR5 was associated with a stronger chemotactic response of IFN-DCs to the β-chemokines CCL5(RANTES), CCL3(MIP-1α), and, especially, CCL4( MIP-1β). PMID:11790543, PMID:15356122 CCR5 as a critical NK-cell homing receptor, CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. References_end </body> </html> </notes> <label text="CCR5"/> <clone/> <bbox w="80.0" h="50.0" x="5879.0" y="1600.0"/> <glyph class="unit of information" id="_3421713f-1e7f-4165-a02d-a14b461ba86f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5896.5" y="1595.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4974_sa2189" 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: HUGO:MERTK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK PMID:19631584 The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. PMID:25695599 Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells downstream of PROS1 and Gas6 References_end </body> </html> </notes> <label text="MERTK"/> <clone/> <bbox w="80.0" h="50.0" x="7752.5" y="1335.0"/> <glyph class="unit of information" id="_139ac35a-5f18-4c7e-8800-6fa856139fb7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7770.0" y="1330.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4974_sa2190" 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: HUGO:MERTK Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:MERTK PMID:19631584 The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. PMID:25695599 Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells downstream of PROS1 and Gas6 References_end </body> </html> </notes> <label text="MERTK"/> <clone/> <bbox w="80.0" h="50.0" x="7752.5" y="1425.0"/> <glyph class="unit of information" id="_fdacbaee-9e4d-4a05-a2a9-47696843dc32"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7770.0" y="1420.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4975_sa2195" 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> Maps_Modules_begin: MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:CR1 PMID:11120776, PMID:2972794 CR1 is a receptor for all the primary opsonins of complement, namely, MBL, C1q, C4b, and C3b. PMID:7584139, PMID:8326130 CR1 pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+. References_end </body> </html> </notes> <label text="CR1"/> <clone/> <bbox w="80.0" h="50.0" x="9826.5" y="1325.0"/> <glyph class="unit of information" id="_65aa6f37-ff93-46e1-a675-3e4e51c8c6eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9844.0" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4975_sa2208" 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> Maps_Modules_begin: MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:CR1 PMID:11120776, PMID:2972794 CR1 is a receptor for all the primary opsonins of complement, namely, MBL, C1q, C4b, and C3b. PMID:7584139, PMID:8326130 CR1 pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+. References_end </body> </html> </notes> <label text="CR1"/> <clone/> <bbox w="80.0" h="50.0" x="9827.5" y="1435.0"/> <glyph class="unit of information" id="_6d93e967-e96f-4ee3-939a-1cab3afaf8b7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="9845.0" y="1430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4976_sa2636" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE::P2RY2 PMID:19741708 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. UTP and ATP act via P2RY2 and promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo. References_end </body> </html> </notes> <label text="P2RY2"/> <clone/> <bbox w="80.0" h="50.0" x="6912.5" y="1355.0"/> <glyph class="unit of information" id="_0cf59c0f-90ab-4471-866f-ca2187482c38"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6930.0" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4976_sa2637" 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> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE::P2RY2 PMID:19741708 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. UTP and ATP act via P2RY2 and promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo. References_end </body> </html> </notes> <label text="P2RY2"/> <clone/> <bbox w="80.0" h="50.0" x="6912.5" y="1465.0"/> <glyph class="unit of information" id="_bd110a25-61ea-47ff-84da-e69c2369af12"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6930.0" y="1460.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4977_sa2721" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="16185.0" y="5365.0"/> <glyph class="unit of information" id="_648d7ddc-bda4-4ee3-90d6-291d446e7035"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16202.5" y="5360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4977_sa2723" 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: 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"/> <clone/> <bbox w="80.0" h="50.0" x="16200.0" y="5270.0"/> <glyph class="unit of information" id="_357179f7-b6af-4ead-b640-61de71505a72"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="16217.5" y="5265.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4981_sa2437" 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: HUGO:ICOSLG Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CHEKPOINTS MODULE:IMMUNE_SUPPRESSION MODULE:EFFECTOR_INHIBITION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL3 CASCADE:CD40LG PMID: 17200410, PMID:23125331, PMID:15034038 pDCs stimulated with IL-3 plus CD40L induce production ICOS-L and expression of OX40L. PMID:24778133 Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL. References_end </body> </html> </notes> <label text="B7H2*"/> <bbox w="80.0" h="40.0" x="1340.0" y="7997.5"/> </glyph> <glyph class="macromolecule" id="s4984_sa322" 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: HUGO:LAMP1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15744339 LAMP1 (CD107a) surface presentation is a marker of NK cell degranulation and antitumor activity. References_end </body> </html> </notes> <label text="LAMP1"/> <bbox w="80.0" h="40.0" x="9170.0" y="7960.0"/> </glyph> <glyph class="macromolecule" id="s4987_sa747" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="40.0" x="11820.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s4987_sa799" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="40.0" x="2860.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s4993_sa1159"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="5160.0" y="1125.0"/> </glyph> <glyph class="macromolecule" id="s4994_sa2140"> <notes> <html xmlns="http://www.w3.org/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:C5 MAP:MDSC PMID:25050844, PMID:23028051 Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness PMID:18820683 C5a via C5AR regulates the accumulation and migration of MDSCs in tumor References_end </body> </html> </notes> <label text="C5"/> <bbox w="80.0" h="40.0" x="5651.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s5003_sa398" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ULBP3 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:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end </body> </html> </notes> <label text="ULBP3"/> <bbox w="80.0" h="40.0" x="12670.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5004_sa400" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ULBP1 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:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end </body> </html> </notes> <label text="ULBP1"/> <bbox w="80.0" h="40.0" x="12390.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5005_sa399" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ULBP2 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:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end </body> </html> </notes> <label text="ULBP2"/> <bbox w="80.0" h="40.0" x="12540.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5006_sa411" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="12980.0" y="940.0"/> </glyph> <glyph class="macromolecule" id="s5007_sa402" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end </body> </html> </notes> <label text="MICB"/> <bbox w="80.0" h="40.0" x="12260.0" y="950.0"/> </glyph> <glyph class="macromolecule" id="s5008_sa403" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:IL15 MAP:DENDRITIC_CELL CASCADE:IFNAB PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end </body> </html> </notes> <label text="MICA"/> <bbox w="80.0" h="40.0" x="12160.0" y="945.0"/> </glyph> <glyph class="macromolecule" id="s5009_sa405" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCR3LG1 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 PMID:23414611, PMID:19528259, PMID:19528259, PMID:23801635 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. References_end </body> </html> </notes> <label text="B7H6*"/> <bbox w="80.0" h="40.0" x="10640.0" y="925.0"/> </glyph> <glyph class="macromolecule" id="s5010_sa404" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:BAG6 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 PMID:23414611, PMID:18055229 BAG6 (BAT3) is a NKp30 ligand expressed on tumor cells. NKp30 recognises BAG6, which leads to NK cell killing of the tumour cell. References_end </body> </html> </notes> <label text="BAG6"/> <bbox w="80.0" h="40.0" x="10760.0" y="925.0"/> </glyph> <glyph class="macromolecule" id="s5011_sa395"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HSPA1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TLR2_4 PMID:25103413 Hypoxia downregulates HSP70 level in membrane. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. References_end </body> </html> </notes> <label text="HSP70*"/> <bbox w="80.0" h="40.0" x="15320.0" y="1150.0"/> </glyph> <glyph class="macromolecule" id="s5012_sa1504"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HMGB1 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 MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL18 CASCADE:TLR2_4 CASCADE:IFNG CASCADE:TNF PMID:15802534 Activated NK cells release HMGB1, which promotes inflammation and induces DC maturation. IL-18 induces HMGB1 secretion by NK cells PMID:12646658 IFNG upregulates protein level and secretion of HMGB1 partially via TNF induction in macrophages References_end </body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="15180.0" y="1150.0"/> </glyph> <glyph class="macromolecule" id="s5013_sa444" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="7120.0" y="4050.0"/> <glyph class="state variable" id="_82d54fd2-a2b0-4411-96e7-df3ebda8365a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7115.0" y="4065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5013_sa2262" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="8220.0" y="3310.0"/> <glyph class="state variable" id="_027b8715-5e08-4a46-a27e-62e255a7829c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8215.0" y="3325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5014_sa447" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="7510.0" y="4050.0"/> <glyph class="state variable" id="_11df4399-7771-4e53-80c3-0a6d3a1c2558"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7505.0" y="4065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5014_sa2261" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="8110.0" y="3310.0"/> <glyph class="state variable" id="_073af390-852a-4fb2-9ca0-6bdfc50d9ac8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="8105.0" y="3325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5015_sa453" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="9865.0" y="2960.0"/> </glyph> <glyph class="macromolecule" id="s5015_sa2356" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="9685.0" y="2960.0"/> </glyph> <glyph class="macromolecule" id="s5016_sa454" 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:SOS1 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 GENECARDS:SOS1 HUGO:SOS2 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 GENECARDS:SOS2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: son of sevenless homolog 1 (Drosophila) REACTOME:64848 KEGG:6654 ATLASONC:GC_SOS1 WIKI:SOS1 son of sevenless homolog 2 (Drosophila) REACTOME:64850 ATLASONC:GC_SOS2 WIKI:SOS2 GINGF "gingival fibromatosis hereditary 1" "son of sevenless (Drosophilia) homolog 2" 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="SOS*"/> <clone/> <bbox w="90.0" h="50.0" x="9335.0" y="3290.0"/> </glyph> <glyph class="macromolecule" id="s5016_sa479" 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:SOS1 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 GENECARDS:SOS1 HUGO:SOS2 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 GENECARDS:SOS2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: son of sevenless homolog 1 (Drosophila) REACTOME:64848 KEGG:6654 ATLASONC:GC_SOS1 WIKI:SOS1 son of sevenless homolog 2 (Drosophila) REACTOME:64850 ATLASONC:GC_SOS2 WIKI:SOS2 GINGF "gingival fibromatosis hereditary 1" "son of sevenless (Drosophilia) homolog 2" 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="SOS*"/> <clone/> <bbox w="80.0" h="40.0" x="9345.0" y="3380.0"/> </glyph> <glyph class="macromolecule" id="s5017_sa474" 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:CYTH1 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:11050434 The cytohesin and centaurin protein families are potential targets for PtdIns(3,4,5)P3 that also regulate and interact with Arf GTPases. PMID:1511013, PMID:10652308 Cytohesin-1 (B2-1) found at high levels in natural killer and cytotoxic T-cells and at very low levels in monocytes and several cultured cell lines. The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Cytohesin-1 can activate ARF6 References_end </body> </html> </notes> <label text="CYTH1"/> <clone/> <bbox w="80.0" h="40.0" x="8805.0" y="3260.0"/> </glyph> <glyph class="macromolecule" id="s5017_sa522" 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:CYTH1 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:11050434 The cytohesin and centaurin protein families are potential targets for PtdIns(3,4,5)P3 that also regulate and interact with Arf GTPases. PMID:1511013, PMID:10652308 Cytohesin-1 (B2-1) found at high levels in natural killer and cytotoxic T-cells and at very low levels in monocytes and several cultured cell lines. The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Cytohesin-1 can activate ARF6 References_end </body> </html> </notes> <label text="CYTH1"/> <clone/> <bbox w="80.0" h="40.0" x="8805.0" y="3140.0"/> </glyph> <glyph class="macromolecule" id="s5018_sa496" 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:ROCK1 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 PMID:12778124 The kinase activity of ROCKs is moderately enhanced after Rho binding. PMID:11698448 p160ROCK plays a fundamental role in the development of cellular cytotoxicity via LIMK1 phosphorylation. But it does not affect conjugate formation. 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="ROCK1"/> <clone/> <bbox w="80.0" h="40.0" x="7066.25" y="3565.0"/> </glyph> <glyph class="macromolecule" id="s5018_sa517" 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:ROCK1 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 PMID:12778124 The kinase activity of ROCKs is moderately enhanced after Rho binding. PMID:11698448 p160ROCK plays a fundamental role in the development of cellular cytotoxicity via LIMK1 phosphorylation. But it does not affect conjugate formation. 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="ROCK1"/> <clone/> <bbox w="80.0" h="40.0" x="7059.75" y="3457.0"/> </glyph> <glyph class="macromolecule" id="s5019_sa504" 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:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL4 CASCADE:NKP80 CASCADE:NKG2D CASCADE:NKP46 CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNAB CASCADE:IFNG PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:12040186 The regulatory subunit maintains the p110 catalytic subunit in a low-activity state in quiescent cells and mediates its activation by direct interaction with phosphotyrosine residues of activated growth factor receptors or adaptor proteins. Direct binding of p110 to activated Ras protein (also induced by growth factor stimulation) further stimulates PI3K activity. The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:11062502, PMID:11385609 PI3K /RAC1/PAK1/MEK /ERK pathway controls NK cytolitic activity downstream of NKp30 and NKp46. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:8294866 Phosphatidylinositol-3 kinase activation induced upon Fc gamma RIIIA-ligand interaction in NK cells 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. References_end </body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="8900.0" y="3235.0"/> </glyph> <glyph class="macromolecule" id="s5019_sa505" 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:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL4 CASCADE:NKP80 CASCADE:NKG2D CASCADE:NKP46 CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNAB CASCADE:IFNG PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:12040186 The regulatory subunit maintains the p110 catalytic subunit in a low-activity state in quiescent cells and mediates its activation by direct interaction with phosphotyrosine residues of activated growth factor receptors or adaptor proteins. Direct binding of p110 to activated Ras protein (also induced by growth factor stimulation) further stimulates PI3K activity. The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:11062502, PMID:11385609 PI3K /RAC1/PAK1/MEK /ERK pathway controls NK cytolitic activity downstream of NKp30 and NKp46. PMID:18287025 NKG2D-mediated cytotoxicity is PI3K-dependent. PMID:8294866 Phosphatidylinositol-3 kinase activation induced upon Fc gamma RIIIA-ligand interaction in NK cells 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. References_end </body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="8900.0" y="3375.0"/> </glyph> <glyph class="macromolecule" id="s5020_sa506" 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:VAV3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end </body> </html> </notes> <label text="VAV3"/> <clone/> <bbox w="80.0" h="40.0" x="7490.0" y="2935.0"/> </glyph> <glyph class="macromolecule" id="s5020_sa508" 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:VAV3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end </body> </html> </notes> <label text="VAV3"/> <clone/> <bbox w="80.0" h="40.0" x="7490.0" y="3135.0"/> </glyph> <glyph class="macromolecule" id="s5021_sa507" 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:VAV2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end </body> </html> </notes> <label text="VAV2"/> <clone/> <bbox w="80.0" h="40.0" x="7660.0" y="2925.0"/> </glyph> <glyph class="macromolecule" id="s5021_sa509" 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:VAV2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15365099 VAV2 and VAV3 participate in signal transduction downstream of ITAM-containing adapters (CD3zeta, FcR gamma, DAP12) PMID: 12094222 VAV proteins activate RAC1 via induction of GDP/GTP exchange. References_end </body> </html> </notes> <label text="VAV2"/> <clone/> <bbox w="80.0" h="40.0" x="7670.0" y="3125.0"/> </glyph> <glyph class="macromolecule" id="s5022_sa512" 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: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)*"/> <clone/> <bbox w="80.0" h="40.0" x="9045.0" y="3300.0"/> </glyph> <glyph class="macromolecule" id="s5022_sa513" 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: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)*"/> <clone/> <bbox w="80.0" h="40.0" x="9045.0" y="3200.0"/> </glyph> <glyph class="macromolecule" id="s5023_sa514" 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:PIP5K1A 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: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII PMID:21458045 PSD4 is selectively expressed in the immune system and promotes GTP loading of ARL14/ARF7. Probably downstream of PIP5K1A. PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion References_end </body> </html> </notes> <label text="PIP5K1A"/> <clone/> <bbox w="80.0" h="40.0" x="8615.0" y="3190.0"/> </glyph> <glyph class="macromolecule" id="s5023_sa523" 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:PIP5K1A 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: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII PMID:21458045 PSD4 is selectively expressed in the immune system and promotes GTP loading of ARL14/ARF7. Probably downstream of PIP5K1A. PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion References_end </body> </html> </notes> <label text="PIP5K1A"/> <clone/> <bbox w="80.0" h="40.0" x="8455.0" y="3190.0"/> </glyph> <glyph class="macromolecule" id="s5024_sa524" 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:PLD1 HUGO:PLD2 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 CASCADE:Fc_gamma_RIII CASCADE:CR1 PMID:7584139, PMID:8326130 CR1 pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+. PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PLD-dependent pathway is involved in CD16-mediated NK cell granule exocytosis. PMID:8326130 CR3 (CD11b/CD18) pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+ References_end </body> </html> </notes> <label text="PLD*"/> <clone/> <bbox w="80.0" h="40.0" x="8405.0" y="3060.0"/> </glyph> <glyph class="macromolecule" id="s5024_sa537" 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:PLD1 HUGO:PLD2 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 CASCADE:Fc_gamma_RIII CASCADE:CR1 PMID:7584139, PMID:8326130 CR1 pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+. PMID:15817676 Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. CD16-stimulated sPLA2 secretion and enzymatic activity are dependent on PLD activation in human NK cells. PLD-dependent pathway is involved in CD16-mediated NK cell granule exocytosis. PMID:8326130 CR3 (CD11b/CD18) pathway induces phagocytosis via PLD activation and mobilization of intracellular Ca2+ References_end </body> </html> </notes> <label text="PLD*"/> <clone/> <bbox w="80.0" h="40.0" x="8405.0" y="2960.0"/> </glyph> <glyph class="macromolecule" id="s5025_sa532" 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:PAK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:11907067, PMID:11062502 RAC1 activates PAK1 downstream of SYK and PI3K and upstream of ERK and MEK. PMID:12885870 Engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK1. PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end </body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="80.0" h="40.0" x="9580.0" y="3710.0"/> </glyph> <glyph class="macromolecule" id="s5025_sa550" 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:PAK1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP46 CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:11907067, PMID:11062502 RAC1 activates PAK1 downstream of SYK and PI3K and upstream of ERK and MEK. PMID:12885870 Engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK1. PMID:10661401 Cross-Linking of β1 Integrins on Human NK Cells via VAV1 activates Rac1, which controls p38 MAPK Activation. References_end </body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="80.0" h="40.0" x="9590.0" y="3830.0"/> </glyph> <glyph class="macromolecule" id="s5026_sa827" 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:PTN6 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:FCGR2B CASCADE:KIR2DL3 CASCADE:KIR2DL2 CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:KIR3DL1 CASCADE:2B4 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). Additionally probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 (demonstrated in T cells). PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1in NK cells. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs PMID:8986721 SHP-1 participates in ZAP-70, PLC-G dephosphorylation (inactivation) downstream of KIRs. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. PMID:12176909, PMID:12773515 In macrophages SHP-1 inhibits Fcgamma receptor-mediated phagocytosis and the activation of RAC. Probably downstream of FcgammaRII(b) and other receptors. References_end </body> </html> </notes> <label text="PTPN6"/> <clone/> <bbox w="80.0" h="40.0" x="3722.5" y="2890.0"/> </glyph> <glyph class="macromolecule" id="s5026_sa828" 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:PTN6 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:FCGR2B CASCADE:KIR2DL3 CASCADE:KIR2DL2 CASCADE:KIR2DL1 CASCADE:NKG2A CASCADE:KIR3DL1 CASCADE:2B4 MAP:NATURAL_KILLER MAP:MACROPHAGE PMID:25355530, PMID:12917349, PMID:22952938, PMID:22513334 SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. Vav1 dephosphorylation by the tyrosine phosphatase PTPN-6 (SHP-1) as a mechanism for inhibition. of cellular cytotoxicity downstream of KIR-receptor (KIR2DL1). Additionally probably activated SHP-1 binds to Lck (through the Lck SH2 domain), which leads to dephosphorylation and inactivation of Lck by SHP-1 (demonstrated in T cells). PMID:8976179 PTP-1C (SHP-1) binds to and dephosphorylates pp36 (LAT) and disrupted the ability of pp36 (LAT) to associate with Grb2 downstream of KIR3DL1in NK cells. PMID:9765283 SHP-1 can bind and dephosphorylate LCP2 (SLP-76) in NK cells downstream of KIRs PMID:8986721 SHP-1 participates in ZAP-70, PLC-G dephosphorylation (inactivation) downstream of KIRs. PMID:15713798 The phosphorylated third ITSM of 2B4 can recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP. PMID:12176909, PMID:12773515 In macrophages SHP-1 inhibits Fcgamma receptor-mediated phagocytosis and the activation of RAC. Probably downstream of FcgammaRII(b) and other receptors. References_end </body> </html> </notes> <label text="PTPN6"/> <clone/> <bbox w="80.0" h="40.0" x="3722.5" y="3090.0"/> </glyph> <glyph class="macromolecule" id="s5027_sa842" 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:CSK Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:2B4 MAP:NATURAL_KILLER 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:8011291, PMID:8986721 CSK probably inhibit LCK in NK (demonstrated in T-cells only) References_end </body> </html> </notes> <label text="CSK"/> <clone/> <bbox w="80.0" h="40.0" x="3907.5" y="2900.0"/> </glyph> <glyph class="macromolecule" id="s5027_sa843" 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:CSK Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:2B4 MAP:NATURAL_KILLER 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:8011291, PMID:8986721 CSK probably inhibit LCK in NK (demonstrated in T-cells only) References_end </body> </html> </notes> <label text="CSK"/> <clone/> <bbox w="80.0" h="40.0" x="3907.5" y="3080.0"/> </glyph> <glyph class="macromolecule" id="s5028_sa881" 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:ABL1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL1 CASCADE:NKG2A MAP:NATURAL_KILLER PMID:18835194 Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity downstream of KIR2DL1 and NKG2A/CD94 pathway.. References_end </body> </html> </notes> <label text="ABL1"/> <clone/> <bbox w="80.0" h="40.0" x="3439.375" y="2921.25"/> </glyph> <glyph class="macromolecule" id="s5028_sa882" 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:ABL1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:KIR2DL1 CASCADE:NKG2A MAP:NATURAL_KILLER PMID:18835194 Association of CrkII with ALBL1(c-Abl) occurred during inhibition. ABL1 phosphorylates CRK and inhibits CRK activity downstream of KIR2DL1 and NKG2A/CD94 pathway.. References_end </body> </html> </notes> <label text="ABL1"/> <clone/> <bbox w="80.0" h="40.0" x="3442.5" y="3080.0"/> </glyph> <glyph class="macromolecule" id="s5029_sa1500" 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:TRAF6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:IL18 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="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="10915.0" y="2940.0"/> </glyph> <glyph class="macromolecule" id="s5029_sa1501" 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:TRAF6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TLR2_4 CASCADE:IL18 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="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="10665.0" y="2930.0"/> </glyph> <glyph class="macromolecule" id="s5030_sa1980" 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:MAP3K14 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL18 MAP:DENDRITIC_CELL PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:17237376, PMID:21807870 Alternative pathways involeved IKKa activation by MAP3K14 (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 References_end </body> </html> </notes> <label text="MAP3K14"/> <clone/> <bbox w="80.0" h="40.0" x="12075.0" y="3010.0"/> </glyph> <glyph class="macromolecule" id="s5030_sa2675" 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:MAP3K14 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL18 MAP:DENDRITIC_CELL PMID:10679398 IL-18 receptor system consists of a ligand-binding subunit, IL-1Rrp and a signal transducing subunit, AcPL, analogous to the IL-1 receptor system. The activated IL-1R–AcP complex recruits the serine/threonine kinase IL-1-receptor-associated kinase (IRAK) via the adaptor protein, MyD88. After IRAK is phosphorylated, it dissociates from the receptor complex and interacts with TNF-receptor-associated factor 6 (TRAF6), which then relays the signal via NF-κB-inducing kinase (NIK) to two I-κB kinases (IKK-1 and IKK-2) leading to NF-κB activation. PMID:17237376, PMID:21807870 Alternative pathways involeved IKKa activation by MAP3K14 (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 References_end </body> </html> </notes> <label text="MAP3K14"/> <clone/> <bbox w="80.0" h="40.0" x="12075.0" y="2920.0"/> </glyph> <glyph class="macromolecule" id="s5031_sa1997" 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:MAP3K8 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554 immunoprecipitated MAP3K8 TPL-2 could directly phosphorylate and activate both MEK-1 and MKK4 (also known as SEK-1) in vitro. TPL-2 expression is essential for LPS activation of MEK-1⁄2 and ERK-1⁄2 in macrophages PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="MAP3K8"/> <clone/> <bbox w="120.0" h="80.0" x="11395.0" y="3470.0"/> </glyph> <glyph class="macromolecule" id="s5031_sa1999" 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:MAP3K8 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554 immunoprecipitated MAP3K8 TPL-2 could directly phosphorylate and activate both MEK-1 and MKK4 (also known as SEK-1) in vitro. TPL-2 expression is essential for LPS activation of MEK-1⁄2 and ERK-1⁄2 in macrophages PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="MAP3K8"/> <clone/> <bbox w="130.0" h="80.0" x="10930.0" y="3720.0"/> </glyph> <glyph class="macromolecule" id="s5032_sa2000" 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:TNIP2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="TNIP2"/> <clone/> <bbox w="127.0" h="75.0" x="10931.5" y="3502.5"/> </glyph> <glyph class="macromolecule" id="s5032_sa2001" 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:TNIP2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="TNIP2"/> <clone/> <bbox w="125.0" h="60.0" x="11522.5" y="3480.0"/> </glyph> <glyph class="macromolecule" id="s5033_sa2114" 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:ECSIT Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:25371197, TAK1-ECSIT-TRAF6 Complex Plays a Key Role in the TLR4 Signal to Activate NF-κB ECSIT-knockdown monocytic cells exhibited severe impairments in NF-κB activity, cytokine production, and NF-κB-dependent gene expression, whereas those were dramatically restored by reintroduction of wild type (WT) ECSIT gene. IRF7, IL-1β, CD44, NF-κB2, IER3, IL-8, NF-κB1A, and RelB were markedly decreased in the ECSITKD PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. References_end </body> </html> </notes> <label text="ECSIT"/> <clone/> <bbox w="80.0" h="40.0" x="10625.0" y="3040.0"/> </glyph> <glyph class="macromolecule" id="s5033_sa2120" 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:ECSIT Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:25371197, TAK1-ECSIT-TRAF6 Complex Plays a Key Role in the TLR4 Signal to Activate NF-κB ECSIT-knockdown monocytic cells exhibited severe impairments in NF-κB activity, cytokine production, and NF-κB-dependent gene expression, whereas those were dramatically restored by reintroduction of wild type (WT) ECSIT gene. IRF7, IL-1β, CD44, NF-κB2, IER3, IL-8, NF-κB1A, and RelB were markedly decreased in the ECSITKD PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. References_end </body> </html> </notes> <label text="ECSIT"/> <clone/> <bbox w="80.0" h="40.0" x="10835.0" y="3040.0"/> </glyph> <glyph class="macromolecule" id="s5034_sa2115" 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:MAP3K1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. PMID:9582321 DeltaMEKK1 overexpression results in activation of both c-Jun N-terminal kinases/extracellular signal-regulated kinases (JNK/SAPK) and p38 MAPK (non_immune model). PMID:15170913, PMID:9582321, PMID:11668179 MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway upregulates COX2 expression and PGE2 production in macrophages, via activation of transcription factor C/EBP beta. PMID:9379049 MKK3 and MKK4 are capable of phosphorylating p38mapk in macrophages, downstream of TNF/Tnf receptor signaling. PMID:12048245 IFN-γ-Induced Gene Expression is MEKK1/p38 dependent and MEKK1/ERK dependent MEKK1 upregulates CEBPB activation via ERK References_end </body> </html> </notes> <label text="MAP3K1"/> <clone/> <bbox w="80.0" h="40.0" x="10551.0" y="3300.0"/> </glyph> <glyph class="macromolecule" id="s5034_sa2119" 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:MAP3K1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:10465784 ECSIT (evolutionarilyconserved signaling intermediate inToll pathways), is specific for the Toll/IL-1 pathways and is a regulator of MEKK-1 processing. Expression of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-κB ECSIT mutant also strongly inhibited MEKK-1 activation of AP-1 (probably via MAP2K4/JNK), additionally TRAF6-induced signaling is inhibited by dominant-negative constructs of MEKK-1. PMID:9582321 DeltaMEKK1 overexpression results in activation of both c-Jun N-terminal kinases/extracellular signal-regulated kinases (JNK/SAPK) and p38 MAPK (non_immune model). PMID:15170913, PMID:9582321, PMID:11668179 MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway upregulates COX2 expression and PGE2 production in macrophages, via activation of transcription factor C/EBP beta. PMID:9379049 MKK3 and MKK4 are capable of phosphorylating p38mapk in macrophages, downstream of TNF/Tnf receptor signaling. PMID:12048245 IFN-γ-Induced Gene Expression is MEKK1/p38 dependent and MEKK1/ERK dependent MEKK1 upregulates CEBPB activation via ERK References_end </body> </html> </notes> <label text="MAP3K1"/> <clone/> <bbox w="80.0" h="40.0" x="10551.0" y="3190.0"/> </glyph> <glyph class="macromolecule" id="s5035_sa2476" 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: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. PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL3, TNF, and CCL2(MCP1) References_end </body> </html> </notes> <label text="PPARG"/> <clone/> <bbox w="80.0" h="40.0" x="2567.25" y="3801.5"/> </glyph> <glyph class="macromolecule" id="s5035_sa2479" 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: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. PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL3, TNF, and CCL2(MCP1) References_end </body> </html> </notes> <label text="PPARG"/> <clone/> <bbox w="80.0" h="40.0" x="2572.25" y="3890.0"/> </glyph> <glyph class="macromolecule" id="s5036_sa2662" 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:ADCY1 HGNC:232 ENTREZ:107 UNIPROT:Q08828 GENECARDS:ADCY1 HUGO:ADCY2 HGNC:233 ENTREZ:108 UNIPROT:Q08462 GENECARDS:ADCY2 HUGO:ADCY3 HGNC:234 ENTREZ:109 UNIPROT:O60266 GENECARDS:ADCY3 HUGO:ADCY8 HGNC:239 ENTREZ:114 UNIPROT:P40145 GENECARDS:ADCY8 HUGO:ADCY4 HGNC:235 ENTREZ:196883 UNIPROT:Q8NFM4 GENECARDS:ADCY4 HUGO:ADCY5 HGNC:236 ENTREZ:111 UNIPROT:O95622 GENECARDS:ADCY5 HUGO:ADCY6 HGNC:237 ENTREZ:112 UNIPROT:O43306 GENECARDS:ADCY6 HUGO:ADCY7 HGNC:238 ENTREZ:113 UNIPROT:P51828 GENECARDS:ADCY7 HUGO:ADCY9 HGNC:240 ENTREZ:115 UNIPROT:O60503 GENECARDS:ADCY9 HUGO:ADCY10 HGNC:21285 ENTREZ:55811 UNIPROT:Q96PN6 GENECARDS:ADCY10 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: adenylate cyclase 1 (brain) REACTOME:53232 KEGG:107 WIKI:ADCY1 adenylate cyclase 2 (brain) REACTOME:53234 KEGG:108 ATLASONC:GC_ADCY2 WIKI:ADCY2 adenylate cyclase 3 REACTOME:53236 KEGG:114 WIKI:ADCY3 REACTOME:53246 KEGG:114 ATLASONC:GC_ADCY8 WIKI:ADCY8 adenylate cyclase 4 REACTOME:53238 KEGG:196883 WIKI:ADCY4 adenylate cyclase 5 REACTOME:53240 KEGG:111 WIKI:ADCY5 adenylate cyclase 6 REACTOME:53242 KEGG:112 ATLASONC:GC_ADCY6 WIKI:ADCY6 adenylate cyclase 7 REACTOME:53244 KEGG:113 ATLASONC:GC_ADCY7 WIKI:ADCY7 adenylate cyclase 8 REACTOME:53246 KEGG:114 ATLASONC:GC_ADCY8 WIKI:ADCY8 REACTOME:53236 KEGG:114 WIKI:ADCY3 adenylate cyclase 9 REACTOME:53248 KEGG:115 WIKI:ADCY9 adenylate cyclase 10 0 0 KEGG:55811 ATLASONC:GC_ADCY10 WIKI:ADCY10 CASCADE:IL13 PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="Adenylyl_cyclase*"/> <clone/> <bbox w="80.0" h="40.0" x="4200.0" y="3420.0"/> </glyph> <glyph class="macromolecule" id="s5036_sa2663" 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:ADCY1 HGNC:232 ENTREZ:107 UNIPROT:Q08828 GENECARDS:ADCY1 HUGO:ADCY2 HGNC:233 ENTREZ:108 UNIPROT:Q08462 GENECARDS:ADCY2 HUGO:ADCY3 HGNC:234 ENTREZ:109 UNIPROT:O60266 GENECARDS:ADCY3 HUGO:ADCY8 HGNC:239 ENTREZ:114 UNIPROT:P40145 GENECARDS:ADCY8 HUGO:ADCY4 HGNC:235 ENTREZ:196883 UNIPROT:Q8NFM4 GENECARDS:ADCY4 HUGO:ADCY5 HGNC:236 ENTREZ:111 UNIPROT:O95622 GENECARDS:ADCY5 HUGO:ADCY6 HGNC:237 ENTREZ:112 UNIPROT:O43306 GENECARDS:ADCY6 HUGO:ADCY7 HGNC:238 ENTREZ:113 UNIPROT:P51828 GENECARDS:ADCY7 HUGO:ADCY9 HGNC:240 ENTREZ:115 UNIPROT:O60503 GENECARDS:ADCY9 HUGO:ADCY10 HGNC:21285 ENTREZ:55811 UNIPROT:Q96PN6 GENECARDS:ADCY10 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end References_begin: adenylate cyclase 1 (brain) REACTOME:53232 KEGG:107 WIKI:ADCY1 adenylate cyclase 2 (brain) REACTOME:53234 KEGG:108 ATLASONC:GC_ADCY2 WIKI:ADCY2 adenylate cyclase 3 REACTOME:53236 KEGG:114 WIKI:ADCY3 REACTOME:53246 KEGG:114 ATLASONC:GC_ADCY8 WIKI:ADCY8 adenylate cyclase 4 REACTOME:53238 KEGG:196883 WIKI:ADCY4 adenylate cyclase 5 REACTOME:53240 KEGG:111 WIKI:ADCY5 adenylate cyclase 6 REACTOME:53242 KEGG:112 ATLASONC:GC_ADCY6 WIKI:ADCY6 adenylate cyclase 7 REACTOME:53244 KEGG:113 ATLASONC:GC_ADCY7 WIKI:ADCY7 adenylate cyclase 8 REACTOME:53246 KEGG:114 ATLASONC:GC_ADCY8 WIKI:ADCY8 REACTOME:53236 KEGG:114 WIKI:ADCY3 adenylate cyclase 9 REACTOME:53248 KEGG:115 WIKI:ADCY9 adenylate cyclase 10 0 0 KEGG:55811 ATLASONC:GC_ADCY10 WIKI:ADCY10 CASCADE:IL13 PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="Adenylyl_cyclase*"/> <clone/> <bbox w="80.0" h="40.0" x="4200.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s5037_sa2676" 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> Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:IL2 CASCADE:IL18 CASCADE:CSF2 CASCADE:FT3LG CASCADE:IFNG CASCADE:IL1 PMID:10477595 FLT3 induced a high level of NF-κB nuclear translocation and specific DNA binding VEGF inhibited FT3L-inducible activation of transcription factor NF-κB PMID:12133954 IL-2R signals can activate a pathway leading to NF-κB p50/p65 activation in NK cells, 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 ( PMID:20876105, PMID:17027520, IL18 induces expression of NFKBIZ in NK cells provavly via NFkB pathway or via increasing of mRNA stability..). PMID:17404308 CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradation, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. PMID:21826665 NFkB is activated in TANs References_end </body> </html> </notes> <label text="NFkB*"/> <clone/> <bbox w="80.0" h="40.0" x="12985.0" y="4590.0"/> </glyph> <glyph class="macromolecule" id="s5037_sa2724" 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> Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MDSC MAP:NEUTROPHIL MAP:MACROPHAGE CASCADE:IL2 CASCADE:IL18 CASCADE:CSF2 CASCADE:FT3LG CASCADE:IFNG CASCADE:IL1 PMID:10477595 FLT3 induced a high level of NF-κB nuclear translocation and specific DNA binding VEGF inhibited FT3L-inducible activation of transcription factor NF-κB PMID:12133954 IL-2R signals can activate a pathway leading to NF-κB p50/p65 activation in NK cells, 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 ( PMID:20876105, PMID:17027520, IL18 induces expression of NFKBIZ in NK cells provavly via NFkB pathway or via increasing of mRNA stability..). PMID:17404308 CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradation, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. PMID:21826665 NFkB is activated in TANs References_end </body> </html> </notes> <label text="NFkB*"/> <clone/> <bbox w="80.0" h="40.0" x="12985.0" y="4510.0"/> </glyph> <glyph class="macromolecule" id="s5038_sa2075" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="9635.0" y="4655.0"/> </glyph> <glyph class="macromolecule" id="s5038_sa2080" 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: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"/> <clone/> <bbox w="80.0" h="40.0" x="9775.0" y="4655.0"/> </glyph> <glyph class="macromolecule" id="s5039_sa2392" 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:SP1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 PMID:17705132 SP1 directly activate TBX21 (T-Bet) promoter in NK cells downstream of IL12, IL15. Mithramycin A inhibits while monokines increase Sp1 binding to T-BET promoter and downregulates T-BET and IFNG expression in NK cells. References_end </body> </html> </notes> <label text="SP1"/> <clone/> <bbox w="80.0" h="40.0" x="11645.0" y="4645.0"/> </glyph> <glyph class="macromolecule" id="s5039_sa2796" 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:SP1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 PMID:17705132 SP1 directly activate TBX21 (T-Bet) promoter in NK cells downstream of IL12, IL15. Mithramycin A inhibits while monokines increase Sp1 binding to T-BET promoter and downregulates T-BET and IFNG expression in NK cells. References_end </body> </html> </notes> <label text="SP1"/> <clone/> <bbox w="80.0" h="40.0" x="11650.0" y="4515.0"/> </glyph> <glyph class="macromolecule" id="s5040_sa17" 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:ARHGEF2 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. Just TRIF-dependent but Myd88-independent pathway enhanced the RhoB activity in DC after LPS stimulation. References_end </body> </html> </notes> <label text="ARHGEF2"/> <clone/> <bbox w="80.0" h="40.0" x="12550.0" y="7005.0"/> </glyph> <glyph class="macromolecule" id="s5040_sa27" 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:ARHGEF2 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. Just TRIF-dependent but Myd88-independent pathway enhanced the RhoB activity in DC after LPS stimulation. References_end </body> </html> </notes> <label text="ARHGEF2"/> <clone/> <bbox w="80.0" h="40.0" x="12400.0" y="7005.0"/> </glyph> <glyph class="macromolecule" id="s5041_sa74" 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: 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="14526.875" y="7962.5"/> <glyph class="unit of information" id="_90ca5952-3585-4b3c-b199-182264aceb28"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14544.375" y="7957.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5042_sa77" 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: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="14200.0" y="7763.75"/> <glyph class="unit of information" id="_348ffe47-7a5a-4f00-a60a-b65d949aab2f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14217.5" y="7758.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s5043_sa79" 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: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="14070.0" y="7765.0"/> <glyph class="state variable" id="_53825b1c-8043-4be0-bb61-9c04ac1bc0cb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14065.0" y="7780.0"/> </glyph> <glyph class="unit of information" id="_e9a1311e-c7d6-4eb0-87f5-2bd1885a1148"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14087.5" y="7760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5044_sa81" 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> Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:TLR2_4 CASCADE:TNF CASCADE:FLT3LG CASCADE:IFNAB PMID:22076556, PMID:21220452, PMID:24218453 In immature DCs, internalization of MHC class II molecules from the plasma membrane may require the ubiquitin ligase MARCH1, which is controlled by interleukin-10 (IL-10). CD83 on mature DCs prevents this ubiquitylation of MHC class II molecules and thus stabilizes MHC class II molecules on the cell surface. Addidionally it prevents CD86 ubiquitinqtion. 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. 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:25215878 FLT3 ligand upregulates surface expression of CD83 in DCs. PMID:21930769, PMID:21930765, PMID:11964292, PMID:11698286, 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. References_end </body> </html> </notes> <label text="CD83"/> <bbox w="80.0" h="50.0" x="13680.0" y="7940.0"/> <glyph class="unit of information" id="_b2d0d68d-0d1a-4a26-9c5e-65a104d86156"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="13697.5" y="7935.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5045_sa321" 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:LAMP1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15744339 LAMP1 (CD107a) surface presentation is a marker of NK cell degranulation and antitumor activity. References_end </body> </html> </notes> <label text="LAMP1"/> <bbox w="80.0" h="40.0" x="9170.0" y="7780.0"/> </glyph> <glyph class="macromolecule" id="s5046_sa2298" 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:EPAS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG Maps_Modules_end References_begin: PMID:20194441 HIF2a expression is assosiated with M2 phenotype. PMID:11888900, PMID:20644254 HIF2A induces tumor growth and angiogenesis. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. 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="HIF2A*"/> <clone/> <bbox w="80.0" h="40.0" x="3560.625" y="4732.75"/> </glyph> <glyph class="macromolecule" id="s5046_sa2301" 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:EPAS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG Maps_Modules_end References_begin: PMID:20194441 HIF2a expression is assosiated with M2 phenotype. PMID:11888900, PMID:20644254 HIF2A induces tumor growth and angiogenesis. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. 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="HIF2A*"/> <clone/> <bbox w="80.0" h="40.0" x="3560.625" y="4802.75"/> </glyph> <glyph class="macromolecule" id="s5047_sa2302" 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:HIF1A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:IL4 CASCADE:LACTIC CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG PMID:22006996 Hypoxia-induced expression of ADAM10 is HIF-1-dependent. PMID:25103413 Hypoxia downregulates MICA, MICB surface expression via HIF1A. PMID:24006507 HIF1A expression is assotiated with classical activation of macrophages PMID:20427344 HIF1 expression is assotiated with classical activation of macrophages HIF1A upregulates expression of: TNF, IL6, HIF1A downregulates expression of M2 markers CD206 and STAB1. PMID_24006507 IL4 downregulates HIF1a translation. PMID:21765015 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth HIF1A upregulates expression of: TNF, IL6 and downregulates expression of M2 markers CD206 and STAB1 HIF1A upregulates expression of EGLN1, EGLN3, PDK1, Pfkfb3, GLUT1, VEGF, FGF2 Mif, Ccr2, Cxcl2 References_end </body> </html> </notes> <label text="HIF1A"/> <clone/> <bbox w="80.0" h="40.0" x="3745.625" y="4797.5"/> </glyph> <glyph class="macromolecule" id="s5047_sa2305" 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:HIF1A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:IL4 CASCADE:LACTIC CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG PMID:22006996 Hypoxia-induced expression of ADAM10 is HIF-1-dependent. PMID:25103413 Hypoxia downregulates MICA, MICB surface expression via HIF1A. PMID:24006507 HIF1A expression is assotiated with classical activation of macrophages PMID:20427344 HIF1 expression is assotiated with classical activation of macrophages HIF1A upregulates expression of: TNF, IL6, HIF1A downregulates expression of M2 markers CD206 and STAB1. PMID_24006507 IL4 downregulates HIF1a translation. PMID:21765015 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth HIF1A upregulates expression of: TNF, IL6 and downregulates expression of M2 markers CD206 and STAB1 HIF1A upregulates expression of EGLN1, EGLN3, PDK1, Pfkfb3, GLUT1, VEGF, FGF2 Mif, Ccr2, Cxcl2 References_end </body> </html> </notes> <label text="HIF1A"/> <clone/> <bbox w="80.0" h="40.0" x="3735.625" y="4717.5"/> </glyph> <glyph class="macromolecule" id="s5048_sa2357" 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:ID1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: CASCADE:VEGFA MAP:DENDRITIC_CELL PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="ID1"/> <clone/> <bbox w="80.0" h="40.0" x="4540.0" y="4710.0"/> </glyph> <glyph class="macromolecule" id="s5048_sa2358" 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:ID1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: CASCADE:VEGFA MAP:DENDRITIC_CELL PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="ID1"/> <clone/> <bbox w="80.0" h="40.0" x="4540.0" y="4800.0"/> </glyph> <glyph class="macromolecule" id="s5049_sa788" 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:LTA Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:IL2 PMID:11823516 Human immature dendritic cells express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or R:Fc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. PMID:1281193 IL2 induces surface expression of LTA in NK cells. References_end </body> </html> </notes> <label text="LTA"/> <clone/> <bbox w="80.0" h="40.0" x="7385.0" y="7665.0"/> </glyph> <glyph class="macromolecule" id="s5049_sa2764" 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:LTA Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER CASCADE:IL2 PMID:11823516 Human immature dendritic cells express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or R:Fc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. PMID:1281193 IL2 induces surface expression of LTA in NK cells. References_end </body> </html> </notes> <label text="LTA"/> <clone/> <bbox w="80.0" h="40.0" x="7385.0" y="7465.0"/> </glyph> <glyph class="macromolecule" id="s5050_sa2609" 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: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="2550.0" y="3500.0"/> </glyph> <glyph class="macromolecule" id="s5132_sa342" 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:HIF1A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:IL4 CASCADE:LACTIC CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG PMID:22006996 Hypoxia-induced expression of ADAM10 is HIF-1-dependent. PMID:25103413 Hypoxia downregulates MICA, MICB surface expression via HIF1A. PMID:24006507 HIF1A expression is assotiated with classical activation of macrophages PMID:20427344 HIF1 expression is assotiated with classical activation of macrophages HIF1A upregulates expression of: TNF, IL6, HIF1A downregulates expression of M2 markers CD206 and STAB1. PMID_24006507 IL4 downregulates HIF1a translation. PMID:21765015 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth HIF1A upregulates expression of: TNF, IL6 and downregulates expression of M2 markers CD206 and STAB1 HIF1A upregulates expression of EGLN1, EGLN3, PDK1, Pfkfb3, GLUT1, VEGF, FGF2 Mif, Ccr2, Cxcl2 References_end </body> </html> </notes> <label text="HIF1A"/> <clone/> <bbox w="80.0" h="40.0" x="11880.0" y="510.0"/> </glyph> <glyph class="macromolecule" id="s5132_sa347" 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:HIF1A Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE CASCADE:IL4 CASCADE:LACTIC CASCADE:IL13 CASCADE:CSF2 CASCADE:IFNG PMID:22006996 Hypoxia-induced expression of ADAM10 is HIF-1-dependent. PMID:25103413 Hypoxia downregulates MICA, MICB surface expression via HIF1A. PMID:24006507 HIF1A expression is assotiated with classical activation of macrophages PMID:20427344 HIF1 expression is assotiated with classical activation of macrophages HIF1A upregulates expression of: TNF, IL6, HIF1A downregulates expression of M2 markers CD206 and STAB1. PMID_24006507 IL4 downregulates HIF1a translation. PMID:21765015 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth HIF1A upregulates expression of: TNF, IL6 and downregulates expression of M2 markers CD206 and STAB1 HIF1A upregulates expression of EGLN1, EGLN3, PDK1, Pfkfb3, GLUT1, VEGF, FGF2 Mif, Ccr2, Cxcl2 References_end </body> </html> </notes> <label text="HIF1A"/> <clone/> <bbox w="80.0" h="40.0" x="11880.0" y="440.0"/> </glyph> <glyph class="macromolecule" id="s5139_sa358" 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:HSPA1A Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TLR2_4 PMID:25103413 Hypoxia downregulates HSP70 level in membrane. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. References_end </body> </html> </notes> <label text="HSP70*"/> <bbox w="80.0" h="40.0" x="15305.0" y="685.0"/> </glyph> <glyph class="macromolecule" id="s5140_sa370" 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:ULBP3 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:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end </body> </html> </notes> <label text="ULBP3"/> <bbox w="80.0" h="40.0" x="12600.0" y="670.0"/> </glyph> <glyph class="macromolecule" id="s5141_sa371" 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:ULBP1 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:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end </body> </html> </notes> <label text="ULBP1"/> <bbox w="80.0" h="40.0" x="12400.0" y="670.0"/> </glyph> <glyph class="macromolecule" id="s5142_sa377" 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:ULBP2 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:11777960, PMID: 11491531, PMID:11239445 ULBP1,‭ ‬ULBP2,‭ ‬ULBP3‭ ‬proteins also are ligands of NKG2D References_end </body> </html> </notes> <label text="ULBP2"/> <bbox w="80.0" h="40.0" x="12500.0" y="670.0"/> </glyph> <glyph class="macromolecule" id="s5145_sa380" 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: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="12980.0" y="650.0"/> </glyph> <glyph class="macromolecule" id="s5146_sa381" 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:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end </body> </html> </notes> <label text="MICB"/> <bbox w="80.0" h="40.0" x="12290.0" y="670.0"/> </glyph> <glyph class="macromolecule" id="s5147_sa382" 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:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKG2D CASCADE:IL15 MAP:DENDRITIC_CELL CASCADE:IFNAB PMID: 10426993, PMID: 11491531 NKG2D is an activating receptor that initiates NK and T cell–mediated cytotoxicity against transfectants and tumors expressing its ligands,‭ ‬MICA and MICB.‭ References_end </body> </html> </notes> <label text="MICA"/> <bbox w="80.0" h="40.0" x="12160.0" y="670.0"/> </glyph> <glyph class="macromolecule" id="s5148_sa385" 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:NCR3LG1 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 PMID:23414611, PMID:19528259, PMID:19528259, PMID:23801635 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. References_end </body> </html> </notes> <label text="B7H6*"/> <bbox w="80.0" h="40.0" x="10640.0" y="685.0"/> </glyph> <glyph class="macromolecule" id="s5149_sa386" 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:BAG6 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 PMID:23414611, PMID:18055229 BAG6 (BAT3) is a NKp30 ligand expressed on tumor cells. NKp30 recognises BAG6, which leads to NK cell killing of the tumour cell. References_end </body> </html> </notes> <label text="BAG6"/> <bbox w="80.0" h="40.0" x="10770.0" y="695.0"/> </glyph> <glyph class="macromolecule" id="s5157_sa1498" 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:HMGB1 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 MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL18 CASCADE:TLR2_4 CASCADE:IFNG CASCADE:TNF PMID:15802534 Activated NK cells release HMGB1, which promotes inflammation and induces DC maturation. IL-18 induces HMGB1 secretion by NK cells PMID:12646658 IFNG upregulates protein level and secretion of HMGB1 partially via TNF induction in macrophages References_end </body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="15165.0" y="685.0"/> </glyph> <glyph class="macromolecule" id="s5158_sa2143" 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> Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:C5 MAP:MDSC PMID:25050844, PMID:23028051 Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness PMID:18820683 C5a via C5AR regulates the accumulation and migration of MDSCs in tumor References_end </body> </html> </notes> <label text="C5"/> <bbox w="80.0" h="40.0" x="5640.0" y="785.0"/> </glyph> <glyph class="macromolecule" id="s5159_sa2593" 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: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="5150.0" y="785.0"/> </glyph> <glyph class="macromolecule" id="s5163_sa819" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CDH1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. References_end </body> </html> </notes> <label text="CDH1"/> <bbox w="80.0" h="40.0" x="2400.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5164_sa820" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CDH2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. References_end </body> </html> </notes> <label text="CDH2"/> <bbox w="80.0" h="40.0" x="2510.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5165_sa821" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CDH4 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KLRG1 MAP:NATURAL_KILLER PMID:16461340, PMID:16424155, PMID:17617594 Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells. Putative KLRG1 ligands are expressed ubiquitously in melanoma and carcinoma cell lines.1 binds three of the classical cadherins (E (CDH1), N (CDH2), and R(CDH4)). E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. Tumor-associated E-cadherin mutations interfere with KLRG1 interaction, human KLRG1 failed to bind to Δ8 and Δ9 E-cadherin mutants. References_end </body> </html> </notes> <label text="CDH4"/> <bbox w="80.0" h="40.0" x="2630.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5168_sa801" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HLA-B Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR3DL1 MAP:NATURAL_KILLER PMID:9605119 Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. References_end </body> </html> </notes> <label text="HLA-B"/> <bbox w="80.0" h="40.0" x="3300.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5169_sa802" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HLA-G Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:KIR2DL4 CASCADE:LILRB1 MAP:NATURAL_KILLER PMID:11994457, PMID:11513144, PMID:16287995 KIR2DL4 (CD158d) is a receptor for the nonclassical HLA-G. HLA-G is normally expressed only on fetal-derived trophoblast cells that invade the maternal decidua in pregnant women. But it is expressed by many tumor cells and probably provides tumor escape from NK killing. References_end </body> </html> </notes> <label text="HLA-G"/> <bbox w="80.0" h="40.0" x="3500.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5170_sa392" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: CASCADE:INTEGRIN_A4B1 PMID:12626562, PMID:19454690 VCAM1 is a ligand for alpha-4/beta-1 integrin cells. NKG2D ligation leads to increased adhesion NK cells to VCAM1 and ICAM1 and recruitment of integrins to the cytotoxic synapse. References_end </body> </html> </notes> <label text="VCAM1"/> <bbox w="80.0" h="40.0" x="8430.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5172_sa394" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:NEUTROPHIL CASCADE:IL10 CASCADE:IFNG CASCADE:IL18 CASCADE:LFA1 PMID:15356110, PMID:19454690 ICAM1 assosiation with LAF-1 provides NK cell cytotoxicity PMID:14662834 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 via polarization of perforin cytotoxic granules. This signaling is very sensitive to inhibition of actin polymerization by cytochalasin D, of Src family tyrosine kinases by PP1, and was partially sensitive to inhibition of PI3K by wortmannin. LFA-1-dependent cytotoxicity is sensitive to inhibition by killer cell Ig-like receptors ( CD158a and CD158b). PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:1673988 Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. PMID:23364881 Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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: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="ICAM1"/> <bbox w="80.0" h="40.0" x="8700.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5173_sa390" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ICAM2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:LFA1 PMID:20955708 ICAM2 is Associated With a Potential Anti-Tumor Immune Response in Early Intraepithelial Stages of Human Pancreatic Carcinogenesis. The anti-tumor immune reaction changed from an immune response to immune tolerance between the stages of intraductal papillary mucinous adenoma (IPMA) and intraductal papillary mucinous carcinoma (IPMC). Expression levels oF ICAM2 is up-regulated exclusively in IPMA and disappeared from IPMC. References_end </body> </html> </notes> <label text="ICAM2"/> <bbox w="80.0" h="40.0" x="8810.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5174_sa389" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ICAM3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:8579109, PMID:8568591 ICAM-3 is absent on endothelial cells in normal tissues but ICAM-3 expression on endothelial cells was high on both benign and malignant tumors. The increased expression of adhesion molecules ICAM-3 presents on breast cancer endothelium. References_end </body> </html> </notes> <label text="ICAM3"/> <bbox w="80.0" h="40.0" x="8910.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5175_sa396" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PVRL2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:LFA1 PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112). Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. PMID:21383766 In acute myeloid leukaemia an inverse correlation between CD112 expression on AML blasts and DNAM-1 expression on NK cells was described References_end </body> </html> </notes> <label text="PVRL2"/> <bbox w="80.0" h="40.0" x="9010.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5176_sa397" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PVR Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:LFA1 PMID:16730454PMID:16730454, PMID:24343663, PMID:18657862 DNAX accessory molecule-1 (DNAM-1, CD226) isa cell surface molecule capable of enhancing cytolytic activity and cytokine production in NK cells. Its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112) [64]. Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. Level of CD155 and CD112 expression on neuroblastoma cells derived from human patients correlated with their susceptibility to NK cellmediated killing PMID:19801517 Coincubation of NK cells with ovarian carcinoma cells expressing the DNAM-1 ligand CD155 led to reduction of DNAM-1 expression. References_end </body> </html> </notes> <label text="PVR"/> <bbox w="80.0" h="40.0" x="9120.0" y="970.0"/> </glyph> <glyph class="macromolecule" id="s5187_sa352" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="50.0" x="14100.0" y="935.0"/> <glyph class="state variable" id="_75d54b6d-e27e-4cb6-9a89-e6a59a2960d1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="14095.0" y="955.0"/> </glyph> <glyph class="unit of information" id="_bc8ad3f5-48e6-4bf0-80cb-94b5770c8673"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="14117.5" y="930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5187_sa806" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="50.0" x="4100.0" y="945.0"/> <glyph class="state variable" id="_ca8d02d9-67a8-42cd-923a-0d07d33ee861"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4095.0" y="965.0"/> </glyph> <glyph class="unit of information" id="_7d0edd30-a50d-450e-9186-e782f1774e9f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4117.5" y="940.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5188_sa746" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="40.0" x="12000.0" y="950.0"/> </glyph> <glyph class="macromolecule" id="s5188_sa798" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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"/> <clone/> <bbox w="80.0" h="40.0" x="3040.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5189_sa961"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <clone/> <bbox w="80.0" h="40.0" x="238.5" y="5115.0"/> </glyph> <glyph class="macromolecule" id="s5189_sa1859"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 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 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:IL4 CASCADE:Fc_gamma_RIII Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages 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:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. PMID:18250477 LIL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. NK cells stimuletad by IL4 have NK2 subtype () References_end </body> </html> </notes> <label text="IL4"/> <clone/> <bbox w="80.0" h="40.0" x="16600.0" y="5220.0"/> </glyph> <glyph class="macromolecule" id="s5190_sa1005"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <clone/> <bbox w="80.0" h="40.0" x="238.5" y="4695.0"/> </glyph> <glyph class="macromolecule" id="s5190_sa1856"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. PMID:18250477 IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. PMID:21097505 IL-13 upregulates expression of SOCS1 PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 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="IL13"/> <clone/> <bbox w="80.0" h="40.0" x="16600.0" y="5010.0"/> </glyph> <glyph class="macromolecule" id="s5191_sa1077"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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"/> <clone/> <bbox w="80.0" h="40.0" x="238.5" y="6000.0"/> </glyph> <glyph class="macromolecule" id="s5191_sa2699"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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"/> <clone/> <bbox w="80.0" h="40.0" x="4060.0" y="8360.0"/> </glyph> <glyph class="macromolecule" id="s5192_sa1163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end </body> </html> </notes> <label text="FN1"/> <bbox w="80.0" h="40.0" x="8580.0" y="1070.0"/> </glyph> <glyph class="macromolecule" id="s5193_sa1216"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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"/> <clone/> <bbox w="80.0" h="40.0" x="6370.0" y="1105.0"/> </glyph> <glyph class="macromolecule" id="s5193_sa1699"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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"/> <clone/> <bbox w="80.0" h="40.0" x="16600.0" y="2050.0"/> </glyph> <glyph class="macromolecule" id="s5194_sa1441"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LGALS1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:LGALS1 PMID:21191065 Cancer-derived galectin-1 mediates dendritic cell anergy through inhibitor of DNA binding 3/IL-10 signaling pathway. LGALS1 upregulates ID3 expression, then ID3 upregulates expression of IL10 in DC. References_end </body> </html> </notes> <label text="LGALS1"/> <bbox w="80.0" h="40.0" x="780.0" y="1160.0"/> </glyph> <glyph class="macromolecule" id="s5195_sa1485"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LTF 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: CASCADE:LTF MAP:NEUTROPHIL MAP:DENDRITIC_CELL CASCADE:TLR2_4 Gregory and colleagues have made an interesting observation that apoptotic cell supernatants also contain keep-out signals for neutrophils (Bournazou et al., 2009). Specifically, they identified that lactoferrin is released from apoptotic cells (in a caspase-dependent process) and that lactoferrin can act as a potent stop signal for neutrophil migration toward many other chemokines. PMID:18364398 Lactoferrin (LF) is an important protein component of the innate immune system that is broadly distributed within the body fluids. LF is endowed with multiple biological activities. Talactoferrin (TLF), a recombinant human LF, is in clinical development as an anticancer agent and is entering Phase III clinical trials. Here, we show that TLF induces the maturation of human dendritic cells (DCs) derived from monocytes. TLF, at physiologically relevant concentrations (100 microg/ml) up-regulates the expression of human leukocyte antigen (HLA) class II, CD83, CD80, and CD86 costimulatory molecule and CXCR4 and CCR7 chemokine receptors, acting primarily through the p38 MAPK signaling pathway. DCs matured by TLF displayed an enhanced release of IL-8 and CXCL10, as well as a significantly reduced production of IL-6, IL-10, and CCL20. They also display a reduced ability to take up antigen and increased capacity to trigger proliferation and release IFN-gamma in the presence of allogeneic human T cells. TLF-matured DCs are able to prime naive T cells to respond to KLH antigen and display a significantly increased capacity to present Flu-MA(58-66) peptide to HLA-A2-matched T cells. These data suggest that a key immunomodulatory function that may be mediated by TLF is to link the innate with adaptive immunity through DC maturation. PMID:24088817 Recombinant human lactoferrin induces human and mouse dendritic cell maturation via Toll-like receptors 2 and 4 References_end </body> </html> </notes> <label text="LTF"/> <clone/> <bbox w="80.0" h="40.0" x="4900.0" y="1080.0"/> </glyph> <glyph class="macromolecule" id="s5195_sa2669"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LTF 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: CASCADE:LTF MAP:NEUTROPHIL MAP:DENDRITIC_CELL CASCADE:TLR2_4 Gregory and colleagues have made an interesting observation that apoptotic cell supernatants also contain keep-out signals for neutrophils (Bournazou et al., 2009). Specifically, they identified that lactoferrin is released from apoptotic cells (in a caspase-dependent process) and that lactoferrin can act as a potent stop signal for neutrophil migration toward many other chemokines. PMID:18364398 Lactoferrin (LF) is an important protein component of the innate immune system that is broadly distributed within the body fluids. LF is endowed with multiple biological activities. Talactoferrin (TLF), a recombinant human LF, is in clinical development as an anticancer agent and is entering Phase III clinical trials. Here, we show that TLF induces the maturation of human dendritic cells (DCs) derived from monocytes. TLF, at physiologically relevant concentrations (100 microg/ml) up-regulates the expression of human leukocyte antigen (HLA) class II, CD83, CD80, and CD86 costimulatory molecule and CXCR4 and CCR7 chemokine receptors, acting primarily through the p38 MAPK signaling pathway. DCs matured by TLF displayed an enhanced release of IL-8 and CXCL10, as well as a significantly reduced production of IL-6, IL-10, and CCL20. They also display a reduced ability to take up antigen and increased capacity to trigger proliferation and release IFN-gamma in the presence of allogeneic human T cells. TLF-matured DCs are able to prime naive T cells to respond to KLH antigen and display a significantly increased capacity to present Flu-MA(58-66) peptide to HLA-A2-matched T cells. These data suggest that a key immunomodulatory function that may be mediated by TLF is to link the innate with adaptive immunity through DC maturation. PMID:24088817 Recombinant human lactoferrin induces human and mouse dendritic cell maturation via Toll-like receptors 2 and 4 References_end </body> </html> </notes> <label text="LTF"/> <clone/> <bbox w="80.0" h="40.0" x="15460.0" y="1150.0"/> </glyph> <glyph class="macromolecule" id="s5196_sa2621"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MAST_CELL CASCADE:TNF CASCADE:CSF2 MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 MAP:NATURAL_KILLER CASCADE:IL8 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself iDC in ovarian cancer ascites promote angiogenesis in vivo through production of TNF and CXCL8 PMID:18980965 Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, References_end </body> </html> </notes> <label text="IL8*"/> <clone/> <bbox w="80.0" h="40.0" x="5400.0" y="1125.0"/> </glyph> <glyph class="macromolecule" id="s5196_sa2787"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MAST_CELL CASCADE:TNF CASCADE:CSF2 MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 MAP:NATURAL_KILLER CASCADE:IL8 CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:18633355 TAM express many pro-angiogenic and angiogenesis-modulating factors in vitro, such as VEGF, basic fibroblast growth factor (bFGF, also known as FGF2), tumour necrosis factor (TNF), interleukin 1 (IL1), chemokine (C-X-C motif) ligand 8 (CXCL8; also known as IL8), cyclooxygenase 2 (COX2, also known as PTGS2), plasminogen activator, urokinase (uPA, also known as PLAU), platelet derived growth factor beta. Release of the pro-angiogenic chemokines CXCL8 and CXCL1 by neutrophils is also triggered by TNF, and by granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), platelet-activating factor and CXCL8 itself iDC in ovarian cancer ascites promote angiogenesis in vivo through production of TNF and CXCL8 PMID:18980965 Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, References_end </body> </html> </notes> <label text="IL8*"/> <clone/> <bbox w="80.0" h="40.0" x="4550.0" y="8190.0"/> </glyph> <glyph class="nucleic acid feature" id="s27_sa2370" 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:TNF Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:MIF CASCADE:Fc_gamma_RIII CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 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:1431106 TNF is ploinfammatory cytokine induced tumoricidal activity of macrophages 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 References_end </body> </html> </notes> <label text="TNF"/> <bbox w="125.0" h="62.5" x="12733.75" y="5533.75"/> <glyph class="unit of information" id="_81d36ec8-feed-49de-8051-35029bbb09b1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12786.25" y="5528.75"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s31_sa387" 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:BAG6 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:23414611, PMID:18055229 BAG6 (BAT3) is a NKp30 ligand expressed on tumor cells. NKp30 recognises BAG6, which leads to NK cell killing of the tumour cell. References_end </body> </html> </notes> <label text="BAG6"/> <bbox w="90.0" h="25.0" x="10795.0" y="542.5"/> <glyph class="unit of information" id="_4e07e75f-c95b-49d2-8cbf-70eb5ae07860"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10830.0" y="537.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s46_sa383" 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:NCR3LG1 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:23414611, PMID:19528259, PMID:19528259 B7H6 (NCR3LG) is a Nkp30 ligand.It is selectively expressed on tumor cells. Interaction of B7H6 with NKp30 (NCR3) results in natural killer (NK) cell activation and cytotoxicity. References_end </body> </html> </notes> <label text="B7H6*"/> <bbox w="90.0" h="25.0" x="10665.0" y="532.5"/> <glyph class="unit of information" id="_24259075-e489-4484-98ce-09858abf92e9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10700.0" y="527.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s77_sa1809" 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:IL1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:TLR2_4 Maps_Modules_end References_begin: 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="IL1A"/> <bbox w="90.0" h="25.0" x="4415.0" y="6657.5"/> <glyph class="unit of information" id="_4e38d405-07ac-4669-aad3-9d0b14b3c4fa"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4450.0" y="6652.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s78_sa1317" 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:IL1B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:TLR2_4 MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1B. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="90.0" h="25.0" x="4685.0" y="6477.5"/> <glyph class="unit of information" id="_bc097fbe-036d-4fbf-954b-808f7cf2bcb4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4720.0" y="6472.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s114_sa1262" 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:IL12B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:MIF CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. 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. 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 References_end </body> </html> </notes> <label text="IL12p40*"/> <bbox w="90.0" h="25.0" x="12327.75" y="5312.5"/> <glyph class="unit of information" id="_c5e09154-20c2-4c46-b9e6-9a265a71d34f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12362.75" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s116_sa1252" 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:IL6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:STING CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:9743347 IL-13 blocks NF-κB-dependent production of IL6 PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC References_end </body> </html> </notes> <label text="IL6"/> <bbox w="90.0" h="25.0" x="2417.5" y="5605.0"/> <glyph class="unit of information" id="_24b27f66-72fc-4932-be1a-deaa65a7cb0e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2452.5" y="5600.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s121_sa985" 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:IL4R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP: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:12907458, PMID:12193690 IL10 upregulates expression of IL4RA in STAT3 dependent manner. PMID:24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="90.0" h="25.0" x="1345.0" y="4759.0"/> <glyph class="unit of information" id="_1e301d99-a3a2-404e-b974-06e6d1a950b2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1380.0" y="4754.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s139_sa1104" 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:NOS2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:TGFB CASCADE:MIF CASCADE:IL10 CASCADE:IFNG Maps_Modules_end References_begin: PMID:17476345 NOS2, a heme-containing enzyme that catalyzes the synthesis of NO and citrulline from l‐Arg, is expressed by various cells of the immune system, and its activa- tion is considered a hallmark of classically activated macrophages (also known as M1 macrophages), a macrophage subset that pro- duces proinflammatory cytokines and acts as the effector cell in the killing of invading pathogens and tumor cells. 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 References_end </body> </html> </notes> <label text="NOS2"/> <bbox w="126.0" h="52.5" x="6327.5938" y="5390.9375"/> <glyph class="unit of information" id="_2b9ebc0a-b284-49d2-80e2-1f12e544dd15"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6380.5938" y="5385.9375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s143_sa1382" 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:MMP9 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:MIF CASCADE:IL10 CASCADE:IL4 CASCADE:IFNAB MAP:NEUTROPHIL Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis probavly via upregulation of MMP9, VEGF expression in macrophages and activates tumor invasion References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="90.0" h="25.0" x="3045.0" y="6507.5"/> <glyph class="unit of information" id="_495981fc-13fa-4f72-bcd0-5dc2198c7754"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3080.0" y="6502.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s147_sa1089" 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:ARG1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:LACTIC CASCADE:TGFB CASCADE:MIF Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces arginase-2 expression Up-regulation of IL4RA by IL10 correlates with increased IL4-dependent expression of arginase-1 (ARG1). References_end </body> </html> </notes> <label text="ARG1"/> <bbox w="127.0" h="43.5" x="5520.3438" y="5365.9375"/> <glyph class="unit of information" id="_1f5d5992-b452-4284-b45f-fc96159052a3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5573.8438" y="5360.9375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s148_sa1090" 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:ARG2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:IL10 Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces ARG2 (arginase-2) expression References_end </body> </html> </notes> <label text="ARG2"/> <bbox w="124.0" h="45.5" x="5681.8438" y="5365.4375"/> <glyph class="unit of information" id="_ff0833f2-f6ec-416f-89d2-b3615f221a6b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5733.8438" y="5360.4375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s153_sa1988" 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:NFKBID Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MAP:MACROPHAGE CASCADE:IL10 Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="90.0" h="25.0" x="12043.0" y="3270.5"/> <glyph class="unit of information" id="_9dc602b8-131e-4557-ada4-7269e1480155"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12078.0" y="3265.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s155_sa1288" 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:CSF3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="CSF3"/> <bbox w="90.0" h="25.0" x="4565.0" y="5337.5"/> <glyph class="unit of information" id="_a029c3fe-b45e-4f89-aec7-0ee603c6f6b2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4600.0" y="5332.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s217_sa1318" 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:IL18 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="IL18"/> <bbox w="90.0" h="25.0" x="13391.25" y="5312.5"/> <glyph class="unit of information" id="_9d22e211-84ef-4fc2-a33d-7e1a1592904c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13426.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s220_sa1272" 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:IL12A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TLR2_4 CASCADE:CSF2 Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="90.0" h="25.0" x="12421.25" y="5312.5"/> <glyph class="unit of information" id="_5eedabcd-1476-4911-8218-9c3364682a92"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12456.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s319_sa2816" 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:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:STING Maps_Modules_end References_begin: PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. References_end </body> </html> </notes> <label text="TGFB1"/> <bbox w="90.0" h="25.0" x="3117.5" y="5875.0"/> <glyph class="unit of information" id="_9967e199-49f1-45f3-b167-e1958a6c630c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3152.5" y="5870.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s321_sa1006" 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:IL13RA2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="90.0" h="25.0" x="1345.0" y="4352.5"/> <glyph class="unit of information" id="_56d8ff19-4ccd-431d-9749-d95a12f5c8dd"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1380.0" y="4347.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s347_sa1002" 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:IL13RA1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE: Maps_Modules_end References_begin: 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 References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="90.0" h="25.0" x="1435.0" y="3542.5"/> <glyph class="unit of information" id="_03774499-3caf-47aa-b116-6626774f08f0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1470.0" y="3537.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s439_sa2472" 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:ALOX15 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end </body> </html> </notes> <label text="ALOX15"/> <bbox w="90.0" h="25.0" x="2358.25" y="3728.505"/> <glyph class="unit of information" id="_b064c3d2-2ab3-4cf6-aa35-0340b0d76e25"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2393.25" y="3723.505"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s442_sa2469" 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:MAOA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:23124025 MAOA activation incuces generation of intracellular ROS during the oxidation of biogenic amines. References_end </body> </html> </notes> <label text="MAOA"/> <bbox w="90.0" h="25.0" x="6298.5938" y="7132.9424"/> <glyph class="unit of information" id="_adb1aaac-07ac-433c-9cfc-5fcfe6a8e6c6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6333.5938" y="7127.9424"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s445_sa2485" 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:CD36 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:IL13 CASCADE:IL4 Maps_Modules_end References_begin: PMID:10432118 ALOX15 activation results in induction of CD36 expression downstream of IL4 and IL13 via PRARG CD36 gene expression is directly controlled by 15-LO expression/activity in IL-13-driven monocytes/macrophages References_end </body> </html> </notes> <label text="CD36"/> <bbox w="90.0" h="25.0" x="7917.5" y="1945.6274"/> <glyph class="unit of information" id="_4e146356-4699-4bfb-a425-7d6462a34cea"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7952.5" y="1940.6274"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s448_sa2495" 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:DUSP1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 CASCADE:IL10 Maps_Modules_end References_begin: PMID:23124025, PMID:16184516 IL13 induces DUSP1 expression via TYK2 and probably STAT6 References_end </body> </html> </notes> <label text="DUSP1"/> <bbox w="90.0" h="25.0" x="2965.0" y="3427.005"/> <glyph class="unit of information" id="_e965dda4-59cd-46c1-b60b-1197bc9008ef"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3000.0" y="3422.005"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s451_sa2491" 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:TIMP3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:IL4 Maps_Modules_end References_begin: PMID:23124025 IL4 induces expression of TIMP3 via JAK1 pathway References_end </body> </html> </notes> <label text="TIMP3"/> <bbox w="90.0" h="25.0" x="3325.0" y="6501.5"/> <glyph class="unit of information" id="_5a8bf984-24c3-4b34-8407-70d090ac737c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3360.0" y="6496.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s457_sa2475" 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:PPARG Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end </body> </html> </notes> <label text="PPARG"/> <bbox w="90.0" h="25.0" x="2567.25" y="3737.5"/> <glyph class="unit of information" id="_5445d7a1-6d92-41ea-aecf-c069f4ddb398"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2602.25" y="3732.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s459_sa2378" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD163 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 CASCADE:IL10 Maps_Modules_end References_begin: PMID:22176642 CD163 is a M2 marker PMID:15749903 CD163 expression in macrophages is IL10 dependent References_end </body> </html> </notes> <label text="CD163"/> <bbox w="90.0" h="25.0" x="1886.75" y="588.125"/> <glyph class="unit of information" id="_b00fc228-66e2-4c4d-ae26-c5f17dbf60dc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1921.75" y="583.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s462_sa2379" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MRC1 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:MIF CASCADE:LGALS3 CASCADE:IL4 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 References_end </body> </html> </notes> <label text="MRC1"/> <bbox w="90.0" h="25.0" x="1990.6488" y="588.125"/> <glyph class="unit of information" id="_0f4ae69b-4094-4c3f-9a3d-fa7863e0cd1f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2025.6488" y="583.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s465_sa1247" 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:CCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TGFB Maps_Modules_end </body> </html> </notes> <label text="CCL3"/> <bbox w="90.0" h="25.0" x="5755.0" y="2532.5"/> <glyph class="unit of information" id="_4cd39a47-3337-4b14-8828-4112149bad75"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5790.0" y="2527.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s468_sa1256" 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:CCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TGFB CASCADE:CSF1 Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="90.0" h="25.0" x="5655.0" y="2532.5"/> <glyph class="unit of information" id="_d2f0c460-e069-4a9f-b4ab-7f2f7a75e242"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5690.0" y="2527.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s501_sa1268" 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:CCL7 MODULE:RECRUITMENT_OF_IMMUNE_CELLS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end </body> </html> </notes> <label text="CCL7"/> <bbox w="90.0" h="25.0" x="6085.0" y="2532.5"/> <glyph class="unit of information" id="_43d3bb99-f6f8-45a7-a552-fa9b40f02351"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6120.0" y="2527.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s506_sa2497" 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:KDM6B Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. References_end </body> </html> </notes> <label text="KDM6B"/> <bbox w="90.0" h="25.0" x="2525.0" y="4647.5"/> <glyph class="unit of information" id="_832db446-fe29-4163-a84e-7a62b7091023"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2560.0" y="4642.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s511_sa2510" 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: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="2855.0" y="4767.5"/> <glyph class="unit of information" id="_4cb3def3-0d3a-41e6-b5ed-4b8b231b7d15"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2890.0" y="4762.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s521_sa1390" 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:CCL24 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IL4 Maps_Modules_end </body> </html> </notes> <label text="CCL24"/> <bbox w="90.0" h="25.0" x="6405.0" y="2522.5"/> <glyph class="unit of information" id="_91879c63-65bb-48f6-8cd5-0b6677533d07"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6440.0" y="2517.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s523_sa2518" 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:MPP6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:MATRIX_REMODELLING CASCADE:IL4 Maps_Modules_end </body> </html> </notes> <label text="MPP6"/> <bbox w="90.0" h="25.0" x="3165.0" y="6507.0"/> <glyph class="unit of information" id="_e61b3727-9a3b-45c7-aa6e-89827f009e71"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3200.0" y="6502.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s525_sa1391" 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:IL1RN Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL10 CASCADE:IL4 MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 References_end </body> </html> </notes> <label text="IL1RN"/> <bbox w="90.0" h="25.0" x="3317.5" y="5405.0"/> <glyph class="unit of information" id="_eec98984-e1b4-4115-aa46-443100f4d725"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3352.5" y="5400.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s555_sa2383" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MRC2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:TGFB Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="MRC2"/> <bbox w="90.0" h="25.0" x="2083.75" y="588.125"/> <glyph class="unit of information" id="_caf87ecf-4980-4c9d-be6a-7e51db6726f3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2118.75" y="583.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s561_sa2405" 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:MIF Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:TLR2_4 CASCADE:IL4 CASCADE:IL13 CASCADE:TNF Maps_Modules_end References_begin: PMID:23390297, PMID:22461508, PMID:8195715 MIF is expresed by macrophages References_end </body> </html> </notes> <label text="MIF"/> <bbox w="90.0" h="25.0" x="2607.5" y="5595.0"/> <glyph class="unit of information" id="_2299c93d-5073-4a4e-855d-384480013d44"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2642.5" y="5590.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s572_sa2304" 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:HIF1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 CASCADE:IL13 CASCADE:IFNG Maps_Modules_end References_begin: PMID_24006507 HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="90.0" h="25.0" x="3730.625" y="4665.0"/> <glyph class="unit of information" id="_8834b48a-3dcc-4b30-acff-056097d37311"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3765.625" y="4660.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s573_sa2299" 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:EPAS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 CASCADE:IL13 CASCADE:IFNG Maps_Modules_end References_begin: PMID:20194441 HIF2a expression is assosiated with M2 phenotype. PMID:11888900, PMID:20644254 HIF2A induces tumor growth and angiogenesis. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. 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References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="90.0" h="25.0" x="5235.0" y="2032.5"/> <glyph class="unit of information" id="_c1e67550-8405-45ee-9ebb-9c4efd9eca81"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5270.0" y="2027.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s587_sa1168" 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:FN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:FN1 Maps_Modules_end References_begin: PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. References_end </body> </html> </notes> <label text="FN1"/> <bbox w="90.0" h="25.0" x="6165.0" y="2252.5"/> <glyph class="unit of information" id="_c1960e1f-a74c-46f2-9e3f-e87f49c03bdb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6200.0" y="2247.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s685_sa1274" 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:CXCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="90.0" h="25.0" x="4945.0" y="2552.5"/> <glyph class="unit of information" id="_71e7e904-b96a-4c7a-b2b4-d8af968b8711"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4980.0" y="2547.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s695_sa1532" 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:TLR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 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="TLR2"/> <bbox w="90.0" h="25.0" x="15070.0" y="1977.5"/> <glyph class="unit of information" id="_ae27dafd-f5cd-4891-b9d1-c6e30706fc4c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15105.0" y="1972.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s696_sa1533" 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:TLR4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:MIF MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 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. PMID:10734131, PMID:12803886, PMID:16283355 MIF upregulates expression of TLR4 in macrothages via PU.1 (SPI1) activation via PU.1 (SPI1) activation; PU.1 (SPI1) together with IRF8 relulates TLR4 expression in myeloid cells References_end </body> </html> </notes> <label text="TLR4"/> <bbox w="90.0" h="25.0" x="15180.0" y="1967.5"/> <glyph class="unit of information" id="_cf1f648b-8aa8-488f-881e-2c5f8922da1f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15215.0" y="1962.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s699_sa1281" 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:CCL4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine CCL4 (MIP1B). References_end </body> </html> </notes> <label text="CCL4"/> <bbox w="90.0" h="25.0" x="5855.0" y="2532.5"/> <glyph class="unit of information" id="_0b61a5d6-bcd6-4862-8053-a7925d9db112"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5890.0" y="2527.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s725_sa1535" 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:LY96 Identifiers_end Maps_Modules_begin: 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="90.0" h="25.0" x="15280.0" y="1967.5"/> <glyph class="unit of information" id="_5722cd4e-8060-4269-94bc-b03576a34bd0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15315.0" y="1962.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s727_sa1516" 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:MYD88 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:TLR2_4 CASCADE:IFNG CASCADE:IL15 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="MYD88"/> <bbox w="90.0" h="25.0" x="15380.0" y="1967.5"/> <glyph class="unit of information" id="_3e07ad5f-1ddf-4e2f-b9f0-2e4baaf4bd7e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15415.0" y="1962.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s733_sa1549" 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:SOCS1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IFNG CASCADE:IL4 Maps_Modules_end </body> </html> </notes> <label text="SOCS1"/> <bbox w="90.0" h="25.0" x="15009.0" y="2542.5"/> <glyph class="unit of information" id="_d9654c9f-f14f-40e2-999f-4815a4e4cd05"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15044.0" y="2537.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s735_sa2740" 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:RELA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IFNG Maps_Modules_end </body> </html> </notes> <label text="RELA"/> <bbox w="90.0" h="25.0" x="13300.0" y="3587.5"/> <glyph class="unit of information" id="_f10de9bb-c3cf-41ad-a6a8-8e9490c15063"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13335.0" y="3582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s788_sa1552" 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:RIPK1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IFNG 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="90.0" h="25.0" x="15400.0" y="3197.5"/> <glyph class="unit of information" id="_60937d26-a3cf-4316-8986-217b1039aa5a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15435.0" y="3192.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s911_sa965" 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:MAF Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL4 Maps_Modules_end References_begin: PMID:15749884 IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="MAF"/> <bbox w="90.0" h="25.0" x="4395.0" y="4434.375"/> <glyph class="unit of information" id="_1bfb8f46-87c8-474c-a79a-722016a5b762"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4430.0" y="4429.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s915_sa2130" 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:MYC Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:NEUTROPHIL MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:GSF3 CASCADE:IL4 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. References_end </body> </html> </notes> <label text="MYC"/> <bbox w="90.0" h="25.0" x="5065.0" y="4644.375"/> <glyph class="unit of information" id="_08880482-b09a-4551-949a-a1374588a56c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5100.0" y="4639.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s918_sa980" 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:STAT6 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:IL4 CASCADE:IL13 Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expression of STAT6 ans enhances downstream IL4 signaling. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="90.0" h="25.0" x="1635.0" y="3862.5"/> <glyph class="unit of information" id="_8315147c-40b0-4acf-9291-ba344481c4f3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1670.0" y="3857.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s923_sa977" 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:KLF4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:21670502 IL4 upregulates expression of KLF4 via STAT6 in M2 macrophages. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. References_end </body> </html> </notes> <label text="KLF4"/> <bbox w="90.0" h="25.0" x="4415.0" y="4707.5"/> <glyph class="unit of information" id="_caab8662-5517-47e1-ac60-1a0b96ef235a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4450.0" y="4702.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s927_sa1299" 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:IFNA1 HUGO:IFNA2 HUGO:IFNA4 HUGO:IFNA5 HUGO:IFNA6 HUGO:IFNA7 HUGO:IFNA8 HUGO:IFNA10 HUGO:IFNA13 HUGO:IFNA14 HUGO:IFNA16 HUGO:IFNA17 HUGO:IFNA21 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induces IFNA expression in macrophages References_end </body> </html> </notes> <label text="INFA*"/> <bbox w="90.0" h="25.0" x="13511.25" y="5312.5"/> <glyph class="unit of information" id="_c1c9a36d-678d-45bc-b883-ee3f748e012e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13546.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s960_sa375" 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:ULBP2 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="ULBP2"/> <bbox w="90.0" h="25.0" x="12485.0" y="567.5"/> <glyph class="unit of information" id="_ab43d9bb-c86c-4bd4-ab62-ddecc11edcb4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12520.0" y="562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s966_sa369" 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:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB 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="MICA"/> <bbox w="90.0" h="25.0" x="12145.0" y="567.5"/> <glyph class="unit of information" id="_1f4e497b-6ae1-4513-ba0f-9b70f2044a08"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12180.0" y="562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s967_sa368" 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:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB 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="MICB"/> <bbox w="90.0" h="25.0" x="12265.0" y="567.5"/> <glyph class="unit of information" id="_cd3a5714-c5e3-4914-af1c-0867e297521b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12300.0" y="562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s968_sa367" 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:ULBP1 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22754780, PMID:21764762 Wild-type p53, but not mutant p53 interacts with UDLPs promoters and induces UDLP2 and UDLP1 expression in tumor cells and increases tumor immunogenicity. UDLPs activate NKG2D* signaling in NK cells.Induction of wtp53 expression in tumor cells leads to their enhanced recognition by primary NK cells in a NKG2D-dependent manner. References_end </body> </html> </notes> <label text="UDLP1"/> <bbox w="90.0" h="25.0" x="12385.0" y="567.5"/> <glyph class="unit of information" id="_8028b9a8-2de2-4f5f-b5d2-13e708dbba5d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12420.0" y="562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s969_sa366" 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:ULBP3 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="UDLP3"/> <bbox w="90.0" h="25.0" x="12585.0" y="567.5"/> <glyph class="unit of information" id="_bfbf136c-4dce-4a06-9fb1-0039b8935cbb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12620.0" y="562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s980_sa359" 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:ADAM10 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22006996 Hypoxia-induced expression of ADAM10 is HIF-1-dependent. References_end </body> </html> </notes> <label text="ADAM10"/> <bbox w="90.0" h="25.0" x="11745.0" y="417.5"/> <glyph class="unit of information" id="_08141134-dac6-4590-944c-487b4dfb5386"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11780.0" y="412.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1019_sa2126" 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:CEBPB Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MDSC CASCADE:GSF3 PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. References_end </body> </html> </notes> <label text="CEBPB"/> <bbox w="90.0" h="25.0" x="4705.0" y="4524.375"/> <glyph class="unit of information" id="_4a3bbb5b-417e-4068-a372-b042a09279e3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4740.0" y="4519.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1064_sa1179" 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:S100A8 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC MAP:MACROPHAGE PMID:18809714 STAT3 depletion resulted in the down-regulation of S100A8 and S100A9 gene expression The promoter regions of S100A8 and S100A9 contain several potential STAT3 binding sites (TTCCC G/A G/T AA). In chromatin immunoprecipitation assays of 32D myeloid cells, STAT3 interacted with the promoter regions of both S100A8 and S100A9. References_end </body> </html> </notes> <label text="S100A8"/> <bbox w="90.0" h="25.0" x="4935.0" y="2192.5"/> <glyph class="unit of information" id="_9682399f-545b-4b55-a9a9-70058ac1b19e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4970.0" y="2187.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1065_sa1178" 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:S100A9 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC MAP:MACROPHAGE PMID:18809714 STAT3 depletion resulted in the down-regulation of S100A8 and S100A9 gene expression The promoter regions of S100A8 and S100A9 contain several potential STAT3 binding sites (TTCCC G/A G/T AA). In chromatin immunoprecipitation assays of 32D myeloid cells, STAT3 interacted with the promoter regions of both S100A8 and S100A9. References_end </body> </html> </notes> <label text="S100A9"/> <bbox w="90.0" h="25.0" x="4835.0" y="2192.5"/> <glyph class="unit of information" id="_8e16d48f-525b-4a91-adda-3aa7bdfef151"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4870.0" y="2187.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1119_sa227" 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:GZMB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24795729 PI3K–AKT–mTOR pathway is required for granzyme B production downstream of IL15 PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity.. References_end </body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="8365.0" y="6587.5"/> <glyph class="unit of information" id="_ca7ec0a9-c35a-4641-8fac-291d75144c12"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="8400.0" y="6582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1132_sa1377" 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:FGF2 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:MAST_CELL PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. PMID:11874475 Mast cells express end secrete FGF2 References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="90.0" h="25.0" x="3935.0" y="6667.5"/> <glyph class="unit of information" id="_4a80d47f-cccd-4a0e-91e6-b73e4dab3df3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3970.0" y="6662.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1168_sa235" 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:PRF1 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL12 CASCADE:IL2 CASCADE:IL15 CASCADE:IFNAB PMID:9841920 Induction of perforin mRNA by IL-2 and IL-15 was markedly decreased in Stat5b−/− splenocytes PMID:21960590 Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells. PMID:22649192 miR-378 and miR-30e suppress IFN-α–upregulated granzyme B and perforin expression in human NK cells. miR-378 and miR-30e are markedly decreased in activated NK cells by IFNA, miR-378 and miR-30e directly targeted granzyme B and perforin, respectively and suppress of human NK cell cytotoxicity. PMID:24698324 miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. PMID:15084276 T-bet is a key factor in the terminal maturation and peripheral homeostasis of NK and Vα14i NKT cells. Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="8505.0" y="6587.5"/> <glyph class="unit of information" id="_b67153d0-698b-41ae-8b26-7c5d39b2bc49"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="8540.0" y="6582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1171_sa226" 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:GZMA Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24973821 mTOR has positive influence on GZMA level in the NK cells. References_end </body> </html> </notes> <label text="GZMA"/> <bbox w="90.0" h="25.0" x="8245.0" y="6587.5"/> <glyph class="unit of information" id="_d5cdf014-3ba2-45ee-a239-d3456b666a98"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="8280.0" y="6582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1244_sa1837" 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:IFNG 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 MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:IL4 CASCADE:KLRB1 CASCADE:IL12 CASCADE:IL15 CASCADE:Fc_gamma_RIII CASCADE:IL18 PMID:8700208, PMID:9715265, PMID:11449378 IL-12 signaling induces STAT4 tyrosine phosphorylation. And induces IFNG production via binding of Stat4 to IFNG promoter GAS element. PMID:11801649, PMID:11449378 IL 12and IL-18 synergistically enhance IFN-gamma production in human NK cells. IL-12-activated STAT4 interacts with c-Jun to form a protein-protein complex. c-Jun induced by IL-12 plus IL-18 exhibits a markedly enhanced AP-1-binding activity and induces INFG promoter. PMID:12759422 IL-18 induces NF-κB binding to the IFN-γ gene promoter and induction of gene expression. IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFNG gene. PMID:18768831, PMID:16713975 TGF-β inhibits NK cell IFN-γ and TNF-α production following CD16 activation. TGF-β signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET. SMAD3 can directly interact with IFNG promoter. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="82.5" h="26.25" x="11383.75" y="5298.75"/> <glyph class="unit of information" id="_4259d070-53ab-41d4-8a66-10d561f06e07"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11415.0" y="5293.75"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1273_sa424" 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: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="12870.0" y="2037.5"/> <glyph class="unit of information" id="_167f5639-ea15-4709-b603-94e0ccc66d39"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12905.0" y="2032.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1289_sa245" 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:FASLG Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: CASCADE:NKG2A CASCADE:Fc_gamma_RIII CASCADE:2B4 CASCADE:IFNAB CASCADE:IL18 CASCADE:LFA1 PMID:12967644 IFNA signaling via STAT1 up-regulates gene expression of cytolytic effectors Fas-L in NK cells. References_end </body> </html> </notes> <label text="FASL*"/> <bbox w="90.0" h="25.0" x="7720.625" y="7412.5"/> <glyph class="unit of information" id="_f34177a2-9f7c-4b89-b4a3-064bde0a448f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7755.625" y="7407.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1293_sa233" 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:TNFSF10 Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNAB CASCADE:IL12 CASCADE:IFNG PMID:11257133 Administration of IL-12 selectively upregulated TRAIL expression on NK cells. IL-12 stimulates TRAIL-mediated antimetastatic activity of NK cells. The cytotoxicity of NK cells was inhibited partially by anti-TRAIL mAb. TRAIL is a key effector molecule mediating the IFNG–dependent antimetastatic effect of IL-12. IFN-γ induced both liver and spleen NK cell TRAIL expression. By contrast, treatment with either IL-12 or α-GalCer did not induce NK cell TRAIL. These data directly supported the conclusion that IFN-γ plays a key role in TRAIL expression and TRAIL-mediated antimetastatic function of NK cells. References_end </body> </html> </notes> <label text="TRAIL*"/> <bbox w="90.0" h="25.0" x="7620.625" y="7412.5"/> <glyph class="unit of information" id="_c7936a22-e2c7-45a6-95bc-4157e99e19ee"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7655.625" y="7407.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1307_sa2398" 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:NFKBIZ Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: CASCADE:IL18 MAP:NATURAL_KILLER PMID:21224476 NFkB p65/p50 induces expression of NFKBIZ downstream of IL18. References_end </body> </html> </notes> <label text="NFKBIZ"/> <bbox w="90.0" h="25.0" x="11825.0" y="4802.5"/> <glyph class="unit of information" id="_fa68486d-51ae-4e4c-af84-c7ebc7acff32"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11860.0" y="4797.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1327_sa2394" 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:TBX21 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:MACROPHAGE MAP:DENDRITIC_CELL CASCADE:TGFB CASCADE:Fc_gamma_RIII CASCADE:IL2 CASCADE:IL15 CASCADE:IL18 CASCADE:IL12 CASCADE:IL21 CASCADE:IFNG PMID:10761931, PMID:12055627, PMID:18768831, PMID:16713975 The pattern of T-bet expression correlates well with the production of IFNG in NK cells. The induction of T-bet expression and secretion of IFNγ in NK cells that produce IFNγ exists only upon treatment with IL-2, IL15,IL18 and IL-12 and CD16 pathway activation.. T-bet regulates IFNG expression in NK cells, probably via chromatin remodeling. References_end </body> </html> </notes> <label text="TBX21"/> <bbox w="90.0" h="25.0" x="11640.0" y="4802.5"/> <glyph class="unit of information" id="_cec83fd7-e607-422f-a270-965eccf0057a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11675.0" y="4797.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1329_sa2391" 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:HLX Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:14614857 GATA-3-deficient NK cells produced less IFN-γ compared to control NK cells. T-bet expression was approximately 4-fold reduced in GATA-3° NK cells compared to controls, while Hlx expression was about 10-fold reduced (provavly via T-bet). References_end </body> </html> </notes> <label text="HLX"/> <bbox w="90.0" h="25.0" x="11510.0" y="4882.5"/> <glyph class="unit of information" id="_7cd9d994-2ce8-4e8c-a799-32365ae3b271"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11545.0" y="4877.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1351_sa742" 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: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="11980.0" y="1917.5"/> <glyph class="unit of information" id="_15f44131-4494-4cd0-a1da-fe4304b5ae99"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12015.0" y="1912.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1373_sa898" 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:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB CASCADE:IL12 CASCADE:IL15 CASCADE:IL18 PMID:16713975 IL12,IL15 and IL18 significantly suppresse TGF-BRII mRNA expression. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="90.0" h="25.0" x="1430.0" y="2247.5"/> <glyph class="unit of information" id="_a34a3cfd-ffd6-4728-8d9e-feb698d6cae7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1465.0" y="2242.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1374_sa915" 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:SMAD2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL12 CASCADE:IL18 PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="90.0" h="25.0" x="1635.0" y="2202.5"/> <glyph class="unit of information" id="_993f6b1e-87a1-4cbe-baf5-ce292b07d9cf"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1670.0" y="2197.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1376_sa933" 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:SMAD3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="90.0" h="25.0" x="1875.0" y="2192.5"/> <glyph class="unit of information" id="_6c4a9c4e-7448-4a08-8aee-42ce90040005"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1910.0" y="2187.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1379_sa420" 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:NCR3 Identifiers_end References_begin: MAP:NATURAL_KILLER CASCADE:TGFB PMID:12646700 TGFB1 downderulates NKp30 and NKG2D mRNA and protein level.. References_end </body> </html> </notes> <label text="NKp30*"/> <bbox w="90.0" h="25.0" x="10630.0" y="1927.5"/> <glyph class="unit of information" id="_14dd6a9c-20a1-430e-ac03-e06ee1f14925"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10665.0" y="1922.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1517_sa836" 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:KLRB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:INHIBITION_OF_TUMOR_RECOGNITION MODULE:NK_INHIBITING_RECEPTORS Maps_Modules_end References_begin: CASCADE:IL12 CASCADE:KLRB1 PMID:9603467 IL-12-induced up-regulation of NKRP1A expression in human NK cells and consequent NKRP1Amediated down-regulation of NK cell activation. References_end </body> </html> </notes> <label text="KLRB1"/> <bbox w="90.0" h="25.0" x="2360.0" y="1927.5"/> <glyph class="unit of information" id="_f3a644d1-fdad-48be-8494-85231f133fe8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2395.0" y="1922.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1527_sa1927" 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: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="15192.5" y="3795.0"/> <glyph class="unit of information" id="_0a5e1f00-381c-45b0-8631-3e7a4300e3b9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15227.5" y="3790.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1569_sa837" 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: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="2693.5" y="2947.5"/> <glyph class="unit of information" id="_52666a2d-5fd3-45f9-b167-9ebdbf9b8bca"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2728.5" y="2942.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1574_sa440" 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:LCP2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24227772 mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. References_end </body> </html> </notes> <label text="LCP2"/> <bbox w="90.0" h="25.0" x="12480.0" y="2507.5"/> <glyph class="unit of information" id="_8346eaf6-a93c-49e5-821c-e433c3fd157e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12515.0" y="2502.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1652_sa2682" 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:IL18R1 Identifiers_end References_begin: CASCADE:IL15 CASCADE:IL21 MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNG PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end </body> </html> </notes> <label text="IL18R1"/> <bbox w="90.0" h="25.0" x="15200.0" y="2747.5"/> <glyph class="unit of information" id="_922e89b7-a9bd-4365-9a55-d042badac283"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15235.0" y="2742.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1653_sa2681" 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:IL18RAP Identifiers_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IFNG CASCADE:IL15 CASCADE:IL21 PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. References_end </body> </html> </notes> <label text="IL18RAP"/> <bbox w="90.0" h="25.0" x="15300.0" y="2747.5"/> <glyph class="unit of information" id="_ffc842ec-0f7b-4829-b694-49cb4ae7baec"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15335.0" y="2742.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1654_sa2683" 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>References_begin: CASCADE:IL15 CASCADE:IL21 CASCADE:IL12 MAP:NATURAL_KILLER References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12RB2 Identifiers_end References_begin: CASCADE:IL15 CASCADE:IL21 CASCADE:IL12 MAP:NATURAL_KILLER PMID:12244150 Both IL-15 and IL-21 up-regulated the expression of the IL-2Rα IL-12Rβ2 IL-18Rα and IL-18Rβ in NK cells. PMID:9834059 NK cells stimulated by IL12 accumulate much higher levels of the IL-12Rbeta2-chain mRNA and are significantly more responsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor. References_end </body> </html> </notes> <label text="IL12RB2"/> <bbox w="90.0" h="25.0" x="14970.0" y="3657.5"/> <glyph class="unit of information" id="_326d4824-cc84-4d4d-a0ad-e4b029f14d08"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15005.0" y="3652.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1659_sa2387" 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:ETS1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL15 CASCADE:IL2 PMID:15563472 Interleukins 15 and IL2 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. References_end </body> </html> </notes> <label text="ETS1"/> <bbox w="90.0" h="25.0" x="11410.0" y="4652.5"/> <glyph class="unit of information" id="_581e8446-e175-4e96-b84d-717f04a61ce0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11445.0" y="4647.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1667_sa418" 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:NCR1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end </body> </html> </notes> <label text="NKp46*"/> <bbox w="90.0" h="25.0" x="10910.0" y="2047.5"/> <glyph class="unit of information" id="_4d5ae78d-2edd-4204-92ae-725ae18bc73b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10945.0" y="2042.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1755_sa456" 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:SH2D1A Identifiers_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB CASCADE:IL12 CASCADE:IL2 PMID:17171759 SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(IC))and to a lesser extent by IFN-α. The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4. References_end </body> </html> </notes> <label text="SH2D1A "/> <bbox w="90.0" h="25.0" x="13490.0" y="1937.5"/> <glyph class="unit of information" id="_c2e9acd6-bf4a-4578-8889-636276534bdf"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13525.0" y="1932.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1834_sa2107" 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:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 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. Additionally CD16 signaling induces NF-AT mRNA expression and protein synthesis via Calmodulin/ Calcineurin. References_end </body> </html> </notes> <label text="NFAT*"/> <bbox w="90.0" h="25.0" x="12400.0" y="4782.5"/> <glyph class="unit of information" id="_90c91e68-68c1-4ca3-b716-0f132465b838"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12435.0" y="4777.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1837_sa1347" 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:CSF2 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 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="90.0" h="25.0" x="11941.25" y="5302.5"/> <glyph class="unit of information" id="_ab6ac1db-141e-491a-867b-e095cae7295a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11976.25" y="5297.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1840_sa1340" 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: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 PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="IL2"/> <bbox w="90.0" h="25.0" x="11801.25" y="5292.5"/> <glyph class="unit of information" id="_264fed77-8c86-4d99-8a41-b0156a91de2e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="11836.25" y="5287.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1842_sa1356" 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:IL4 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:Fc_gamma_RIII PMID:7650486, PMID:9973469, PMID:9374532 NF-AT, migrates to the nucleus and activates transcription of cytokines TNF, GM-CSF , IL-2, IL-4. Fas ligand ( FasL ) and, possibly, IFNG. References_end </body> </html> </notes> <label text="IL4"/> <bbox w="90.0" h="25.0" x="3712.745" y="5433.25"/> <glyph class="unit of information" id="_391e19ec-47f3-456a-a06d-be6256169aa2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3747.745" y="5428.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1922_sa2547" 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:IL5 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IL4 PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end </body> </html> </notes> <label text="IL5"/> <bbox w="90.0" h="25.0" x="4045.0" y="5437.5"/> <glyph class="unit of information" id="_8d00bf9f-870d-44cc-85ca-025368758540"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4080.0" y="5432.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1962_sa1827" 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: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 CASCADE:IFNAB PMID:11466332, PMID:14607946 I IFN induces IL-15 and IL-15Rα in human and murine DCs via common receptor. References_end </body> </html> </notes> <label text="IL15"/> <bbox w="90.0" h="25.0" x="13971.25" y="5312.5"/> <glyph class="unit of information" id="_b7807f63-0797-480d-b845-f6cd4d0d2350"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14006.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1966_sa1823" 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:IL15RA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:11466332, PMID:14607946 I IFN induces IL-15 and IL-15Rα in human and murine DCs via common receptor. References_end </body> </html> </notes> <label text="IL15RA"/> <bbox w="90.0" h="25.0" x="15270.0" y="3577.5"/> <glyph class="unit of information" id="_3b71c949-ad34-4b23-868f-4d0404085f84"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15305.0" y="3572.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2043_sa1213" 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:CCR7 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNAB CASCADE:CATENINB PMID:17936032 Beta-catenin signaling 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 node References_end </body> </html> </notes> <label text="CCR7"/> <bbox w="90.0" h="25.0" x="5995.0" y="2012.5"/> <glyph class="unit of information" id="_161ae32c-2d0a-442d-a2b4-80d0e2ffdc02"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6030.0" y="2007.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2060_sa1364" 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:INHBA Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 CASCADE:IL13 PMID:24204259 IL-4Rα-deficient DCs produced reduced IL-12, and IL18 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses. probably via STAT6 References_end </body> </html> </notes> <label text="INHBA"/> <bbox w="90.0" h="25.0" x="3615.0" y="5606.25"/> <glyph class="unit of information" id="_42a55800-02b5-4d90-a0bf-62000f10d7ef"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3650.0" y="5601.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2107_sa93" 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: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:24777831, PMID:19811323 The expression of MHC Class I molecules (controlled by STAT-1 and IRF-1) was increased following IFN-γ treatment References_end </body> </html> </notes> <label text="MHC class I*"/> <bbox w="90.0" h="25.0" x="14805.0" y="6135.0"/> <glyph class="unit of information" id="_5e64175a-f056-4d1c-8fb5-7262f64de3c5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14840.0" y="6130.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2118_sa2708" 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:SOCS2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL4 PMID:14764699 SOCS1 and SOCS3 are upregulated in mature DC. SOCS2 in immature DC. SOCS1 and SOCS2 expression is induced by IL4 signaling, and SOCS3 expression is upregulated more by GM-CSF (CSF2). References_end </body> </html> </notes> <label text="SOCS2"/> <bbox w="90.0" h="25.0" x="14780.0" y="2507.5"/> <glyph class="unit of information" id="_e6954d32-44f3-40e8-9193-e702e960d7e1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14815.0" y="2502.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2126_sa104" 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: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: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:MIF CASCADE:IL10 CASCADE:CSF2 CASCADE:IFNG 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 References_end </body> </html> </notes> <label text="MHC class II*"/> <bbox w="90.0" h="25.0" x="14625.0" y="6135.0"/> <glyph class="unit of information" id="_b482bf0e-ba26-4a88-94c9-defed81dd950"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14660.0" y="6130.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2128_sa88" 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:CIITA Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IL4 CASCADE:CSF2 CASCADE:IFNG PMID: 19224634 STAT5 promotes expression of MHC class II transactivator protein (CIITA) and upregulates MHC class II expression downstream of CSF2 ( PMID:16785500 ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages. PMID:11514596 Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (Ciita) Expression and down regulation of MHCII expression. References_end </body> </html> </notes> <label text="CIITA"/> <bbox w="90.0" h="25.0" x="14715.0" y="5955.0"/> <glyph class="unit of information" id="_5c9068a8-7bea-408f-8e85-415d9219c0d9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14750.0" y="5950.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2265_sa98" 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: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: 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. References_end </body> </html> </notes> <label text="CD1*"/> <bbox w="90.0" h="25.0" x="14515.0" y="6127.5"/> <glyph class="unit of information" id="_9bdc4592-63fc-406e-a239-da07e5189f05"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14550.0" y="6122.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2316_sa1212" 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:CCL19 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IFNAB PMID:11698286 IFNA induces mRNA expression both CCR7 and it's ligand CCL19 in Dcs and induces Dcs migration References_end </body> </html> </notes> <label text="CCL19"/> <bbox w="90.0" h="25.0" x="6305.0" y="2552.5"/> <glyph class="unit of information" id="_557e0c0e-c9e9-4bfb-8c0e-b4c99cd2b154"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6340.0" y="2547.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2319_sa1330" 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:CCL18 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: CASCADE:IFNAB MAP:DENDRITIC_CELL PMID:11698286 IFNA upregulates chemokine mRNA expression CCL18 (DC-DK1), CXCL10 (IP10) , References_end </body> </html> </notes> <label text="CCL18"/> <bbox w="90.0" h="25.0" x="6205.0" y="2522.5"/> <glyph class="unit of information" id="_b3aad0b8-f6aa-400a-927a-3f143ada2dae"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6240.0" y="2517.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2464_sa1972" 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:TNIP3 MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE 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="TNIP3"/> <bbox w="90.0" h="25.0" x="12450.0" y="3207.5"/> <glyph class="unit of information" id="_b973b142-bc2b-473e-9b54-bb46a9c2f10c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12485.0" y="3202.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2701_sa926" 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:RUNX1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:15084276 Granzyme B, perforin and Runx1 are direct and positievly regulated targets of TBX21 (T-BET) in NK cells. References_end </body> </html> </notes> <label text="RUNX1"/> <bbox w="90.0" h="25.0" x="3435.0" y="4448.125"/> <glyph class="unit of information" id="_ca79752b-963a-4c3d-ac55-4b63720b637c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3470.0" y="4443.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2750_sa970" 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:IL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:MIF CASCADE:TGFB CASCADE:CSF1 CASCADE:STING CASCADE:TLR2_4 CASCADE:FLT3LG CASCADE:IFNG CASCADE:IL4 Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:17404308 CSF1 induces IL10 and CCL2 mRNA expression in macrophages PMID:16424049 IFNG induces INOS and IL10 expression and TGFB secretion in MDSC References_end </body> </html> </notes> <label text="IL10"/> <bbox w="150.5" h="48.5" x="2137.25" y="5613.25"/> <glyph class="unit of information" id="_0ede2f11-0931-4587-a097-0b205d838e33"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2202.5" y="5608.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2885_sa1172" 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:CCR2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:TNF Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. TNF inhibit CCR2 expression in tumor associated macrophages. References_end </body> </html> </notes> <label text="CCR2"/> <bbox w="90.0" h="25.0" x="5655.0" y="2012.5"/> <glyph class="unit of information" id="_b88ae6ec-a082-4131-bf9e-e156ad654cde"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5690.0" y="2007.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2922_sa1295" 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:IL23A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:TLR2_4 CASCADE:CSF2 CASCADE:CSF1 CASCADE:IL13 CASCADE:IL4 PMID:24204259 IL4RA signaling upregulates IL18 expression and downregulates IL10 expression and also mRNA expression of IL-23p19 and INHBA (activin A), cytokines previously implicated in promoting Th2 responses Maps_Modules_end References_begin: 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="IL23A"/> <bbox w="90.0" h="25.0" x="2975.0" y="5477.5"/> <glyph class="unit of information" id="_0299d423-b6d9-4126-96b3-25104b24a519"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3010.0" y="5472.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2925_sa1300" 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:IFNB1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION CASCADE:TGFB CASCADE:STING CASCADE:TLR2_4 CASCADE:TNF Maps_Modules_end References_begin: PMID:18345002 TNF induced IFNB expression through IRF1. TNF-induced Ifnb1 expression was completely abrogated in IRF1-deficient macrophages. References_end </body> </html> </notes> <label text="INFB*"/> <bbox w="90.0" h="25.0" x="13621.25" y="5312.5"/> <glyph class="unit of information" id="_92441602-c213-41cb-a4f4-b56f3822aad5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13656.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2928_sa1806" 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:MICA Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB 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="MICA"/> <bbox w="90.0" h="25.0" x="13741.25" y="5312.5"/> <glyph class="unit of information" id="_f085df37-a09c-44aa-b1d5-ba8d76e79867"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13776.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2932_sa1807" 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:MICB Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS MODULE:EFFECTOR_ACTIVATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:NATURAL_KILLER MAP:DENDRITIC_CELL CASCADE:IL15 CASCADE:IFNAB 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="MICB"/> <bbox w="90.0" h="25.0" x="13861.25" y="5312.5"/> <glyph class="unit of information" id="_ad82d0d0-922d-4992-a50a-799ce4ac0038"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13896.25" y="5307.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2949_sa1353" 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:IL13 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:NATURAL_KILLER CASCADE:IL4 CASCADE:IL13 PMID:11870632, PMID:9834059 Stimulation of NK cells with IL-4 inhibited IFN-gamma, but increased IL5, IL-13 production. References_end </body> </html> </notes> <label text="IL13"/> <bbox w="90.0" h="25.0" x="3925.0" y="5447.5"/> <glyph class="unit of information" id="_03d94680-a163-4240-bccb-931719b54505"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3960.0" y="5442.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s2995_sa1378" 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:VEGFA Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:LACTIC CASCADE:MIF CASCADE:IL4 CASCADE:CSF2 CASCADE:IFNAB MAP:NEUTROPHIL Maps_Modules_end References_begin: HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. MIF signaling induces angiogenesis probavly via upregulation of MMP9, VEGF expression in macrophages and activates tumor invasion References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="90.0" h="25.0" x="4125.0" y="6647.5"/> <glyph class="unit of information" id="_b765c020-5ccc-40ae-b9a9-7e89a840bbd1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4160.0" y="6642.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3075_sa1522" 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:TNFRSF1A Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IFNG Maps_Modules_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="90.0" h="25.0" x="15410.0" y="3137.5"/> <glyph class="unit of information" id="_0b8f669f-35a6-4e05-83a3-3eb49767d85f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15445.0" y="3132.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3078_sa1538" 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:IRAK3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:TGFB Maps_Modules_end References_begin: PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. References_end </body> </html> </notes> <label text="IRAK3"/> <bbox w="90.0" h="25.0" x="10600.0" y="2847.5"/> <glyph class="unit of information" id="_ce264aed-0bc2-400e-b55f-f9bc24f565e7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10635.0" y="2842.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3286_sa1815" 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: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:24829413 STAT5 is phosphorylated downstream IL2, It upregulate the promoter activity of both IL2RA and IFNG in dendritic cells downstream of IL2 References_end </body> </html> </notes> <label text="IL2RA"/> <bbox w="90.0" h="25.0" x="14770.0" y="4657.5"/> <glyph class="unit of information" id="_59c6eac4-2180-4243-af95-b244e36ff0ef"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14805.0" y="4652.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3329_sa1909" 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:FLT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:TLR2_4 CASCADE:FLT3LG PMID:20510871 PU.1 as 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. At The same time enforced expression of STAT3 or PU.1 in DC progenitors led to the up-regulation of Flt3 mRNA levels, so there is a positive loop in this signaling. Enforced STAT3 or PU.1 expression instructs progenitors to differentiate into Dcs. Additionaly it induces expression of cytokine receptors for G-CSF, M-CSF, and GM-CSF probably downstream of STAT3. References_end </body> </html> </notes> <label text="FLT3"/> <bbox w="90.0" h="25.0" x="15110.0" y="5717.5"/> <glyph class="unit of information" id="_04d3174c-dcff-44e5-bee0-54b73cb5be43"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15145.0" y="5712.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3484_sa2009" 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:FOS Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: PMID:16394015 PMID:19667062 TPL-2 ERK pathway induces Fos expression in macrophages ( PMID:21385848 c-Fos has binding sites for mir155, Fos mRNA was reduced in DC2114 cells overexpressing miR155. cFos is inhibited during the DC maturations. c-Fos–transduced DC2114 cells retained the ability to up-regulate the expression of proinflammatory cytokine mRNAs during maturation, this induction tended to be reduced 2- to 3-fold relative to untransduced DC2114 References_end </body> </html> </notes> <label text="FOS"/> <bbox w="90.0" h="25.0" x="2750.625" y="4485.625"/> <glyph class="unit of information" id="_ffafd5d6-c6f1-41a4-b9b2-a8392e1d386a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2785.625" y="4480.625"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3542_sa1266" 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:CXCL10 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS CASCADE:IFNAB CASCADE:TLR2_4 MAP:DENDRITIC_CELL Maps_Modules_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="90.0" h="25.0" x="5035.0" y="2512.5"/> <glyph class="unit of information" id="_7dbcc7fb-0197-4aad-a32a-621e584a9af3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5070.0" y="2507.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3564_sa2073" 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: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: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="90.0" h="25.0" x="4266.0" y="4434.375"/> <glyph class="unit of information" id="_fc6aeecd-5333-412f-acb1-e57d4cda1dfe"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4301.0" y="4429.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3567_sa2078" 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:SPI1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:FLT3LG References_end </body> </html> </notes> <label text="SPI1"/> <bbox w="90.0" h="25.0" x="9620.0" y="4582.5"/> <glyph class="unit of information" id="_8f8f459c-2534-416d-8ba0-9bb1bb8e20c7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="9655.0" y="4577.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3570_sa2082" 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:IRF8 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:GSF3 CASCADE:GSF2 PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. References_end </body> </html> </notes> <label text="IRF8"/> <bbox w="90.0" h="25.0" x="10135.0" y="4574.0"/> <glyph class="unit of information" id="_a63899bd-bebf-4d2b-8e54-ad1ab483f8da"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10170.0" y="4569.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3572_sa2084" 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:IRF5 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:MIF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as IRF5 References_end </body> </html> </notes> <label text="IRF5"/> <bbox w="90.0" h="25.0" x="10265.0" y="4579.0"/> <glyph class="unit of information" id="_c932efad-193b-46da-b69b-7cdd9c43195c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10300.0" y="4574.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3576_sa1519" 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:IRF1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY CASCADE:IL2 CASCADE:TNF CASCADE:IFNAB CASCADE:IFNG Maps_Modules_end References_begin: PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="90.0" h="25.0" x="10440.0" y="4592.5"/> <glyph class="unit of information" id="_cdcb904e-b6d7-43e7-b51c-55993629eaf2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10475.0" y="4587.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3584_sa2097" 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:PTGS2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION CASCADE:MIF CASCADE:TLR2_4 Maps_Modules_end References_begin: 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 References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="90.0" h="25.0" x="4135.0" y="5837.5"/> <glyph class="unit of information" id="_119397f5-a5a4-4f15-9dd3-bff7f939b811"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4170.0" y="5832.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3606_sa2135" 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:CEBPD Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE:TLR2_4 PMID:11668179 CEBPD syntesis and activity are induced downstream of TLR4/p38 signaling. It regulates COX2 expression. References_end </body> </html> </notes> <label text="CEBPD"/> <bbox w="90.0" h="25.0" x="4136.0" y="4434.375"/> <glyph class="unit of information" id="_1b0e6a26-b968-49bd-8dcf-959dff68ebcd"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4171.0" y="4429.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3918_sa2333" 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: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: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. References_end </body> </html> </notes> <label text="cREL*"/> <bbox w="90.0" h="25.0" x="12710.0" y="3587.5"/> <glyph class="unit of information" id="_28c3748c-83b0-4082-8da9-47d6c9b0cefe"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12745.0" y="3582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3920_sa2335" 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: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: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. References_end </body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="25.0" x="13040.0" y="3607.5"/> <glyph class="unit of information" id="_6b260fbe-5eb9-45d9-8d4d-f45b822bda76"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13075.0" y="3602.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3939_sa2354" 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:ID3 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC CASCADE:LGALS1 CASCADE:IL10 PMID:21191065 regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. References_end </body> </html> </notes> <label text="ID3"/> <bbox w="90.0" h="25.0" x="4026.0" y="4434.375"/> <glyph class="unit of information" id="_f36a76ee-8e0b-4dab-87c3-e4e071fec6b7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4061.0" y="4429.375"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3958_sa2376" 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:LGALS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION CASCADE:TGFB PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as MCR2 and LGALS3 (Galectin-3) and induces AKT activation in macrophages Maps_Modules_end References_begin: Identifiers_end References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="90.0" h="25.0" x="3825.0" y="5637.5"/> <glyph class="unit of information" id="_d3d4b0cd-4d46-4002-a35c-8a1e42358e72"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3860.0" y="5632.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3960_sa2403" 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:CCL5 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:NEUTROPHIL CASCADE:TGFB PMID:19732719 Inhibition of TGF-ß signaling downregulates Arginase1, CCL5 and CCL2 expression and upregulates TNF, ICAM1,CCL3 expression (mRNA) in tumor neutrophiles (TAN) References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="90.0" h="25.0" x="5965.0" y="2537.5"/> <glyph class="unit of information" id="_a9ad7424-8400-4947-9106-424e70b36e3e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6000.0" y="2532.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3963_sa2408" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAB1 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:MIF 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 References_end </body> </html> </notes> <label text="STAB1"/> <bbox w="90.0" h="25.0" x="2183.75" y="588.125"/> <glyph class="unit of information" id="_ba783036-8dce-4268-8543-c0d903f300d0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2218.75" y="583.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3964_sa2409" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FCER2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:MIF Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="FCER2"/> <bbox w="90.0" h="25.0" x="2283.75" y="588.125"/> <glyph class="unit of information" id="_27a7aafd-7232-4b74-9ed0-508324eec6b1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2318.75" y="583.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3979_sa2429" 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:GST3 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL6 PMID:16286017 Cystatin C is an inhibitor of cathepsin S. IL-6-Mediated STAT3 Activation Reduced Cystatin C mRNA Level in DCs and upregulates cathepsin S activity References_end </body> </html> </notes> <label text="CST3"/> <bbox w="90.0" h="25.0" x="12705.0" y="5907.5"/> <glyph class="unit of information" id="_b8fcec4d-274e-41b3-8f76-52a12837437e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12740.0" y="5902.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3992_sa2443" 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:HMOX1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. References_end </body> </html> </notes> <label text="HMOX1"/> <bbox w="90.0" h="25.0" x="3607.25" y="3412.5"/> <glyph class="unit of information" id="_804b96a1-dd6c-4673-94a9-4b36854fa7d7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3642.25" y="3407.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3994_sa2446" 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:SOCS3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL10 CASCADE:TLR2_4 CASCADE:TNF CASCADE:CSF2 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12907458 IL10 induces SOCS3 expression in STAT3 dependent manner. PMID:10606755 LPS and TNFalpha were found to induce the expression of SOCS3 mRNA in each of the investigated type of macrophages but not in HepG2 cells. Using a specific inhibitor, evidence is presented that the p38 MAP kinase might be involved, especially for the inhibitory effect of TNF-alpha. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="90.0" h="25.0" x="14620.0" y="2507.5"/> <glyph class="unit of information" id="_9407b8a5-d7d9-41cd-9353-4091caf84421"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14655.0" y="2502.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s3997_sa2452" 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:BCL3 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSUPPRESSIVE CASCADE:IL10 Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="90.0" h="25.0" x="3575.5" y="4402.625"/> <glyph class="unit of information" id="_b6017bd9-ce75-4463-8b16-dd3950284bda"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3610.5" y="4397.625"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4011_sa2467" 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:MARCH1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CHEKPOINTS MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:IL10 PMID:22076556, PMID:21220452, PMID:24218453 In immature DCs, internalization of MHC class II molecules from the plasma membrane may require the ubiquitin ligase MARCH1, which is controlled by interleukin-10 (Measurement of March1 mRNA by quantitative PCR in these DC cultures demonstrated that IL-10 increased March1 mRNA by approximately sixfold). CD83 on mature DCs prevents this ubiquitylation of MHC class II molecules and thus stabilizes MHC class II molecules on the cell surface. Addidionally it prevents CD86 ubiquitinqtion by MARCH1. References_end </body> </html> </notes> <label text="MARCH1"/> <bbox w="90.0" h="25.0" x="13525.0" y="7817.5"/> <glyph class="unit of information" id="_28ed21d8-8df4-44a8-936f-497ee3a1b831"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="13560.0" y="7812.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4017_sa2490" compartmentRef="c7_ca7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD209 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE CASCADE:IL4 Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expresion of CD209 downstream of IL4, probably via STAT6. References_end </body> </html> </notes> <label text="CD209"/> <bbox w="90.0" h="25.0" x="2377.25" y="588.125"/> <glyph class="unit of information" id="_738cee1e-1d52-40d8-8764-cfa685164daa"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2412.25" y="583.125"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4035_sa2545" 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:CSF1R Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS CASCADE:GSF1 Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. References_end </body> </html> </notes> <label text=" CSF1R"/> <bbox w="90.0" h="25.0" x="1385.0" y="2547.5"/> <glyph class="unit of information" id="_0031b277-d2d7-4402-8943-092eec469c32"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1420.0" y="2542.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4099_sa2630" 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: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 PMID:18003603 RUNX proteins down-regulates IFNG expression in NK cells and upregulates expression of CD122 (IL-2/IL-15 common receptor beta subunit) via direct binding to its promoter. PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. References_end </body> </html> </notes> <label text="IL2RB"/> <bbox w="90.0" h="25.0" x="15390.0" y="3577.5"/> <glyph class="unit of information" id="_2162bee2-d4e6-4aee-bb4b-0d53be4cd43e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="15425.0" y="3572.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4101_sa2632" 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:LTB Identifiers_end Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:APOPTOSIS_INDUCING_LIGANDS MODULE:EXOCYTOSIS_AND_PHAGOCYTOSIS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:NATURAL_KILLER PMID:22608498 ETS1 binds directly to the Tbx21 and IL2RB (CD122) genes and induces its expression in NK cells. expression of Ncr1 (NKp46), Cd122 (il2RB), Idb2, Ltb, Lair1 and Tbx21 mRNA is reduced in NK cells after knockdown of ETS1. References_end </body> </html> </notes> <label text="LTB"/> <bbox w="90.0" h="25.0" x="7500.0" y="7412.5"/> <glyph class="unit of information" id="_29ab11b5-7db5-48a4-a3c4-c946d3c7522d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7535.0" y="7407.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4177_sa2704" 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:FLT1 Identifiers_end References_begin: MAP:DENDRITIC_CELL PMID:16002046 Id1−/− DCs did not respond to the VEGF stimulus because of defective Flt-1 signaling in these mutant mice. Thus, Flt-1 seems to be an important player in VEGF–DC interactions. References_end </body> </html> </notes> <label text="FLT1"/> <bbox w="90.0" h="25.0" x="1360.0" y="6102.5"/> <glyph class="unit of information" id="_7635d382-ec28-4546-96ac-e232c9d73344"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1395.0" y="6097.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4178_sa2705" 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:FLT1 Identifiers_end References_begin: MAP:MACROPHAGE CASCADE:CSF2 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="90.0" h="25.0" x="1515.0" y="6197.5"/> <glyph class="unit of information" id="_5c25428b-eb8b-41c8-b7be-a35fe00316b8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1550.0" y="6192.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4180_sa2713" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LY75 Identifiers_end Maps_Modules_begin: MODULE:MARKERS_DC Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:10784619 LY75 (DEC-205) it is a a marker of dendritic cells with regulatory effects on CD8 T cell responses. PMID:8920882 FLT3 ligand upregulates surface expression of LY75 (DEC-205) in DCs. References_end </body> </html> </notes> <label text="LY75"/> <bbox w="90.0" h="25.0" x="2048.75" y="140.0"/> <glyph class="unit of information" id="_8db54b3c-4217-47e7-9971-60e5b091390f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2083.75" y="135.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4182_sa2715" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAX Identifiers_end References_begin: MAP:DENDRITIC_CELL CASCADE:FLT3LG PMID:8920882 FLT3 ligand upregulates surface expression of CD11c in DCs. References_end </body> </html> </notes> <label text="CD11c*"/> <bbox w="90.0" h="25.0" x="2048.75" y="260.0"/> <glyph class="unit of information" id="_2cc000e2-cfd5-416f-84a2-15469dcc9fbf"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2083.75" y="255.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4184_sa973" 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:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MAP:DENDRITIC_CELL CASCADE:IL10 CASCADE:FLT3LG CASCADE:IFNAB PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="90.0" h="25.0" x="1685.0" y="4352.5"/> <glyph class="unit of information" id="_a0047427-b5ea-4481-af8d-2916cd240658"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1720.0" y="4347.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4184_sa2717" 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:STAT3 Identifiers_end Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MAP:MDSC MAP:DENDRITIC_CELL CASCADE:IL10 CASCADE:FLT3LG CASCADE:IFNAB PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. References_end </body> </html> </notes> <label text="STAT3"/> <clone/> <bbox w="90.0" h="25.0" x="14720.0" y="5247.5"/> <glyph class="unit of information" id="_52d0d408-5b79-4402-8d50-a0d2aec26fb8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="14755.0" y="5242.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4199_sa2733" 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:IRF9 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:MIRNA_TF_IMMUNOSTIMULATORY Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:IFNAB PMID:25960930 INFA induced expression of IRF9 is PKC-θ-dependent in NK. References_end </body> </html> </notes> <label text="IRF9"/> <bbox w="90.0" h="25.0" x="10010.0" y="4582.5"/> <glyph class="unit of information" id="_5ba750a1-ebf6-436a-8193-50452514cb8d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="10045.0" y="4577.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4210_sa2751" 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:IDO1 Identifiers_end Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:IFNG CASCADE:TLR2_4 CASCADE:TNF PMID:8663541 IFNG induces IDO expression via STAT1 and IRF-1 References_end </body> </html> </notes> <label text="IDO1"/> <bbox w="90.0" h="25.0" x="4515.0" y="5827.5"/> <glyph class="unit of information" id="_8bf92ec3-f0ab-4bc6-9741-b7f6b8f8d096"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4550.0" y="5822.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4229_sa1261" 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:CXCL8 HUGO:IL8 CASCADE:TLR2_4 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:NATURAL_KILLER MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="90.0" h="25.0" x="4265.0" y="6667.5"/> <glyph class="unit of information" id="_58c96cd5-4e6f-4829-a8b5-2bf08b9171be"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4300.0" y="6662.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4259_sa2794" 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:CXCL16 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. References_end </body> </html> </notes> <label text="CXCL16"/> <bbox w="90.0" h="25.0" x="5175.0" y="2512.5"/> <glyph class="unit of information" id="_35208f97-5fa2-43c7-a6b1-52092e27d13b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5210.0" y="2507.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s39_sa406" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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:NKP44 CASCADE:NKP30 PMID:23414611, PMID:19196184, PMID:15294952 Heparin is ligand of NKp30, NKp44 and Nkp46. The NCRs initiate tumor targeting by recognition of heparan sulfate on cancer cells. Tumor cells expressing cell surface heparanase or lacking membranal heparan manifest reduced recognition by NKp30 and NKp46 and are lysed to a lesser extent by NK cells. References_end </body> </html> </notes> <label text="Heparin"/> <bbox w="70.0" h="25.0" x="11125.0" y="977.5"/> </glyph> <glyph class="simple chemical" id="s42_sa9" compartmentRef="c43_ca43"> <label text="Lipid_antigen"/> <bbox w="115.0" h="42.5" x="11572.5" y="8858.75"/> </glyph> <glyph class="simple chemical" id="s352_sa1123"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: CHEBI:16480 KEGGCOMPOUND:C00533 CAS:10102-43-9 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22006996, PMID:18559521 Nitric oxide inhibits the hypoxia-induced expression of ADAM10 and the hypoxia-induced accumulation of HIF1A and decrease MIC shedding. NO attenuates in vivo tumor growth by sensitizing tumor cells to recognition and elimination by the innate immune system. References_end </body> </html> </notes> <label text="NO"/> <bbox w="70.0" h="25.0" x="6545.0" y="8157.5"/> </glyph> <glyph class="simple chemical" id="s353_sa56" 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: CHEBI:15379, KEGGCOMPOUND:C00007, CAS:7782-44-7 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: 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="O2"/> <bbox w="70.0" h="25.0" x="11679.824" y="6151.028"/> </glyph> <glyph class="simple chemical" id="s354_sa1098" compartmentRef="c12_ca12"> <label text="NADPH"/> <bbox w="70.0" h="25.0" x="6319.2188" y="5914.6875"/> </glyph> <glyph class="simple chemical" id="s368_sa1106" compartmentRef="c12_ca12"> <label text="NADP+"/> <bbox w="70.0" h="25.0" x="6154.2188" y="6113.1875"/> </glyph> <glyph class="simple chemical" id="s369_sa1111" compartmentRef="c12_ca12"> <label text="L-citrulin"/> <bbox w="70.0" h="25.0" x="6144.2188" y="6243.1875"/> </glyph> <glyph class="simple chemical" id="s370_sa1107" 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>Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end </body> </html> </notes> <label text="Urea"/> <bbox w="70.0" h="25.0" x="5509.2188" y="6114.6875"/> </glyph> <glyph class="simple chemical" id="s371_sa1108" 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>Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end </body> </html> </notes> <label text="L-ornitine"/> <bbox w="70.0" h="25.0" x="5589.2188" y="6144.6875"/> </glyph> <glyph class="simple chemical" id="s375_sa52" 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>Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION CHEBI:16240, KEGGCOMPOUND:C00027, CAS:7722-84-1 MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end </body> </html> </notes> <label text="H2O2"/> <bbox w="70.0" h="25.0" x="11769.824" y="6241.028"/> </glyph> <glyph class="simple chemical" id="s377_sa53" 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: CHEBI:18421, KEGGCOMPOUND:C00704, CAS:11062-77-4 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: 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="O2-"/> <bbox w="70.0" h="25.0" x="11676.824" y="6240.028"/> </glyph> <glyph class="simple chemical" id="s378_sa55" 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: CHEBI:29191, CAS:3352-57-6 Identifiers_end Maps_Modules_begin: MAP:DENDRITIC_CELL MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end </body> </html> </notes> <label text="hydroxyl"/> <bbox w="70.0" h="25.0" x="11775.0" y="6152.5"/> </glyph> <glyph class="simple chemical" id="s394_sa2561" 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>Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS CASCADE:IL13 Maps_Modules_end References_begin: PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="cAMP"/> <bbox w="70.0" h="25.0" x="4325.0" y="3527.5"/> </glyph> <glyph class="simple chemical" id="s397_sa548" 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>Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: PMID:18287025 PLCG is upstream of JNK in the pathway of NKG2D-mediated cytotoxicity PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. References_end </body> </html> </notes> <label text="IP3"/> <bbox w="70.0" h="25.0" x="5435.0" y="3417.5"/> </glyph> <glyph class="simple chemical" id="s405_sa529" compartmentRef="c12_ca12"> <label text="PI4,5-P2"/> <bbox w="70.0" h="25.0" x="5485.0" y="3137.5"/> </glyph> <glyph class="simple chemical" id="s406_sa549" 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>References_begin: CASCADE:IFNAB PMID:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 References_end </body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="5705.0" y="3347.5"/> </glyph> <glyph class="simple chemical" id="s454_sa2478" 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>Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="13(S)-HPODE"/> <bbox w="70.0" h="25.0" x="2462.25" y="3849.0"/> </glyph> <glyph class="simple chemical" id="s455_sa2474" 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>Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPPRESSIVE_CORE_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="linoleic acid"/> <bbox w="70.0" h="25.0" x="2462.25" y="3779.0"/> </glyph> <glyph class="simple chemical" id="s744_sa19" 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>References_begin: PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. References_end </body> </html> </notes> <label text="PIP2*"/> <clone/> <bbox w="70.0" h="25.0" x="13545.0" y="7397.5"/> </glyph> <glyph class="simple chemical" id="s744_sa511" 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>References_begin: PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. References_end </body> </html> </notes> <label text="PIP2*"/> <clone/> <bbox w="70.0" h="25.0" x="8700.0" y="3267.5"/> </glyph> <glyph class="simple chemical" id="s745_sa510" 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>Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:NKP80 CASCADE:NKG2D CASCADE:IL4 CASCADE:NKP46 CASCADE:Fc_gamma_RIII CASCADE:IL15 CASCADE:CSF2 CASCADE:IFNG PMID:11062502, PMID:11385609, PMID:11907067, PMID:15536084 Nkp46 controls NK cytolitic activity via PI3K /RAC1/PAK1/MEK /ERK pathway, probably throught SYK PMID:11777960 ULBP2 through NKG2D induces SCF2 (GM-CSF), CLL4 (MIP1B) and IFNG secretion via PI3K pathway PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:9438848 PI3K product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav proteins PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. References_end </body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="8700.0" y="3457.5"/> </glyph> <glyph class="simple chemical" id="s1056_sa1097" compartmentRef="c12_ca12"> <label text="heme"/> <bbox w="70.0" h="25.0" x="6078.5938" y="6463.4375"/> </glyph> <glyph class="simple chemical" id="s1086_sa2102" 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>Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. References_end </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="4055.0" y="6047.5"/> </glyph> <glyph class="simple chemical" id="s1371_sa1086"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:LACTIC MAP:DENDRITIC_CELL MAP:MACROPHAGE PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth PMID:16278308, PMID:23506875 Lactate is transported into the cell probably by the monocarboxylate transporters (MCTs) and this process is strictly pH dependent Tumor-derived lactic acid inhibits DC maturation and T cell activation. References_end </body> </html> </notes> <label text="lactic acid "/> <bbox w="70.0" h="25.0" x="243.5" y="5767.5"/> </glyph> <glyph class="simple chemical" id="s1866_sa20" 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>References_begin: PMID:15817676 PIP2 is mainly synthesized by the phosphorylation of phosphatidylinositol4-phosphate (PI4P) at the D-5 position of the inositol ring by phosphatidylinositol4phosphate 5-kinase type I (PI5KI) References_end </body> </html> </notes> <label text="PtdIns(4)-P"/> <clone/> <bbox w="70.0" h="25.0" x="13645.0" y="7397.5"/> </glyph> <glyph class="simple chemical" id="s1866_sa473" 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>References_begin: PMID:15817676 PIP2 is mainly synthesized by the phosphorylation of phosphatidylinositol4-phosphate (PI4P) at the D-5 position of the inositol ring by phosphatidylinositol4phosphate 5-kinase type I (PI5KI) References_end </body> </html> </notes> <label text="PtdIns(4)-P"/> <clone/> <bbox w="70.0" h="25.0" x="8700.0" y="3107.5"/> </glyph> <glyph class="simple chemical" id="s2167_sa1434" 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>References_begin: PMID:12809603 LPC is secreted by apoptotic cells PMID:12165488 Mature dendritic cell generation promoted by lysophosphatidylcholine. LPC acts through G protein-coupled receptors on differentiating monocytes to generate mature dendritic cells with the ability to stimulate IL-2 and IFN-γ production by allogeneic T lymphocytes. LPC stimulates CD86 surface expression. References_end </body> </html> </notes> <label text="Lysophosphatidylcholine"/> <bbox w="165.0" h="32.5" x="6975.0" y="1248.75"/> </glyph> <glyph class="simple chemical" id="s2168_sa1433" 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>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: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. References_end </body> </html> </notes> <label text="Sphingosine 1-phosphate"/> <bbox w="175.0" h="32.5" x="6665.0" y="863.75"/> </glyph> <glyph class="simple chemical" id="s2170_sa1431"> <notes> <html xmlns="http://www.w3.org/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:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:STING CASCADE::P2RX7 CASCADE::P2RY2 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. PMID:19741708 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. UTP and ATP act via P2RY2 and promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo. References_end </body> </html> </notes> <label text="ATP"/> <bbox w="70.0" h="25.0" x="7007.5" y="1127.5"/> </glyph> <glyph class="simple chemical" id="s2171_sa1430"> <notes> <html xmlns="http://www.w3.org/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:DANGER_SIGNAL_PATHWAYS MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MACROPHAGE CASCADE::P2RY2 PMID:19741708 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. UTP and ATP act via P2RY2 and promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo. References_end </body> </html> </notes> <label text="UTP"/> <bbox w="70.0" h="25.0" x="6927.5" y="1127.5"/> </glyph> <glyph class="simple chemical" id="s2199_sa1439" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:DANGER_SIGNAL_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON Maps_Modules_end References_begin: CASCADE:INTEGRIN_AVB3 MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:CD36 CASCADE:MERTK CASCADE:TIMD4 CASCADE:HAVCR1 CASCADE:ADGRB1 CASCADE:STAB2 PMID:22035837 The ‘bridging’ molecule MFG-E8 (which binds to PtdSer on apoptotic cells and facilitate engulfment by engaging the integrin αvβ3 on phagocytes References_end </body> </html> </notes> <label text="PtdSer"/> <bbox w="70.0" h="25.0" x="7455.0" y="917.5"/> </glyph> <glyph class="simple chemical" id="s2417_sa2147" 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>Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL CASCADE:STING cyclic-GMP-AMP PMID:24766893 Cytosolic DNA activates cGAS to form a dimeric cGAS-DNA complex which synthesizes 2′3′-cGAMP from ATP and GTP. References_end </body> </html> </notes> <label text="cGAMP"/> <bbox w="70.0" h="25.0" x="6912.5" y="2147.5"/> </glyph> <glyph class="simple chemical" id="s2805_sa1093" compartmentRef="c12_ca12"> <label text="FAD"/> <bbox w="70.0" h="25.0" x="6078.5938" y="6413.4375"/> </glyph> <glyph class="simple chemical" id="s2809_sa1114" 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>Maps_Modules_begin: MAP:MACROPHAGE MAP:NEUTROPHIL MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:TGFB Maps_Modules_end References_begin: PMID:19732719 Inhibition of TGF-ß signaling in vivo increases CD11b+ cell cytotoxicity via an oxygen radical-dependent mechanism (superoxide and H2O2 production) in neutrophils 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 References_end </body> </html> </notes> <label text="H2O2"/> <bbox w="70.0" h="25.0" x="5954.5938" y="6944.4375"/> </glyph> <glyph class="simple chemical" id="s2810_sa1115" 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>Maps_Modules_begin: MAP:NEUTROPHIL MAP:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:TGFB Maps_Modules_end References_begin: 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:19732719 Inhibition of TGF-ß signaling in vivo increases CD11b+ cell cytotoxicity via an oxygen radical-dependent mechanism (superoxide and H2O2 production) in neutrophils References_end </body> </html> </notes> <label text="O2-"/> <bbox w="70.0" h="25.0" x="5825.5938" y="6942.4375"/> </glyph> <glyph class="simple chemical" id="s2811_sa1116" 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>Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end </body> </html> </notes> <label text="hydroxyl"/> <bbox w="70.0" h="25.0" x="6078.5938" y="6943.4375"/> </glyph> <glyph class="simple chemical" id="s2881_sa1158"> <notes> <html xmlns="http://www.w3.org/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: CASCADE:MIF CASCADE:PGE2 MAP:MDSC PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. 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:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation in macrophages. References_end </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="5055.0" y="1122.5"/> </glyph> <glyph class="simple chemical" id="s3413_sa1151"> <notes> <html xmlns="http://www.w3.org/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 </body> </html> </notes> <label text="Cystine"/> <bbox w="70.0" h="25.0" x="15135.0" y="8402.5"/> </glyph> <glyph class="simple chemical" id="s3414_sa1152"> <notes> <html xmlns="http://www.w3.org/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 </body> </html> </notes> <label text="Cysteine"/> <bbox w="70.0" h="25.0" x="15275.0" y="8407.5"/> </glyph> <glyph class="simple chemical" id="s3586_sa2100" 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>References_begin: PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. References_end </body> </html> </notes> <label text="Arachidonic acid"/> <bbox w="105.0" h="32.5" x="4217.5" y="6043.75"/> </glyph> <glyph class="simple chemical" id="s3704_sa2184" compartmentRef="c39_ca39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: 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="O2"/> <bbox w="70.0" h="25.0" x="8045.0" y="927.5"/> </glyph> <glyph class="simple chemical" id="s3705_sa2185"> <notes> <html xmlns="http://www.w3.org/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:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: Oxidized phosphatidylserine MAP:DENDRITIC_CELL CASCADE:CD36 References_end </body> </html> </notes> <label text="oxPS"/> <bbox w="70.0" h="25.0" x="8047.5" y="1117.5"/> </glyph> <glyph class="simple chemical" id="s4211_sa2752" 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>Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end </body> </html> </notes> <label text="N-formyl-kynurenine"/> <bbox w="70.0" h="25.0" x="4655.0" y="6047.5"/> </glyph> <glyph class="simple chemical" id="s4212_sa2753" 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>Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end </body> </html> </notes> <label text="Tryptophan"/> <bbox w="70.0" h="25.0" x="4395.0" y="6047.5"/> </glyph> <glyph class="simple chemical" id="s4261_sa2797" 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>References_begin: MAP:MAST_CELL PMID:15099563 Mast cells produce heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, References_end </body> </html> </notes> <label text="Heparin"/> <bbox w="70.0" h="25.0" x="4865.0" y="7422.5"/> </glyph> <glyph class="simple chemical" id="s4263_sa2799" 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>Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:MAST_CELL PMID:10353253, PMID:18347416 Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase in mast cells. It plays dual role in cancer. References_end </body> </html> </notes> <label text="Histidine"/> <bbox w="70.0" h="25.0" x="3745.0" y="6047.5"/> </glyph> <glyph class="simple chemical" id="s4264_sa2800" 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>Maps_Modules_begin: MODULE:EFFECTOR_INHIBITION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_EXPRESSION MODULE:IMMUNE_SUPPRESSION Maps_Modules_end References_begin: MAP:MAST_CELL PMID:10353253, PMID:18347416 Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase in mast cells. It plays dual role in cancer. PMID:11153522 immunosuppressive action of histamine from Mast cells promotes scin cancer development References_end </body> </html> </notes> <label text="Histamine"/> <bbox w="70.0" h="25.0" x="3945.0" y="6047.5"/> </glyph> <glyph class="simple chemical" id="s4458_sa2328" 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>Maps_Modules_begin: MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: CASCADE:LACTIC MAP:DENDRITIC_CELL MAP:MACROPHAGE PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth PMID:16278308, PMID:23506875 Lactate is transported into the cell probably by the monocarboxylate transporters (MCTs) and this process is strictly pH dependent Tumor-derived lactic acid inhibits DC maturation and T cell activation. References_end </body> </html> </notes> <label text="lactic acid "/> <bbox w="70.0" h="25.0" x="1325.0" y="5747.5"/> </glyph> <glyph class="simple chemical" id="s4915_sa29" 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: CHEBI:17552 KEGGCOMPOUND:C00035 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="GDP"/> <clone/> <bbox w="70.0" h="25.0" x="13435.0" y="7087.5"/> </glyph> <glyph class="simple chemical" id="s4915_sa65" 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: CHEBI:17552 KEGGCOMPOUND:C00035 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="GDP"/> <clone/> <bbox w="70.0" h="25.0" x="12585.0" y="7222.5"/> </glyph> <glyph class="simple chemical" id="s4915_sa461" 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: CHEBI:17552 KEGGCOMPOUND:C00035 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="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="7993.75" y="4386.875"/> </glyph> <glyph class="simple chemical" id="s4915_sa477" 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: CHEBI:17552 KEGGCOMPOUND:C00035 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="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="9323.75" y="3476.875"/> </glyph> <glyph class="simple chemical" id="s4915_sa485" 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: CHEBI:17552 KEGGCOMPOUND:C00035 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="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="6650.0" y="3376.875"/> </glyph> <glyph class="simple chemical" id="s4915_sa498" 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: CHEBI:17552 KEGGCOMPOUND:C00035 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="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="7223.75" y="3576.875"/> </glyph> <glyph class="simple chemical" id="s4915_sa518" compartmentRef="c12_ca12"> <notes> <html 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id="s4918_sa66" 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: CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 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="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="12495.0" y="7222.5"/> </glyph> <glyph class="simple chemical" id="s4918_sa103" 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: CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 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="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="9390.0" y="3477.5"/> </glyph> <glyph class="simple chemical" id="s4918_sa484" 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: CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: 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text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="8740.0" y="2937.5"/> </glyph> <glyph class="simple chemical" id="s4918_sa557" 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: CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 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="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="8665.0" y="4192.5"/> </glyph> <glyph class="simple chemical" id="s4918_sa2160" 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: CHEBI:15996 KEGGCOMPOUND:C00044 CAS:86-01-1 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="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="6715.0" y="2097.5"/> </glyph> <glyph class="simple chemical" id="s4930_sa1091" 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>Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. References_end </body> </html> </notes> <label text="L-arginine"/> <clone/> <bbox w="100.0" h="28.0" x="5894.2188" y="5553.1875"/> </glyph> <glyph class="simple chemical" id="s4930_sa1124" 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>Maps_Modules_begin: MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. References_end </body> </html> </notes> <label text="L-arginine"/> <clone/> <bbox w="100.0" h="28.0" x="5394.2188" y="7193.1875"/> </glyph> <glyph class="simple chemical" id="s4931_sa1099" 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>Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:S100A Maps_Modules_end References_begin: 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:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. References_end </body> </html> </notes> <label text="O2"/> <clone/> <bbox w="70.0" h="25.0" x="6249.2188" y="5884.6875"/> </glyph> <glyph class="simple chemical" id="s4931_sa1112" 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>Maps_Modules_begin: MAP:MACROPHAGE MAP:MDSC MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:NO_ROS_PRODUCTION CASCADE:S100A Maps_Modules_end References_begin: 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:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. References_end </body> </html> </notes> <label text="O2"/> <clone/> <bbox w="70.0" h="25.0" x="5948.5938" y="6883.4375"/> </glyph> <glyph class="simple chemical" id="s4932_sa1109" 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>Maps_Modules_begin: CASCADE:TLR2_4 Maps_Modules_end References_begin: PMID:15644117, PMID:17260466 HMGB1 induces NO production probably via NFkB dependent upregulation of INOS expression in rodent macrophage 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 References_end </body> </html> </notes> <label text="NO"/> <bbox w="70.0" h="25.0" x="6488.5938" y="6393.4375"/> </glyph> <glyph class="simple chemical" id="s4933_sa1144" 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>Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end </body> </html> </notes> <label text="Cystine"/> <bbox w="70.0" h="25.0" x="15115.0" y="7777.5"/> </glyph> <glyph class="simple chemical" id="s4935_sa1149" 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>Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end </body> </html> </notes> <label text="Cysteine"/> <bbox w="70.0" h="25.0" x="15265.0" y="7777.5"/> </glyph> <glyph class="simple chemical" id="s4953_sa2159" 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>Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:STING CASCADE::P2RX7 CASCADE::P2RY2 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. PMID:19741708 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. UTP and ATP act via P2RY2 and promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo. References_end </body> </html> </notes> <label text="ATP"/> <clone/> <bbox w="70.0" h="25.0" x="6665.0" y="2147.5"/> </glyph> <glyph class="simple chemical" id="s4953_sa2562" 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>Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:DANGER_SIGNAL_PATHWAYS Maps_Modules_end References_begin: MAP:DENDRITIC_CELL MAP:MACROPHAGE CASCADE:STING CASCADE::P2RX7 CASCADE::P2RY2 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. PMID:19741708 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. UTP and ATP act via P2RY2 and promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo. References_end </body> </html> </notes> <label text="ATP"/> <clone/> <bbox w="70.0" h="25.0" x="4325.0" y="3437.5"/> </glyph> <glyph class="simple chemical" id="s5131_sa340" 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: CHEBI:16480 KEGGCOMPOUND:C00533 CAS:10102-43-9 Identifiers_end References_begin: MAP:NATURAL_KILLER PMID:22006996, PMID:18559521 Nitric oxide inhibits the hypoxia-induced expression of ADAM10 and the hypoxia-induced accumulation of HIF1A and decrease MIC shedding. NO attenuates in vivo tumor growth by sensitizing tumor cells to recognition and elimination by the innate immune system. References_end </body> </html> </notes> <label text="NO"/> <bbox w="70.0" h="25.0" x="11665.0" y="602.5"/> </glyph> <glyph class="macromolecule" id="s5204_sa2882" 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: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="7230.0" y="3940.0"/> <glyph class="state variable" id="_46f87929-7449-4f26-8ce0-46131152634f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7225.0" y="3955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5205_sa2884" compartmentRef="c13_ca13"> <label text="FADD"/> <bbox w="80.0" h="40.0" x="16190.0" y="3190.0"/> </glyph> <glyph class="macromolecule" id="s5206_sa2885" compartmentRef="c12_ca12"> <label text="FADD"/> <bbox w="80.0" h="40.0" x="15423.5" y="3242.0"/> </glyph> <glyph class="complex" id="s5210_csa83" 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:FN1:ITGA5:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A5B1 PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. References_end </body> </html> </notes> <label text="s1884"/> <bbox w="110.0" h="205.0" x="8857.5" y="1607.5"/> <glyph class="macromolecule" id="s5211_sa651"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGA5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A5B1 PMID:24202395, PMID:22067905 References_end </body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="50.0" x="8870.0" y="1615.0"/> <glyph class="unit of information" id="_7ed0f5bc-0e63-4f45-8a74-c491d915d0b7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8887.5" y="1610.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5212_sa652"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="8870.0" y="1665.0"/> <glyph class="unit of information" id="_7a4f4c59-edfe-47e4-bad0-415f759effd6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8887.5" y="1660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5209_sa2888"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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:FN1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 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:24202395, PMID:22067905 Fibronectin plays important role in tumor microenviroment. Primary tumors upregulate fibronectin expression by resident fibroblasts in secondary organs. Fibronectin (FN) controls the growth and survival of tumor cells. FN signaling is transmitted via integrins that eventually determine the cellular response to the changes in cell shape, mobility, and proliferation. References_end </body> </html> </notes> <label text="FN1"/> <bbox w="80.0" h="40.0" x="8870.0" y="1720.0"/> </glyph> </glyph> <glyph class="complex" id="s5214_csa352" 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:LCP2:MIR155 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24227772 mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. References_end </body> </html> </notes> <label text="s5214"/> <bbox w="100.0" h="120.0" x="12700.0" y="2450.0"/> <glyph class="nucleic acid feature" id="s1577_sa638"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LCP2 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:NK_ACTIVATING_RECEPTORS Maps_Modules_end References_begin: MAP:NATURAL_KILLER PMID:24227772 mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. SLP76, IKBKE mRNA are MIR55 targets. References_end </body> </html> </notes> <label text="LCP2"/> <bbox w="90.0" h="25.0" x="12705.0" y="2507.5"/> <glyph class="unit of information" id="_18980ad4-3022-410d-b584-1587ecc90225"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="12740.0" y="2502.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5213_sa639"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO: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="12705.0" y="2477.5"/> <glyph class="unit of information" id="_c2c0efe7-2d0e-4635-a372-6ab45e2ae420"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="12735.0" y="2472.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5215_csa353" 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="15855.0" y="3230.0"/> <glyph class="macromolecule" id="s5217_sa2890"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15970.0" y="3340.0"/> </glyph> <glyph class="macromolecule" id="s5219_sa2892"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15975.0" y="3240.0"/> </glyph> <glyph class="macromolecule" id="s5220_sa2893"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="15970.0" y="3285.0"/> <glyph class="unit of information" id="_db5b6f0a-221d-47b3-8dd0-682b989a4171"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15987.5" y="3280.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5221_sa2894"> <label text="FADD"/> <bbox w="80.0" h="40.0" x="15870.0" y="3240.0"/> </glyph> <glyph class="macromolecule" id="s5223_sa2895"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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: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="15870.0" y="3290.0"/> <glyph class="state variable" id="_3845f0ad-02c4-41ed-8492-d63289d1dd8f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15945.0" y="3305.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s5222_sa2896"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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: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="15870.0" y="3340.0"/> <glyph class="state variable" id="_e691a716-0aa9-4b8d-89dd-fc6bc30201b7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15945.0" y="3353.6672"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5224_csa354" 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:STAT1:TNFR1* Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 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="s5224"/> <bbox w="100.0" h="120.0" x="15690.0" y="2980.0"/> <glyph class="macromolecule" id="s5225_sa2897"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAT1 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MAP:DENDRITIC_CELL MAP:NATURAL_KILLER MAP:MDSC MODULE:INPUT_INHIBITORS MODULE:IMMUNE_SUPPRESSION MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:INPUT_ACTIVATORS MODULE:IMMUNE_STIMULATION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS CASCADE:IL13 CASCADE:IL15 CASCADE:IL21 CASCADE:SCF2 CASCADE:IFNAB Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. PMID:21930765, PMID:8683106, PMID:12967644 IFNA and IFNB act via STAT1 pathway in DC and NK cells PMID:25960930 Reduced IFNα-induced STAT-1 phosphorylation in Ser727 and CXCL10 secretion in NK cells derived from PKC-θ−/− mice 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="STAT1"/> <bbox w="70.0" h="45.0" x="15705.0" y="2987.5"/> <glyph class="state variable" id="_2ce7a189-461a-4223-895f-11fd88344b9c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="15769.83" y="3027.5"/> </glyph> <glyph class="state variable" id="_c4a3101f-4ad2-4e01-a40b-fee7be0bb944"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="15697.5" y="3003.5513"/> </glyph> </glyph> <glyph class="macromolecule" id="s5226_sa2898"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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: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="15700.0" y="3035.0"/> <glyph class="unit of information" id="_6ffa39a9-288a-4f49-b3f4-a49f4a0ee615"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15717.5" y="3030.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5227_csa355" 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:IL1R1:IL1RAP:trILB1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:IL1 References_end </body> </html> </notes> <label text="s5227"/> <bbox w="200.0" h="130.0" x="6200.0" y="1715.0"/> <glyph class="macromolecule" id="s5228_sa2899"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL1R Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1R1"/> <bbox w="80.0" h="50.0" x="6220.0" y="1780.0"/> <glyph class="unit of information" id="_59363f66-ae83-4c7e-ab32-12a3116f6ba3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6237.5" y="1775.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5229_sa2900"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ILB1 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:EFFECTOR_INHIBITION MODULE:TUMOR_GROWTH MODULE:ANGIOGENIC_FACTORS Maps_Modules_end References_begin: MAP:MACROPHAGE MAP:MDSC MAP:DENDRITIC_CELL MAP:MAST_CELL CASCADE:P2RX7 CASCADE:TLR2_4 CASCADE:IL15 CASCADE:IL1 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) PMID: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. PMID:24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. References_end </body> </html> </notes> <label text="trILB1"/> <bbox w="80.0" h="40.0" x="6310.0" y="1755.0"/> <glyph class="unit of information" id="_54c32fab-202f-49a7-9531-638ba823dfcc"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="6325.0" y="1750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5230_sa2901"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL1RAP Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1RAP"/> <bbox w="80.0" h="50.0" x="6220.0" y="1720.0"/> <glyph class="unit of information" id="_4ac4bc38-faf8-41d2-9d86-fc8b2c669bdf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6237.5" y="1715.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5234_csa356" 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*:RELA Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS MAP:MACROPHAGE MAP:MDSC CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF Maps_Modules_end </body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="13182.5" y="3722.5"/> <glyph class="macromolecule" id="s69_sa2039"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <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="13205.75" y="3743.0"/> <glyph class="state variable" id="_47a2d216-6442-4142-8834-0856f89d069e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="13200.75" y="3758.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5235_sa2902"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns: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="80.0" h="40.0" x="13200.0" y="3780.0"/> </glyph> <glyph class="macromolecule" id="s5236_sa2903"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 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="13197.5" y="3829.5"/> <glyph class="unit of information" id="_33357a67-3d4a-4393-8169-754fac1c978d"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="13212.5" y="3824.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5237_csa357" 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:MAP3K8:NFKB1_p105*:TNIP2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 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="s5237"/> <bbox w="260.0" h="170.0" x="11300.0" y="3180.0"/> <glyph class="macromolecule" id="s12_sa2069"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 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="NFKB1_p105*"/> <bbox w="110.0" h="60.0" x="11375.0" y="3190.0"/> <glyph class="state variable" id="_54a6077e-f909-484d-9d9a-05bb71aae0c8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="11370.0" y="3215.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5238_sa2070"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MAP3K8 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554 immunoprecipitated MAP3K8 TPL-2 could directly phosphorylate and activate both MEK-1 and MKK4 (also known as SEK-1) in vitro. TPL-2 expression is essential for LPS activation of MEK-1⁄2 and ERK-1⁄2 in macrophages PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="MAP3K8"/> <bbox w="105.0" h="70.0" x="11307.5" y="3265.0"/> </glyph> <glyph class="macromolecule" id="s87_sa2071"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNIP2 Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE PMID:22435554, PMID:15169888 In unstimulated cells, TPL-2 is conﬁned to a cytoplasmic complex with the NF-jB1 precursor protein p105, and the ubiquitin-binding protein ABIN-2. Interactions with both p105 and ABIN-2 are required to maintain TPL-2 protein stability, while TPL-2 association with p105 also inhibits TPL-2 phosphorylation of its substrates MEK-1⁄2 References_end </body> </html> </notes> <label text="TNIP2"/> <bbox w="87.0" h="65.0" x="11446.5" y="3267.5"/> </glyph> </glyph> <glyph class="complex" id="s5240_csa359" 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*:NFKBID Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS Maps_Modules_end References_begin: MAP:MACROPHAGE References_end </body> </html> </notes> <label text="s5240"/> <bbox w="120.0" h="160.0" x="11910.0" y="3360.0"/> <glyph class="macromolecule" id="s2466_sa2061"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKBID Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CORE_PATHWAYS CASCADE:IL10 Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="110.0" h="50.0" x="11915.0" y="3365.0"/> </glyph> <glyph class="macromolecule" id="s2467_sa2062"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" 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="110.833336" h="73.333336" x="11914.583" y="3413.3333"/> <glyph class="unit of information" id="_591e6422-642e-4b6b-a318-22bc77f20597"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="11945.0" y="3408.3333"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5241_csa360" 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:IL1R1:IL1RAP Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:IL1 References_end </body> </html> </notes> <label text="s5241"/> <bbox w="100.0" h="120.0" x="6100.0" y="1320.0"/> <glyph class="macromolecule" id="s1102_sa1592"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL1R Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1R1"/> <bbox w="80.0" h="50.0" x="6110.0" y="1375.0"/> <glyph class="unit of information" id="_23dfc524-dee2-4593-99a8-3086b34da935"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6127.5" y="1370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1103_sa1593"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL1RAP Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: MAP:MDSC CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1RAP"/> <bbox w="80.0" h="50.0" x="6110.0" y="1325.0"/> <glyph class="unit of information" id="_c674befb-9f39-472b-8bbb-570869dba822"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6127.5" y="1320.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5242_csa361" 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:ITGA5:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A5B1 PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. References_end </body> </html> </notes> <label text="s5242"/> <bbox w="100.0" h="120.0" x="8800.0" y="1340.0"/> <glyph class="macromolecule" id="s1882_sa647"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGA5 Identifiers_end Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A5B1 PMID:24202395, PMID:22067905 References_end </body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="50.0" x="8810.0" y="1355.0"/> <glyph class="unit of information" id="_56a28a7b-f08f-48cd-a5f3-3f924cc3c8cd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8827.5" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5243_sa648"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:INPUT_ACTIVATORS MODULE:TUMOR_RECOGNTITON MODULE:INTEGRINS Maps_Modules_end References_begin: MAP:NATURAL_KILLER CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 PMID:19454690 NKG2D ligation leads to increased adhesion and recruitment of beta1 and beta2 integrins to the cytotoxic synapse. PMID:9973479 Beta 1 integrin cross-linking inhibits CD16-induced phospholipase D and secretory phospholipase A2 activity and granule exocytosis in human NK cells. PMID:9763606 Cross-linking of β1 Integrins on Human NK Cells Induces Shc Tyrosine Phosphorylation and Grb2 Association via Pyk-2end resulted in RAS/ERK activation. References_end </body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="50.0" x="8810.0" y="1395.0"/> <glyph class="unit of information" id="_e6310936-5a38-4a63-820e-1d58e620ab6f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="8827.5" y="1390.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5244_sa1146" 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: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="15190.0" y="7625.0"/> <glyph class="unit of information" id="_e50be826-ac9c-4fb2-a6af-7106fec6eb02"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="15207.5" y="7620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5245_sa2905" 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: 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="12200.0" y="6780.0"/> <glyph class="unit of information" id="_9a25f2f8-05e4-4781-b95b-5cf3745b28fa"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="12215.0" y="6775.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5247_sa2906" 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: HUGO:CTSB Identifiers_end Maps_Modules_begin: MODULE:IMMUNE_STIMULATION MODULE:ANTIGEN_PRESENTATION MODULE:EFFECTOR_ACTIVATION Maps_Modules_end References_begin: MAP:DENDRITIC_CELL PMID:16237087 CTSD (aspartic cathepsin D) and CTSG (cathepsin G) participate in antigen processing in DC. PMID:12776207 Cathepsins B,D,L, S and AEP (LGMN) are the lysosomal proteases implicated in antigen presentation in DC. References_end </body> </html> </notes> <label text="CTSB"/> <bbox w="80.0" h="40.0" x="12000.0" y="6510.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_46e92b8d-c1fc-4521-ae6c-89deb528dd9d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10837075 Immature DCs are very efficient in Ag capture and can use several pathways, such as (a) macropinocytosis; (b) receptor-mediated endocytosis via C-type lectin receptors (mannose receptor, DEC-205) or Fcγ receptor types I (CD64) and II (CD32) [uptake of immune complexes or opsonized particles ]; and (c) phagocytosis of particles such as latex beads , apoptotic and necrotic cell fragments (involving CD36 and αvβ3 or αvβ5 integrins), viruses, and bacteria including mycobacteria, as well as intracellular parasites such as Leishmania major. DCs can also internalize the peptide loaded heat shock proteins gp96 and Hsp70 through presently unknown mechanisms References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="11440.0" y="7615.0"/> <port id="pr_46e92b8d-c1fc-4521-ae6c-89deb528dd9d_p1" x="11445.0" y="7635.0"/> <port id="pr_46e92b8d-c1fc-4521-ae6c-89deb528dd9d_p2" x="11445.0" y="7605.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_a7058929-a5f7-4756-b6cc-d6a85d044300"> <bbox w="10.0" h="10.0" x="11920.0" y="6260.0"/> <port id="pr_a7058929-a5f7-4756-b6cc-d6a85d044300_p1" x="11910.0" y="6265.0"/> <port id="pr_a7058929-a5f7-4756-b6cc-d6a85d044300_p2" x="11940.0" y="6265.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2cb111ad-c924-4c76-9d20-eb33d358458c"> <bbox w="10.0" h="10.0" x="13134.223" y="8197.563"/> <port id="pr_2cb111ad-c924-4c76-9d20-eb33d358458c_p1" x="13124.223" y="8202.563"/> <port id="pr_2cb111ad-c924-4c76-9d20-eb33d358458c_p2" x="13154.223" y="8202.563"/> </glyph> <glyph class="process" orientation="vertical" id="pr_eaa28554-7b4d-42c0-88ed-b3ddf5ade1dc"> <bbox w="10.0" h="10.0" x="13775.0" y="6155.0"/> <port id="pr_eaa28554-7b4d-42c0-88ed-b3ddf5ade1dc_p1" x="13780.0" y="6145.0"/> <port id="pr_eaa28554-7b4d-42c0-88ed-b3ddf5ade1dc_p2" x="13780.0" y="6175.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9fec53ae-848e-4c43-a959-0e4e43991910"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="14027.588" y="6515.1113"/> <port id="pr_9fec53ae-848e-4c43-a959-0e4e43991910_p1" x="14032.588" y="6505.1113"/> <port id="pr_9fec53ae-848e-4c43-a959-0e4e43991910_p2" x="14032.588" y="6535.1113"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_10a75d4f-5036-4bee-b8cf-07e8349ff184"> <bbox w="10.0" h="10.0" x="13819.341" y="7501.25"/> <port id="pr_10a75d4f-5036-4bee-b8cf-07e8349ff184_p1" x="13839.341" y="7506.25"/> <port id="pr_10a75d4f-5036-4bee-b8cf-07e8349ff184_p2" x="13809.341" y="7506.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_36ac3c2d-972b-471a-9b21-c1c25aa9b161"> <bbox w="10.0" h="10.0" x="13334.791" y="8217.5"/> <port id="pr_36ac3c2d-972b-471a-9b21-c1c25aa9b161_p1" x="13339.791" y="8207.5"/> <port id="pr_36ac3c2d-972b-471a-9b21-c1c25aa9b161_p2" x="13339.791" y="8237.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_16255c37-62cc-4dbd-8e15-25611f7718d5"> <bbox w="10.0" h="10.0" x="14550.676" y="6723.972"/> <port id="pr_16255c37-62cc-4dbd-8e15-25611f7718d5_p1" x="14570.676" y="6728.972"/> <port id="pr_16255c37-62cc-4dbd-8e15-25611f7718d5_p2" x="14540.676" y="6728.972"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3ab47699-2d12-4147-a7aa-a92889327057"> <bbox w="10.0" h="10.0" x="14356.24" y="6896.4307"/> <port id="pr_3ab47699-2d12-4147-a7aa-a92889327057_p1" x="14361.24" y="6916.4307"/> <port id="pr_3ab47699-2d12-4147-a7aa-a92889327057_p2" x="14361.24" y="6886.4307"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_a6735aa3-e39a-48c6-873e-e4369efee386"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:22790179 The SNARE SEC22B, which localizes in the ER–Golgi intermediate compartment (ERGIC) and interacts with syntaxin 4 on phagosomes, mediates the recruitment of a subset of ER components, including transporter associated with antigen processing (TAP), to phagosomes. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="13210.0" y="6315.8076"/> <port id="pr_a6735aa3-e39a-48c6-873e-e4369efee386_p1" x="13230.0" y="6320.8076"/> <port id="pr_a6735aa3-e39a-48c6-873e-e4369efee386_p2" x="13200.0" y="6320.8076"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9c68d355-b0a9-4672-abb8-2d0a83366d0f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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 antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecules. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="12020.0" y="7420.0"/> <port id="pr_e5cccac8-c5ce-4e68-a840-745f3d526b32_p1" x="12025.0" y="7410.0"/> <port id="pr_e5cccac8-c5ce-4e68-a840-745f3d526b32_p2" x="12025.0" y="7440.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6b22f50d-1b25-4e85-8e80-8c7460544e56"> <bbox w="10.0" h="10.0" x="12812.5" y="8198.654"/> <port id="pr_6b22f50d-1b25-4e85-8e80-8c7460544e56_p1" x="12802.5" y="8203.654"/> <port id="pr_6b22f50d-1b25-4e85-8e80-8c7460544e56_p2" x="12832.5" y="8203.654"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0f14413d-361f-47a4-a866-96e02ca2b114"> <bbox w="10.0" h="10.0" x="11753.324" y="6248.028"/> <port id="pr_0f14413d-361f-47a4-a866-96e02ca2b114_p1" x="11743.324" y="6253.028"/> <port id="pr_0f14413d-361f-47a4-a866-96e02ca2b114_p2" x="11773.324" y="6253.028"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d428282d-ddc4-4506-99ed-5f12c6fc8562"> <bbox w="10.0" h="10.0" x="11708.324" y="6203.028"/> <port id="pr_d428282d-ddc4-4506-99ed-5f12c6fc8562_p1" x="11713.324" y="6193.028"/> <port id="pr_d428282d-ddc4-4506-99ed-5f12c6fc8562_p2" x="11713.324" y="6223.028"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7d47681e-d27a-40c7-bf69-6d4fd778c24d"> <bbox w="10.0" h="10.0" x="11802.412" y="6204.2637"/> <port id="pr_7d47681e-d27a-40c7-bf69-6d4fd778c24d_p1" x="11807.412" y="6224.2637"/> <port id="pr_7d47681e-d27a-40c7-bf69-6d4fd778c24d_p2" x="11807.412" y="6194.2637"/> </glyph> <glyph class="process" orientation="vertical" id="pr_003dc8f0-5818-45b5-9a53-47d1d822be36"> <bbox w="10.0" h="10.0" x="12428.125" y="6542.5"/> <port id="pr_003dc8f0-5818-45b5-9a53-47d1d822be36_p1" x="12433.125" y="6532.5"/> <port id="pr_003dc8f0-5818-45b5-9a53-47d1d822be36_p2" x="12433.125" y="6562.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c8dedd56-0521-45ff-bb50-013bb4d4f9c2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="12246.844" y="6694.255"/> <port id="pr_c8dedd56-0521-45ff-bb50-013bb4d4f9c2_p1" x="12266.844" y="6699.255"/> <port id="pr_c8dedd56-0521-45ff-bb50-013bb4d4f9c2_p2" x="12236.844" y="6699.255"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a3412e86-91d6-4d11-b4f2-4979be52d61a"> <bbox w="10.0" h="10.0" x="12080.325" y="6762.0"/> <port id="pr_a3412e86-91d6-4d11-b4f2-4979be52d61a_p1" x="12085.325" y="6752.0"/> <port id="pr_a3412e86-91d6-4d11-b4f2-4979be52d61a_p2" x="12085.325" y="6782.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_92e77c58-ead1-43c9-a818-9c48ca183e47"> <bbox w="10.0" h="10.0" x="13145.625" y="6606.25"/> <port id="pr_92e77c58-ead1-43c9-a818-9c48ca183e47_p1" x="13165.625" y="6611.25"/> <port id="pr_92e77c58-ead1-43c9-a818-9c48ca183e47_p2" x="13135.625" y="6611.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6e5ec3d0-6d21-476e-925a-7f377c9b02c5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="12459.828" y="7436.25"/> <port id="pr_6e5ec3d0-6d21-476e-925a-7f377c9b02c5_p1" x="12464.828" y="7426.25"/> <port id="pr_6e5ec3d0-6d21-476e-925a-7f377c9b02c5_p2" x="12464.828" y="7456.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_262fdb22-5c6e-4725-abd7-fe9465862348"> <bbox w="10.0" h="10.0" x="13500.0" y="7175.0"/> <port id="pr_262fdb22-5c6e-4725-abd7-fe9465862348_p1" x="13520.0" y="7180.0"/> <port id="pr_262fdb22-5c6e-4725-abd7-fe9465862348_p2" x="13490.0" y="7180.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9ccca0b1-dc03-4ebb-ab31-9f3c96345ce5"> <bbox w="10.0" h="10.0" x="13625.0" y="7405.0"/> <port id="pr_9ccca0b1-dc03-4ebb-ab31-9f3c96345ce5_p1" x="13645.0" y="7410.0"/> <port id="pr_9ccca0b1-dc03-4ebb-ab31-9f3c96345ce5_p2" x="13615.0" y="7410.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1c59979c-325e-475e-8a25-bbfd9f97c5c1"> <bbox w="10.0" h="10.0" x="13575.0" y="7505.0"/> <port id="pr_1c59979c-325e-475e-8a25-bbfd9f97c5c1_p1" x="13595.0" y="7510.0"/> <port id="pr_1c59979c-325e-475e-8a25-bbfd9f97c5c1_p2" x="13565.0" y="7510.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c1d7ff7b-6a2d-4dbf-a892-af6b11d6d7d1"> <bbox w="10.0" h="10.0" x="13269.0" y="7297.0"/> <port id="pr_c1d7ff7b-6a2d-4dbf-a892-af6b11d6d7d1_p1" x="13274.0" y="7287.0"/> <port id="pr_c1d7ff7b-6a2d-4dbf-a892-af6b11d6d7d1_p2" x="13274.0" y="7317.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_945c56e5-bd05-46f3-ac19-cd1b15349142"> <bbox w="10.0" h="10.0" x="12580.0" y="7130.0"/> <port id="pr_945c56e5-bd05-46f3-ac19-cd1b15349142_p1" x="12570.0" y="7135.0"/> <port id="pr_945c56e5-bd05-46f3-ac19-cd1b15349142_p2" x="12600.0" y="7135.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3188e512-87bf-489f-ac85-98b71302221d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="12750.0" y="6230.0"/> <port id="pr_3188e512-87bf-489f-ac85-98b71302221d_p1" x="12740.0" y="6235.0"/> <port id="pr_3188e512-87bf-489f-ac85-98b71302221d_p2" x="12770.0" y="6235.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_eebde212-560d-478b-988c-76b4f32ef0af"> <bbox w="10.0" h="10.0" x="12510.0" y="7020.0"/> <port id="pr_eebde212-560d-478b-988c-76b4f32ef0af_p1" x="12500.0" y="7025.0"/> <port id="pr_eebde212-560d-478b-988c-76b4f32ef0af_p2" x="12530.0" y="7025.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_df238a10-2058-43bf-afaf-416f257b4f93"> <bbox w="10.0" h="10.0" x="12665.0" y="7613.5"/> 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The calcium signal generated by PLCG is required for NKG2D-initiated killing. 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JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. PMID:17404308 CSF1 upregulates expression of IL10 and CCL2 probably via CSF1R. PMID:15749884 c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2207.5" y="5709.0625"/> <port id="pr_08648726-d1f6-4f2a-b515-9c1be9532525_p1" x="2212.5" y="5729.0625"/> <port id="pr_08648726-d1f6-4f2a-b515-9c1be9532525_p2" x="2212.5" y="5699.0625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e5e46939-29f6-479b-a433-96758a90d3e5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:21115385, PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. PMID:‭15833879 ‭Anti IL-10 receptor–specific antibody switched TAMs from an M2 to an M1 macrophage–like phenotype. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="885.0" y="4064.5"/> <port id="pr_e5e46939-29f6-479b-a433-96758a90d3e5_p1" x="890.0" y="4084.5"/> <port id="pr_e5e46939-29f6-479b-a433-96758a90d3e5_p2" x="890.0" y="4054.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_eb8f676f-82b3-4ef4-bdab-bb60fdfe607f"> <bbox w="10.0" h="10.0" x="1790.0" y="4440.0"/> <port id="pr_eb8f676f-82b3-4ef4-bdab-bb60fdfe607f_p1" x="1780.0" y="4445.0"/> <port id="pr_eb8f676f-82b3-4ef4-bdab-bb60fdfe607f_p2" x="1810.0" y="4445.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_cb268720-ccce-4ff7-822f-2c08ed8693d2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2207.5" y="5568.4375"/> <port id="pr_cb268720-ccce-4ff7-822f-2c08ed8693d2_p1" x="2212.5" y="5588.4375"/> <port id="pr_cb268720-ccce-4ff7-822f-2c08ed8693d2_p2" x="2212.5" y="5558.4375"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_74849740-8281-49b7-b339-94d52ab63e5e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20547845 TLR4 signaling downstream of HMGB1 induces secretion of IL10 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1230.3911" y="4713.1875"/> <port id="pr_74849740-8281-49b7-b339-94d52ab63e5e_p1" x="1250.3911" y="4718.1875"/> <port id="pr_74849740-8281-49b7-b339-94d52ab63e5e_p2" x="1220.3911" y="4718.1875"/> </glyph> <glyph class="process" orientation="vertical" id="pr_91033ae9-51e6-491a-ae6e-2d85def0bea1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12907458, PMID:12193690 IL10 upregulates expression of IL4RA in STAT3 dependent manner. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1382.5" y="4800.75"/> <port id="pr_91033ae9-51e6-491a-ae6e-2d85def0bea1_p1" x="1387.5" y="4820.75"/> <port id="pr_91033ae9-51e6-491a-ae6e-2d85def0bea1_p2" x="1387.5" y="4790.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_d8d4ffc8-e3b2-476e-a8b1-b6aab796ff7c"> <bbox w="10.0" h="10.0" x="1045.0938" y="4873.2207"/> <port id="pr_d8d4ffc8-e3b2-476e-a8b1-b6aab796ff7c_p1" x="1065.0938" y="4878.2207"/> <port id="pr_d8d4ffc8-e3b2-476e-a8b1-b6aab796ff7c_p2" x="1035.0938" y="4878.2207"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c246b887-744b-43f4-af44-44eee4f714c7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20435894 IL10 inhibits miR155 expression via STAT3. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="12210.0" y="4589.375"/> <port id="pr_c246b887-744b-43f4-af44-44eee4f714c7_p1" x="12215.0" y="4609.375"/> <port id="pr_c246b887-744b-43f4-af44-44eee4f714c7_p2" x="12215.0" y="4579.375"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_fa4a7484-6c83-447e-9527-60038ee40334"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="739.125" y="4481.297"/> <port id="pr_fa4a7484-6c83-447e-9527-60038ee40334_p1" x="729.125" y="4486.297"/> <port id="pr_fa4a7484-6c83-447e-9527-60038ee40334_p2" x="759.125" y="4486.297"/> </glyph> <glyph class="process" orientation="vertical" id="pr_110182d8-7514-40a4-9688-789a3a4da452"> <bbox w="10.0" h="10.0" x="868.2857" y="5162.88"/> <port id="pr_110182d8-7514-40a4-9688-789a3a4da452_p1" x="873.2857" y="5152.88"/> <port id="pr_110182d8-7514-40a4-9688-789a3a4da452_p2" x="873.2857" y="5182.88"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ec8a0ba2-f839-4775-a389-363d92fc3571"> <bbox w="10.0" h="10.0" x="705.0" y="4810.2812"/> <port id="pr_ec8a0ba2-f839-4775-a389-363d92fc3571_p1" x="710.0" y="4830.2812"/> <port id="pr_ec8a0ba2-f839-4775-a389-363d92fc3571_p2" x="710.0" y="4800.2812"/> </glyph> <glyph class="process" orientation="vertical" id="pr_237b671d-fb13-4bd5-ba1c-7b03536b4bf2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16327802 STAT6 together with NFkB induced expression of IL13RA2 downstream of IL13 and TNF References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1385.0" y="4390.0"/> <port id="pr_237b671d-fb13-4bd5-ba1c-7b03536b4bf2_p1" x="1390.0" y="4410.0"/> <port id="pr_237b671d-fb13-4bd5-ba1c-7b03536b4bf2_p2" x="1390.0" y="4380.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_4420787f-e0ae-4f4d-adc4-621115f71a7c"> <bbox w="10.0" h="10.0" x="1042.5" y="4354.9634"/> <port id="pr_4420787f-e0ae-4f4d-adc4-621115f71a7c_p1" x="1062.5" y="4359.9634"/> <port id="pr_4420787f-e0ae-4f4d-adc4-621115f71a7c_p2" x="1032.5" y="4359.9634"/> </glyph> <glyph class="process" orientation="vertical" id="pr_403c31fd-6326-44f9-87e2-2bb6184614be"> <bbox w="10.0" h="10.0" x="1475.0" y="3585.0"/> <port id="pr_403c31fd-6326-44f9-87e2-2bb6184614be_p1" x="1480.0" y="3605.0"/> <port id="pr_403c31fd-6326-44f9-87e2-2bb6184614be_p2" x="1480.0" y="3575.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_76f1fea5-88c6-482a-b8f3-1c1837d14a35"> <bbox w="10.0" h="10.0" x="1110.1965" y="3988.75"/> <port id="pr_76f1fea5-88c6-482a-b8f3-1c1837d14a35_p1" x="1115.1965" y="3978.75"/> <port id="pr_76f1fea5-88c6-482a-b8f3-1c1837d14a35_p2" x="1115.1965" y="4008.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0889d4ff-0f7d-4c6d-900f-01f6d494425a"> <bbox w="10.0" h="10.0" x="4320.25" y="3799.67"/> <port id="pr_0889d4ff-0f7d-4c6d-900f-01f6d494425a_p1" x="4340.25" y="3804.67"/> <port id="pr_0889d4ff-0f7d-4c6d-900f-01f6d494425a_p2" x="4310.25" y="3804.67"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d21669a1-64bf-42c4-ab76-17f7b4667e81"> <bbox w="10.0" h="10.0" x="9810.0" y="2870.0"/> <port id="pr_d21669a1-64bf-42c4-ab76-17f7b4667e81_p1" x="9815.0" y="2860.0"/> <port id="pr_d21669a1-64bf-42c4-ab76-17f7b4667e81_p2" x="9815.0" y="2890.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_cefbfaf3-39f1-47e1-9b2b-a9e1959a3fbf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:23124025 Tyk2 but not Jak2 is involved in regulating the IL-13-stimulated activation of Stat1(TYR701) PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. 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Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:21469115 PI3K signaling is involved in STAT6 activation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1790.0" y="3930.0"/> <port id="pr_6a4e8e30-c2f5-4ce9-a31e-8f3d0c57f4f7_p1" x="1780.0" y="3935.0"/> <port id="pr_6a4e8e30-c2f5-4ce9-a31e-8f3d0c57f4f7_p2" x="1810.0" y="3935.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3b78eefc-e6a7-4319-9881-3e8fe36ad004"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. 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PMID:10925299, PMID:6357187 IL-13 induces de novo synthesis of arginase I mRNA and protein. Probably via STAT6. PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. 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L-arginin deficiency impairs iNOS protein synthesis and stability. p38 MAPK participates in arginase activation downstream of IL13 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5756.0884" y="5854.6875"/> <port id="pr_0c0e5729-24a3-4705-b18b-e51d437b148b_p1" x="5761.0884" y="5844.6875"/> <port id="pr_0c0e5729-24a3-4705-b18b-e51d437b148b_p2" x="5761.0884" y="5874.6875"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c0184749-6153-4a75-8d9b-f0467debe3ff"> <bbox w="10.0" h="10.0" x="6091.8525" y="7555.9688"/> <port id="pr_c0184749-6153-4a75-8d9b-f0467debe3ff_p1" x="6096.8525" y="7545.9688"/> <port id="pr_c0184749-6153-4a75-8d9b-f0467debe3ff_p2" x="6096.8525" y="7575.9688"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_d8a21576-66d2-473e-af7f-adfc394f95a3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:19732719 Inhibition of TGF-ß signaling in vivo increases CD11b+ cell cytotoxicity via an oxygen radical-dependent mechanism (superoxide and H2O2 production) in neutrophils References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5917.0938" y="6920.4375"/> <port id="pr_d8a21576-66d2-473e-af7f-adfc394f95a3_p1" x="5937.0938" y="6925.4375"/> <port id="pr_d8a21576-66d2-473e-af7f-adfc394f95a3_p2" x="5907.0938" y="6925.4375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e2c61b38-1dfe-4861-b687-a66446732325"> <bbox w="10.0" h="10.0" x="5964.9355" y="7555.4688"/> <port id="pr_e2c61b38-1dfe-4861-b687-a66446732325_p1" x="5969.9355" y="7545.4688"/> <port id="pr_e2c61b38-1dfe-4861-b687-a66446732325_p2" x="5969.9355" y="7575.4688"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_78e53124-a7b0-4ffd-93dd-795c2d9c5c4f"> <bbox w="10.0" h="10.0" x="5920.0938" y="6950.9375"/> <port id="pr_78e53124-a7b0-4ffd-93dd-795c2d9c5c4f_p1" x="5910.0938" y="6955.9375"/> <port id="pr_78e53124-a7b0-4ffd-93dd-795c2d9c5c4f_p2" x="5940.0938" y="6955.9375"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_51a5b7bb-7152-45a6-a85c-b50b3240115f"> <bbox w="10.0" h="10.0" x="6046.5938" y="6951.4375"/> <port id="pr_51a5b7bb-7152-45a6-a85c-b50b3240115f_p1" x="6036.5938" y="6956.4375"/> <port id="pr_51a5b7bb-7152-45a6-a85c-b50b3240115f_p2" x="6066.5938" y="6956.4375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8e2b186f-de12-4164-bf84-2fc245483890"> <bbox w="10.0" h="10.0" x="6029.648" y="7556.4688"/> <port id="pr_8e2b186f-de12-4164-bf84-2fc245483890_p1" x="6034.648" y="7546.4688"/> <port id="pr_8e2b186f-de12-4164-bf84-2fc245483890_p2" x="6034.648" y="7576.4688"/> </glyph> <glyph class="process" orientation="vertical" id="pr_fc260bf4-d8f5-414d-a9e0-62bf8424cc84"> <bbox w="10.0" h="10.0" x="6145.4785" y="5949.0"/> <port id="pr_fc260bf4-d8f5-414d-a9e0-62bf8424cc84_p1" x="6150.4785" y="5939.0"/> <port id="pr_fc260bf4-d8f5-414d-a9e0-62bf8424cc84_p2" x="6150.4785" y="5969.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9b67e096-c6f0-4d4b-beb9-69e392920526"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. 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PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses NF-kB dependent expression NOS2, Ccl3, Ccl7, Cxcl10. PMID:15644117, PMID:17260466 HMGB1 induces NO production probably via NFkB dependent upregulation of INOS expression. PMID:17689680 STAT1 binds to INOS promoter and induces INOS expression and NO production downstream of IFNG in murine macrophages. Acetylation inhibits STAT1 binding to promotor. PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:23390297 MIF inhitits expression of M1 markers such as NOS2 (INOS). PMID;PMID:20194441 HIF1 upregulates expression of INOS. 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h="10.0" x="15155.0" y="8097.5"/> <port id="pr_3af0312a-7706-4920-b5ce-d3fb70ca34e4_p1" x="15160.0" y="8117.5"/> <port id="pr_3af0312a-7706-4920-b5ce-d3fb70ca34e4_p2" x="15160.0" y="8087.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_fdc722fb-f43b-49b5-b289-2784737161ca"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20414655, PMID:18792398 Trx is one of the main intracellular oxido-reductases TXN expression is upregulated in activated macrophages, DC and probably macrophages secrete thioredoxin which reduces extracellular cystine to cysteine, which is then available for the uptake by T cells through their ASC transporter References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15235.0" y="8412.5"/> <port id="pr_fdc722fb-f43b-49b5-b289-2784737161ca_p1" x="15225.0" y="8417.5"/> <port 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TNF inhibit CCR2 expression in tumor associated macrophages. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5700.0" y="2060.0"/> <port id="pr_08a37faa-55d3-4631-ac12-38ee18ccca50_p1" x="5705.0" y="2080.0"/> <port id="pr_08a37faa-55d3-4631-ac12-38ee18ccca50_p2" x="5705.0" y="2050.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_fcdc1ce4-75f0-4c04-bb50-0114b87fa7bf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. TNF inhibit CCR2 expression in tumor associated macrophages. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5690.4165" y="1951.25"/> <port id="pr_fcdc1ce4-75f0-4c04-bb50-0114b87fa7bf_p1" x="5695.4165" y="1971.25"/> <port id="pr_fcdc1ce4-75f0-4c04-bb50-0114b87fa7bf_p2" x="5695.4165" y="1941.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1e934811-e075-4802-b493-18523a27b624"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. 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<title/> </head> <body>References_begin: PMID:16878026, PMID:10952726 HMGB1 induces IL8 secretion probably via NFkB. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4305.0" y="6711.25"/> <port id="pr_d64b98a4-f17f-4287-a6df-f6d317debcf6_p1" x="4310.0" y="6701.25"/> <port id="pr_d64b98a4-f17f-4287-a6df-f6d317debcf6_p2" x="4310.0" y="6731.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_16c270b7-c134-4d7e-a193-f8502e688e40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20547845, PMID:10952726 TLR4 signaling downstream of HMGB1 induces secretion of IL6 probably via NFkB References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2457.5" y="5546.25"/> <port id="pr_16c270b7-c134-4d7e-a193-f8502e688e40_p1" x="2462.5" y="5566.25"/> <port id="pr_16c270b7-c134-4d7e-a193-f8502e688e40_p2" x="2462.5" y="5536.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_cbf1a678-59af-4a5c-a857-45045de7587c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. 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. CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. PMID:23390297 MIF inhitits expression of M1 markers such as IL12p40 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="12367.625" y="5277.5"/> <port id="pr_cbf1a678-59af-4a5c-a857-45045de7587c_p1" x="12372.625" y="5267.5"/> <port id="pr_cbf1a678-59af-4a5c-a857-45045de7587c_p2" x="12372.625" y="5297.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_01576325-5efe-4b60-9646-91a45303d08c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4305.0" y="6632.5"/> <port id="pr_01576325-5efe-4b60-9646-91a45303d08c_p1" x="4310.0" y="6622.5"/> <port id="pr_01576325-5efe-4b60-9646-91a45303d08c_p2" x="4310.0" y="6652.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1d277821-40b5-48bc-b3ac-1e4132092d98"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:9743347 IL-13 blocks NF-κB-dependent production of IL6 PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2452.5" y="5702.5"/> <port id="pr_1d277821-40b5-48bc-b3ac-1e4132092d98_p1" x="2457.5" y="5722.5"/> <port id="pr_1d277821-40b5-48bc-b3ac-1e4132092d98_p2" x="2457.5" y="5692.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d95a8493-b8a0-4c14-8d7e-5839b84f1dbf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4605.0" y="5305.0"/> <port id="pr_d95a8493-b8a0-4c14-8d7e-5839b84f1dbf_p1" x="4610.0" y="5295.0"/> <port id="pr_d95a8493-b8a0-4c14-8d7e-5839b84f1dbf_p2" x="4610.0" y="5325.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b37f58d8-6845-4048-88cc-dcd77d3e4297"> <bbox w="10.0" h="10.0" x="4605.0" y="5381.25"/> <port id="pr_b37f58d8-6845-4048-88cc-dcd77d3e4297_p1" x="4610.0" y="5371.25"/> <port id="pr_b37f58d8-6845-4048-88cc-dcd77d3e4297_p2" x="4610.0" y="5401.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a9646012-4dce-4080-81f9-81fabb7e2b5b"> <bbox w="10.0" h="10.0" x="12461.25" y="5277.5"/> <port id="pr_a9646012-4dce-4080-81f9-81fabb7e2b5b_p1" x="12466.25" y="5267.5"/> <port id="pr_a9646012-4dce-4080-81f9-81fabb7e2b5b_p2" x="12466.25" y="5297.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5f3722ec-ed15-4d9f-9194-b372c5c9e1d1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17404308 CSF2 have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="12461.25" y="5351.25"/> <port id="pr_5f3722ec-ed15-4d9f-9194-b372c5c9e1d1_p1" x="12466.25" y="5341.25"/> <port id="pr_5f3722ec-ed15-4d9f-9194-b372c5c9e1d1_p2" x="12466.25" y="5371.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_11c55a96-d70d-4f49-bdb7-4a0558ff6b28"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="5795.0" y="2580.0"/> <port id="pr_11c55a96-d70d-4f49-bdb7-4a0558ff6b28_p1" x="5800.0" y="2600.0"/> <port id="pr_11c55a96-d70d-4f49-bdb7-4a0558ff6b28_p2" x="5800.0" y="2570.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e9cb88bd-68eb-49bb-a2ae-22bb76e09c97"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17404308, PMI:17404308 CSF1 upregulates expression of CCL2 probably via CSF1R. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5700.0" y="2580.0"/> <port id="pr_e9cb88bd-68eb-49bb-a2ae-22bb76e09c97_p1" x="5705.0" y="2600.0"/> <port id="pr_e9cb88bd-68eb-49bb-a2ae-22bb76e09c97_p2" x="5705.0" y="2570.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7d9eb80b-092e-47a3-a0cf-40aee943aa7a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). PMID:23508573 HMGB1 induces secretion of CCL2, CCL3 and CXCL10 (IP-10) via TLR4 pathway. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5795.0" y="2503.75"/> <port id="pr_7d9eb80b-092e-47a3-a0cf-40aee943aa7a_p1" x="5800.0" y="2523.75"/> <port id="pr_7d9eb80b-092e-47a3-a0cf-40aee943aa7a_p2" x="5800.0" y="2493.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6bf219b9-ee1d-404c-8a45-ec24e6b2253c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). PMID:23508573 HMGB1 induces secretion of CCL2, CCL3 and CXCL10 (IP-10) via TLR4 pathway. PMID:19915063 Phosphorylated STAT1 is critical for IFN-gamma-induced (CCL2)MCP-1 production. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5695.0" y="2503.75"/> <port id="pr_6bf219b9-ee1d-404c-8a45-ec24e6b2253c_p1" x="5700.0" y="2523.75"/> <port id="pr_6bf219b9-ee1d-404c-8a45-ec24e6b2253c_p2" x="5700.0" y="2493.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_abfcfa4c-16ad-4422-bd4e-206dcba68d5d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="6125.0" y="2580.0"/> <port id="pr_abfcfa4c-16ad-4422-bd4e-206dcba68d5d_p1" x="6130.0" y="2600.0"/> <port id="pr_abfcfa4c-16ad-4422-bd4e-206dcba68d5d_p2" x="6130.0" y="2570.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_04f3c526-2b9e-411b-abd9-20c460ed92cd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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> <bbox w="10.0" h="10.0" x="5075.0" y="2565.0"/> <port id="pr_04f3c526-2b9e-411b-abd9-20c460ed92cd_p1" x="5080.0" y="2585.0"/> <port id="pr_04f3c526-2b9e-411b-abd9-20c460ed92cd_p2" x="5080.0" y="2555.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b585a79b-8368-47d0-8c59-9252ca50da2d"> <bbox w="10.0" h="10.0" x="6120.417" y="2498.75"/> <port id="pr_b585a79b-8368-47d0-8c59-9252ca50da2d_p1" x="6125.417" y="2518.75"/> <port id="pr_b585a79b-8368-47d0-8c59-9252ca50da2d_p2" x="6125.417" y="2488.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3db46ae3-2eaf-41e2-9a24-5bba90f299ff"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:23508573 HMGB1 induces secretion of CCL2, CCL3 and CXCL10 (IP-10) via TLR4 pathway. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5075.0" y="2488.75"/> <port id="pr_3db46ae3-2eaf-41e2-9a24-5bba90f299ff_p1" x="5080.0" y="2508.75"/> <port id="pr_3db46ae3-2eaf-41e2-9a24-5bba90f299ff_p2" x="5080.0" y="2478.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0d3236ac-2dfa-4cc2-92f5-6f9fa79f94c7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CXCL2 Identifiers_end Maps_Modules_begin: MAP:MACROPHAGE Maps_Modules_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4985.0" y="2586.75"/> <port id="pr_0d3236ac-2dfa-4cc2-92f5-6f9fa79f94c7_p1" x="4990.0" y="2606.75"/> <port id="pr_0d3236ac-2dfa-4cc2-92f5-6f9fa79f94c7_p2" x="4990.0" y="2576.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f512497d-498b-4a7a-9fc6-c999c17809d7"> <notes> <html xmlns="http://www.w3.org/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: TLR4 signaling downstream of HMGB1 induces secretion of CXCL2 (MIP2). References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4980.341" y="2508.75"/> <port id="pr_f512497d-498b-4a7a-9fc6-c999c17809d7_p1" x="4985.341" y="2528.75"/> <port id="pr_f512497d-498b-4a7a-9fc6-c999c17809d7_p2" x="4985.341" y="2498.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9656bf2e-5ef4-4aa8-bb79-76363ba70bd5"> <bbox w="10.0" h="10.0" x="5895.0" y="2581.75"/> <port id="pr_9656bf2e-5ef4-4aa8-bb79-76363ba70bd5_p1" x="5900.0" y="2601.75"/> <port id="pr_9656bf2e-5ef4-4aa8-bb79-76363ba70bd5_p2" x="5900.0" y="2571.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8b3cc0eb-0fb3-47a1-be2b-a548b76d3fe9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine CCL4 (MIP1B). References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5895.0" y="2503.75"/> <port id="pr_8b3cc0eb-0fb3-47a1-be2b-a548b76d3fe9_p1" x="5900.0" y="2523.75"/> <port id="pr_8b3cc0eb-0fb3-47a1-be2b-a548b76d3fe9_p2" x="5900.0" y="2493.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_913bcbbd-4995-47e6-bdf4-4262fae53d60"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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. CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3015.0" y="5435.0"/> <port id="pr_913bcbbd-4995-47e6-bdf4-4262fae53d60_p1" x="3020.0" y="5425.0"/> <port id="pr_913bcbbd-4995-47e6-bdf4-4262fae53d60_p2" x="3020.0" y="5455.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_99ed9711-32bf-4ef2-9e1a-015a763b906c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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. CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3015.0" y="5526.25"/> <port id="pr_99ed9711-32bf-4ef2-9e1a-015a763b906c_p1" x="3020.0" y="5516.25"/> <port id="pr_99ed9711-32bf-4ef2-9e1a-015a763b906c_p2" x="3020.0" y="5546.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_76bd4b93-ae28-4d45-a86c-0f647fc1582d"> <bbox w="10.0" h="10.0" x="13666.75" y="5275.0"/> <port id="pr_76bd4b93-ae28-4d45-a86c-0f647fc1582d_p1" x="13671.75" y="5265.0"/> <port id="pr_76bd4b93-ae28-4d45-a86c-0f647fc1582d_p2" x="13671.75" y="5295.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e8c7d0a5-df4a-46fb-9706-51ef88db2154"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:18345002 TNF induces IFNA expression in macrophages References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="13551.25" y="5275.0"/> <port id="pr_e8c7d0a5-df4a-46fb-9706-51ef88db2154_p1" x="13556.25" y="5265.0"/> <port id="pr_e8c7d0a5-df4a-46fb-9706-51ef88db2154_p2" x="13556.25" y="5295.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8a8a69f1-9320-4b1b-a46a-34c7df941e92"> <bbox w="10.0" h="10.0" x="13665.833" y="5361.25"/> <port id="pr_8a8a69f1-9320-4b1b-a46a-34c7df941e92_p1" x="13670.833" y="5351.25"/> <port id="pr_8a8a69f1-9320-4b1b-a46a-34c7df941e92_p2" x="13670.833" y="5381.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f4762710-d3b9-4842-92d6-698e398f14b3"> <bbox w="10.0" h="10.0" x="13551.25" y="5361.25"/> <port id="pr_f4762710-d3b9-4842-92d6-698e398f14b3_p1" x="13556.25" y="5351.25"/> <port id="pr_f4762710-d3b9-4842-92d6-698e398f14b3_p2" x="13556.25" y="5381.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7a7396d2-2884-4dea-87e1-103b8d969bdb"> <bbox w="10.0" h="10.0" x="13431.25" y="5275.0"/> <port id="pr_7a7396d2-2884-4dea-87e1-103b8d969bdb_p1" x="13436.25" y="5265.0"/> <port id="pr_7a7396d2-2884-4dea-87e1-103b8d969bdb_p2" x="13436.25" y="5295.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b4be47cf-6998-4b19-8116-f0a4aa4e137c"> <bbox w="10.0" h="10.0" x="13435.833" y="5361.25"/> <port id="pr_b4be47cf-6998-4b19-8116-f0a4aa4e137c_p1" x="13440.833" y="5351.25"/> <port id="pr_b4be47cf-6998-4b19-8116-f0a4aa4e137c_p2" x="13440.833" y="5381.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_09e8e673-beab-4263-98bf-7714cd2791a6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:15465827 BCL3 inhibits expression of IL1B. 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IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="6445.0" y="2575.0"/> <port id="pr_53cc4ead-9ccf-4258-a95a-91d1f630dbd7_p1" x="6450.0" y="2595.0"/> <port id="pr_53cc4ead-9ccf-4258-a95a-91d1f630dbd7_p2" x="6450.0" y="2565.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_121d8d34-dad5-402a-ab24-26e6fd13f698"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. 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expression of MHC II, CD40, CD86, CD80 and IFNGR. 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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:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="10825.0" y="2950.0"/> <port id="pr_066f321f-5456-479d-b005-6d7d2df5a3ff_p1" x="10815.0" y="2955.0"/> <port id="pr_066f321f-5456-479d-b005-6d7d2df5a3ff_p2" x="10845.0" y="2955.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1d1a9860-e409-482c-85f0-fcc5a123a988"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID: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 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="10940.0" y="2855.0"/> <port id="pr_1d1a9860-e409-482c-85f0-fcc5a123a988_p1" x="10960.0" y="2860.0"/> <port id="pr_1d1a9860-e409-482c-85f0-fcc5a123a988_p2" x="10930.0" y="2860.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_89e320ed-f2d8-48fd-8cba-fd37b32d6a8a"> <bbox w="10.0" h="10.0" x="15150.0" y="1370.0"/> <port id="pr_89e320ed-f2d8-48fd-8cba-fd37b32d6a8a_p1" x="15140.0" y="1375.0"/> <port id="pr_89e320ed-f2d8-48fd-8cba-fd37b32d6a8a_p2" x="15170.0" y="1375.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_14b84909-8ae4-4554-ba4b-092b53457f4b"> <bbox w="10.0" h="10.0" x="15150.0" y="1415.0"/> <port id="pr_14b84909-8ae4-4554-ba4b-092b53457f4b_p1" x="15140.0" y="1420.0"/> <port id="pr_14b84909-8ae4-4554-ba4b-092b53457f4b_p2" x="15170.0" y="1420.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1395aaf0-52b8-4c2c-8a84-e7fa899f2e46"> <bbox w="10.0" h="10.0" x="15424.8125" y="1443.3958"/> <port id="pr_1395aaf0-52b8-4c2c-8a84-e7fa899f2e46_p1" x="15414.8125" y="1448.3958"/> <port id="pr_1395aaf0-52b8-4c2c-8a84-e7fa899f2e46_p2" x="15444.8125" y="1448.3958"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b594402d-c12f-4d5f-8db2-e129cdf82389"> <bbox w="10.0" h="10.0" x="15762.375" y="1662.3967"/> <port id="pr_b594402d-c12f-4d5f-8db2-e129cdf82389_p1" x="15767.375" y="1682.3967"/> <port id="pr_b594402d-c12f-4d5f-8db2-e129cdf82389_p2" x="15767.375" y="1652.3967"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c0166fb4-e6e9-45a9-8c85-79ccb3c04711"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:11964313, PMID:11672593, PMID:12811837. INFG upregulates mRNA level and surface expression of TLR4 and TLR2. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15110.0" y="2025.0"/> <port id="pr_c0166fb4-e6e9-45a9-8c85-79ccb3c04711_p1" x="15115.0" y="2045.0"/> <port id="pr_c0166fb4-e6e9-45a9-8c85-79ccb3c04711_p2" x="15115.0" y="2015.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_612488bc-6fd9-4987-a785-59d84dc8b26b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16267105 Exposure of macrofages to HMGB1 resulted in rapid decreases in protein level of both TLR2 and TLR4 receptors. PMID:11672593 CSF1 up-regulates both TLR2 and TLR4 surface expression References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15092.895" y="1713.75"/> <port id="pr_612488bc-6fd9-4987-a785-59d84dc8b26b_p1" x="15097.895" y="1733.75"/> <port id="pr_612488bc-6fd9-4987-a785-59d84dc8b26b_p2" x="15097.895" y="1703.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_95537c50-da3d-4aad-a8d4-b8527fc00701"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:11964313, PMID:11672593, PMID:12032143, PMID:12811837. INFG upregulates mRNA level and surface expression of TLR4 and TLR2. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15220.0" y="2015.0"/> <port id="pr_95537c50-da3d-4aad-a8d4-b8527fc00701_p1" x="15225.0" y="2035.0"/> <port id="pr_95537c50-da3d-4aad-a8d4-b8527fc00701_p2" x="15225.0" y="2005.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d14e7cc9-b938-4c7b-b539-9939a2ad328c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12803886 MIF upregulates membrane expression of TLR4 PMID:16267105 Exposure of macrofages to HMGB1 resulted in rapid decreases in protein level of both TLR2 and TLR4 receptors. PMID:11672593 CSF1 up-regulates both TLR2 and TLR4 surface expression References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15148.928" y="1663.75"/> <port id="pr_d14e7cc9-b938-4c7b-b539-9939a2ad328c_p1" x="15153.928" y="1683.75"/> <port id="pr_d14e7cc9-b938-4c7b-b539-9939a2ad328c_p2" x="15153.928" y="1653.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6c83a699-933d-45c5-b9b4-94d97440a69e"> <bbox w="10.0" h="10.0" x="16635.0" y="2984.0"/> <port id="pr_6c83a699-933d-45c5-b9b4-94d97440a69e_p1" x="16640.0" y="3004.0"/> <port id="pr_6c83a699-933d-45c5-b9b4-94d97440a69e_p2" x="16640.0" y="2974.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_1cc3ce8f-c2f8-40b9-a9cf-c545524ace75"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14647.5" y="3251.3638"/> <port id="pr_1cc3ce8f-c2f8-40b9-a9cf-c545524ace75_p1" x="14667.5" y="3256.3638"/> <port id="pr_1cc3ce8f-c2f8-40b9-a9cf-c545524ace75_p2" x="14637.5" y="3256.3638"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5337362d-58dc-4b8a-8fd9-cce58de1bb67"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:19879327 Probably STAT1 is acetylated by CBP at the lysine residues K410 and K413. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14552.205" y="3190.0"/> <port id="pr_5337362d-58dc-4b8a-8fd9-cce58de1bb67_p1" x="14557.205" y="3210.0"/> <port id="pr_5337362d-58dc-4b8a-8fd9-cce58de1bb67_p2" x="14557.205" y="3180.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_605ac4b4-9849-45e4-a54a-e65b0f6af927"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:19833085, PMID:15699106, PMID:12138178, PMID:12270932 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. PMID:19833085 Probably, acetylation of STAT1 on lysine residues 410 and 413 in the nucleus results in enhanced interaction with TCP45 (PTPN2) and increased dephosphorylation References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14635.0" y="3115.0"/> <port id="pr_605ac4b4-9849-45e4-a54a-e65b0f6af927_p1" x="14625.0" y="3120.0"/> <port id="pr_605ac4b4-9849-45e4-a54a-e65b0f6af927_p2" x="14655.0" y="3120.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_04f9e116-0601-4ba5-afcd-70fec0ec5231"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17689680 HDACs provide STAT1 deacetylation and activation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14720.0" y="3170.0"/> <port id="pr_04f9e116-0601-4ba5-afcd-70fec0ec5231_p1" x="14725.0" y="3160.0"/> <port id="pr_04f9e116-0601-4ba5-afcd-70fec0ec5231_p2" x="14725.0" y="3190.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_46ef526c-a5ae-41a8-965f-0e31545faee1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17689680 HDACs provide STAT1 deacetylation and activation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14552.205" y="3190.0"/> <port id="pr_46ef526c-a5ae-41a8-965f-0e31545faee1_p1" x="14557.205" y="3180.0"/> <port id="pr_46ef526c-a5ae-41a8-965f-0e31545faee1_p2" x="14557.205" y="3210.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_484f97bc-3d0e-4494-9cf1-3a4bff1570f0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:19833085, PMID:15699106, PMID:15699106, PMID:15699106 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14647.5" y="3251.3638"/> <port id="pr_484f97bc-3d0e-4494-9cf1-3a4bff1570f0_p1" x="14637.5" y="3256.3638"/> <port id="pr_484f97bc-3d0e-4494-9cf1-3a4bff1570f0_p2" x="14667.5" y="3256.3638"/> </glyph> <glyph class="process" orientation="vertical" id="pr_551f493c-21dd-4cf6-93d8-469d92902919"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15320.0" y="2015.0"/> <port id="pr_551f493c-21dd-4cf6-93d8-469d92902919_p1" x="15325.0" y="2035.0"/> <port id="pr_551f493c-21dd-4cf6-93d8-469d92902919_p2" x="15325.0" y="2005.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_59951906-e3a4-4a91-92a8-794f0b33d2ab"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15420.0" y="2020.0"/> <port id="pr_59951906-e3a4-4a91-92a8-794f0b33d2ab_p1" x="15425.0" y="2040.0"/> <port id="pr_59951906-e3a4-4a91-92a8-794f0b33d2ab_p2" x="15425.0" y="2010.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_df1ef52c-05ba-4058-9bc4-3661b0f9e9c7"> <bbox w="10.0" h="10.0" x="15273.266" y="1746.25"/> <port id="pr_df1ef52c-05ba-4058-9bc4-3661b0f9e9c7_p1" x="15278.266" y="1766.25"/> <port id="pr_df1ef52c-05ba-4058-9bc4-3661b0f9e9c7_p2" x="15278.266" y="1736.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b7f8ed07-82f4-445f-8745-e75d198d586e"> <bbox w="10.0" h="10.0" x="15324.262" y="1771.25"/> <port id="pr_b7f8ed07-82f4-445f-8745-e75d198d586e_p1" x="15329.262" y="1791.25"/> <port id="pr_b7f8ed07-82f4-445f-8745-e75d198d586e_p2" x="15329.262" y="1761.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_59ac51a4-e62e-4b3b-b6c6-d4634262b407"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12433365 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. 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PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:21097505 IL13 induces SOCS1 expression. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15049.0" y="2580.0"/> <port id="pr_23f87dc0-0714-42f4-a47f-9c2a9a8e6596_p1" x="15054.0" y="2600.0"/> <port id="pr_23f87dc0-0714-42f4-a47f-9c2a9a8e6596_p2" x="15054.0" y="2570.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b438422f-5530-485b-b9ea-48d8111b3381"> <bbox w="10.0" h="10.0" x="15049.417" y="2493.75"/> <port id="pr_b438422f-5530-485b-b9ea-48d8111b3381_p1" x="15054.417" y="2513.75"/> <port id="pr_b438422f-5530-485b-b9ea-48d8111b3381_p2" x="15054.417" y="2483.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_73a0097b-ad23-4bb1-b359-b69a9a2259a2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12193701 INFG upregulates TNFR1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15382.5" y="3143.1099"/> <port id="pr_73a0097b-ad23-4bb1-b359-b69a9a2259a2_p1" x="15372.5" y="3148.1099"/> <port id="pr_73a0097b-ad23-4bb1-b359-b69a9a2259a2_p2" x="15402.5" y="3148.1099"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2744d997-a659-4da7-acb8-286c41cdeddf"> <bbox w="10.0" h="10.0" x="15857.5" y="3129.9072"/> <port id="pr_2744d997-a659-4da7-acb8-286c41cdeddf_p1" x="15847.5" y="3134.9072"/> <port id="pr_2744d997-a659-4da7-acb8-286c41cdeddf_p2" x="15877.5" y="3134.9072"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_eb6f7ad7-9a27-4dda-bd9c-13a68eeac0b3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12193701 INFG upregulates RIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="15375.0" y="3199.5835"/> <port id="pr_eb6f7ad7-9a27-4dda-bd9c-13a68eeac0b3_p1" x="15365.0" y="3204.5835"/> <port id="pr_eb6f7ad7-9a27-4dda-bd9c-13a68eeac0b3_p2" x="15395.0" y="3204.5835"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_e26fc067-408c-40bb-846c-de57c57ef852"> <bbox w="10.0" h="10.0" x="15712.5" y="3174.7222"/> <port id="pr_e26fc067-408c-40bb-846c-de57c57ef852_p1" x="15702.5" y="3179.7222"/> <port id="pr_e26fc067-408c-40bb-846c-de57c57ef852_p2" x="15732.5" y="3179.7222"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_56621431-746b-4c0b-8769-487384aba46d"> <bbox w="10.0" h="10.0" x="16081.75" y="3231.8853"/> <port id="pr_56621431-746b-4c0b-8769-487384aba46d_p1" x="16101.75" y="3236.8853"/> <port id="pr_56621431-746b-4c0b-8769-487384aba46d_p2" x="16071.75" y="3236.8853"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_ec8b55ad-2235-4a8a-a15d-829c7bdbf188"> <bbox w="10.0" h="10.0" x="16105.5" y="3463.4583"/> <port id="pr_ec8b55ad-2235-4a8a-a15d-829c7bdbf188_p1" x="16125.5" y="3468.4583"/> <port id="pr_ec8b55ad-2235-4a8a-a15d-829c7bdbf188_p2" x="16095.5" y="3468.4583"/> </glyph> <glyph class="process" orientation="vertical" id="pr_44b189e4-d662-46f6-b5cd-41e5f1c2a58e"> <bbox w="10.0" h="10.0" x="15380.0" y="3365.0"/> <port id="pr_44b189e4-d662-46f6-b5cd-41e5f1c2a58e_p1" x="15385.0" y="3385.0"/> <port id="pr_44b189e4-d662-46f6-b5cd-41e5f1c2a58e_p2" x="15385.0" y="3355.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_d2105151-e7d6-4c03-8c9f-6eaea72a3029"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14607933 TNF induces the association of STAT-1 and TNFR1 in a tyrosine phosphorylation-independent manner, and and this association attenuates TNF-alpha-mediated NF-kappaB activation but formation of the TNFR1:STAT-1α complex is inhibited upon inclusion of IFNG . 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="16175.0" y="3337.5"/> <port id="pr_39ff4ae5-89ee-4986-865e-08477eaa29a4_p1" x="16180.0" y="3327.5"/> <port id="pr_39ff4ae5-89ee-4986-865e-08477eaa29a4_p2" x="16180.0" y="3357.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_46cb4af9-1c5c-4f69-806b-2b9336c71980"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="10585.0" y="2855.0"/> <port id="pr_46cb4af9-1c5c-4f69-806b-2b9336c71980_p1" x="10575.0" y="2860.0"/> <port id="pr_46cb4af9-1c5c-4f69-806b-2b9336c71980_p2" x="10605.0" y="2860.0"/> </glyph> <glyph class="process" orientation="horizontal" 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<html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17404308 CSF1 induces acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="11742.768" y="3872.125"/> <port id="pr_c6fc1127-984d-4bc1-824b-90928dceee6a_p1" x="11747.768" y="3862.125"/> <port id="pr_c6fc1127-984d-4bc1-824b-90928dceee6a_p2" x="11747.768" y="3892.125"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6e6d5720-c8d0-455d-a03d-cae97e4a068e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2792.8125" y="4619.375"/> <port id="pr_6e6d5720-c8d0-455d-a03d-cae97e4a068e_p1" x="2797.8125" y="4609.375"/> <port id="pr_6e6d5720-c8d0-455d-a03d-cae97e4a068e_p2" x="2797.8125" y="4639.375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_966c90a6-bba2-442e-9fdf-e244790d98d5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 INFG signaling ingibits FOS expression References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2792.8125" y="4444.375"/> <port id="pr_966c90a6-bba2-442e-9fdf-e244790d98d5_p1" x="2797.8125" y="4434.375"/> <port id="pr_966c90a6-bba2-442e-9fdf-e244790d98d5_p2" x="2797.8125" y="4464.375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_90850fcf-951a-4a40-bab0-54ad42a90cd9"> <bbox w="10.0" h="10.0" x="2790.625" y="4534.375"/> <port id="pr_90850fcf-951a-4a40-bab0-54ad42a90cd9_p1" x="2795.625" y="4524.375"/> <port id="pr_90850fcf-951a-4a40-bab0-54ad42a90cd9_p2" x="2795.625" y="4554.375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7aaa4926-a038-4bd9-998b-008feb8c8220"> <bbox w="10.0" h="10.0" x="10817.5" y="4773.75"/> <port id="pr_7aaa4926-a038-4bd9-998b-008feb8c8220_p1" x="10822.5" y="4763.75"/> <port id="pr_7aaa4926-a038-4bd9-998b-008feb8c8220_p2" x="10822.5" y="4793.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2ba9d4be-4178-4f90-812a-8a141469ac04"> <bbox w="10.0" h="10.0" x="10968.875" y="4791.7764"/> <port id="pr_2ba9d4be-4178-4f90-812a-8a141469ac04_p1" x="10958.875" y="4796.7764"/> <port id="pr_2ba9d4be-4178-4f90-812a-8a141469ac04_p2" x="10988.875" y="4796.7764"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bc0642a0-3aa8-4377-9c99-1b49acab7f13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:15145317 The activated IKK complex, predominantly acting through IKKb in an IKKg-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. PMID:17485448 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1.. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="13242.5" y="3925.0"/> <port id="pr_bc0642a0-3aa8-4377-9c99-1b49acab7f13_p1" x="13247.5" y="3915.0"/> <port id="pr_bc0642a0-3aa8-4377-9c99-1b49acab7f13_p2" x="13247.5" y="3945.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_400862aa-7909-4a6c-bb64-0a803d08d605"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:15145317 The activated IKK complex catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="13058.25" y="4193.1704"/> <port id="pr_400862aa-7909-4a6c-bb64-0a803d08d605_p1" x="13078.25" y="4198.1704"/> <port id="pr_400862aa-7909-4a6c-bb64-0a803d08d605_p2" x="13048.25" y="4198.1704"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bc5eb3be-43ab-482a-bbb5-f079a270663d"> <bbox w="10.0" h="10.0" x="12978.736" y="3925.0"/> <port id="pr_bc5eb3be-43ab-482a-bbb5-f079a270663d_p1" x="12983.736" y="3915.0"/> <port id="pr_bc5eb3be-43ab-482a-bbb5-f079a270663d_p2" x="12983.736" y="3945.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f94a59e0-7406-4f64-af92-4619116a588e"> <bbox w="10.0" h="10.0" x="12752.529" y="3928.75"/> <port id="pr_f94a59e0-7406-4f64-af92-4619116a588e_p1" x="12757.529" y="3918.75"/> <port id="pr_f94a59e0-7406-4f64-af92-4619116a588e_p2" x="12757.529" y="3948.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bd6ffcf0-775e-4703-8372-3ba6cd9afb59"> <bbox w="10.0" h="10.0" x="12864.899" y="4211.75"/> <port id="pr_bd6ffcf0-775e-4703-8372-3ba6cd9afb59_p1" x="12869.899" y="4201.75"/> <port id="pr_bd6ffcf0-775e-4703-8372-3ba6cd9afb59_p2" x="12869.899" y="4231.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2c3ee24a-ed77-45e1-8d83-d71b661ae82c"> <bbox w="10.0" h="10.0" x="12696.344" y="4211.75"/> <port id="pr_2c3ee24a-ed77-45e1-8d83-d71b661ae82c_p1" x="12701.344" y="4201.75"/> <port id="pr_2c3ee24a-ed77-45e1-8d83-d71b661ae82c_p2" x="12701.344" y="4231.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1f579d7c-edf2-462f-8777-aaece049e8ab"> <bbox w="10.0" h="10.0" x="12596.762" y="4118.152"/> <port id="pr_1f579d7c-edf2-462f-8777-aaece049e8ab_p1" x="12601.762" y="4108.152"/> <port id="pr_1f579d7c-edf2-462f-8777-aaece049e8ab_p2" x="12601.762" y="4138.152"/> </glyph> <glyph class="process" orientation="vertical" id="pr_185a8de3-cbd2-42a6-bcf5-621c85990ecd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1. PMID:21232017, PMID:21133840, PMID:17301840 PMID:24958845, PMID:24699077 The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex downstream of TNF and upregulates IkBa degradetion. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="12083.0" y="3251.0"/> <port id="pr_184644bf-f2ff-4d3c-bc11-62c2a3a5227b_p1" x="12088.0" y="3241.0"/> <port id="pr_184644bf-f2ff-4d3c-bc11-62c2a3a5227b_p2" x="12088.0" y="3271.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b087f2b0-1e73-4823-8390-d0b0c010becc"> <bbox w="10.0" h="10.0" x="12081.697" y="3302.75"/> <port id="pr_b087f2b0-1e73-4823-8390-d0b0c010becc_p1" x="12086.697" y="3292.75"/> <port id="pr_b087f2b0-1e73-4823-8390-d0b0c010becc_p2" x="12086.697" y="3322.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8e29a3d6-ebdb-427c-aa62-c01afeb080f9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17485448 IL10‭ ‬upregulates expression of‭ ‬TNIP3 (ABIN3). 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This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="10620.0" y="3675.0"/> <port id="pr_8ec43dc8-762a-4ba1-b3ce-b0ac14c966dd_p1" x="10625.0" y="3665.0"/> <port id="pr_8ec43dc8-762a-4ba1-b3ce-b0ac14c966dd_p2" x="10625.0" y="3695.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_cf06e13b-13ad-4708-9387-eb83a8f2395a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:11875494 IL10-induced p38 phosphorylation. PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. PMID:10925299 IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation downstream of IL13. PMID:23508573 HMGB1 induces activation (phosphorylation) of p38 via TLR4. PMID:12811837, PMID:16713974 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. 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id="pr_688a3af6-4be4-4bfc-9357-e98eee5a3eec"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12. PMID:15465827 BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. BCL3 inhibits expression of TNF. PMID:11875494 HMOX1 (HO1) mediates IL-10-induced suppression of TNF production. PMID:16878026, PMID:14660645, PMID:15644117, PMID:10952726 Increased TNF expression downstream of HMGB1 is regulated via MYD88 and probably NFkB. PMID:10754326 Human TNF-alpha gene has binding sites for NF-kappa B. By transient transfection, NF-kappa B p65 and p50 synergistically activated the TNF-alpha promoter. Although both the kappa B1 and kappa B3 sites bound transcriptionally active NF-kappa B p50/p65 heterodimers, only the kappa B1 site contributed to down-regulation by NF-kappa B p50 homodimers. 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. CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. PMID:7594497 TGFB1 and IL10 dowregulate expression of TNF. PMID:23390297 MIF inhitits expression of M1 markers such as TNF. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="12791.25" y="5502.5"/> <port id="pr_688a3af6-4be4-4bfc-9357-e98eee5a3eec_p1" x="12796.25" y="5492.5"/> <port id="pr_688a3af6-4be4-4bfc-9357-e98eee5a3eec_p2" x="12796.25" y="5522.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0c2eab3d-cbc2-446b-98a7-8b0990959e72"> <bbox w="10.0" h="10.0" x="12785.738" y="5620.625"/> <port id="pr_0c2eab3d-cbc2-446b-98a7-8b0990959e72_p1" x="12790.738" y="5610.625"/> <port id="pr_0c2eab3d-cbc2-446b-98a7-8b0990959e72_p2" x="12790.738" y="5640.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8f65df43-c9f2-4fb5-9770-5e35335d8074"> <bbox w="10.0" h="10.0" x="3865.0" y="5615.0"/> <port id="pr_8f65df43-c9f2-4fb5-9770-5e35335d8074_p1" x="3870.0" y="5605.0"/> <port id="pr_8f65df43-c9f2-4fb5-9770-5e35335d8074_p2" x="3870.0" y="5635.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0919a111-8691-43e5-9f92-925d12efe601"> <bbox w="10.0" h="10.0" x="3865.0" y="5681.25"/> <port id="pr_0919a111-8691-43e5-9f92-925d12efe601_p1" x="3870.0" y="5671.25"/> <port id="pr_0919a111-8691-43e5-9f92-925d12efe601_p2" x="3870.0" y="5701.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_55b64b86-839a-4041-bc8e-f677bff65f6b"> <bbox w="10.0" h="10.0" x="2065.0" y="4715.0"/> <port id="pr_55b64b86-839a-4041-bc8e-f677bff65f6b_p1" x="2085.0" y="4720.0"/> <port id="pr_55b64b86-839a-4041-bc8e-f677bff65f6b_p2" x="2055.0" y="4720.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_717b7620-e768-4124-b10d-dc5cb601b3f1"> <bbox w="10.0" h="10.0" x="1926.75" y="565.625"/> <port id="pr_717b7620-e768-4124-b10d-dc5cb601b3f1_p1" x="1931.75" y="555.625"/> <port id="pr_717b7620-e768-4124-b10d-dc5cb601b3f1_p2" x="1931.75" y="585.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3d5795ac-cb9a-4e79-ba08-6c61ed39bc83"> <bbox w="10.0" h="10.0" x="1926.75" y="624.375"/> <port id="pr_3d5795ac-cb9a-4e79-ba08-6c61ed39bc83_p1" x="1931.75" y="614.375"/> <port id="pr_3d5795ac-cb9a-4e79-ba08-6c61ed39bc83_p2" x="1931.75" y="644.375"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9119c08f-76e7-4655-aaef-e3dfd0215bc6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. 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IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="14660.0" y="2555.0"/> <port id="pr_1222e300-a0c2-4290-a715-939230185252_p1" x="14665.0" y="2575.0"/> <port id="pr_1222e300-a0c2-4290-a715-939230185252_p2" x="14665.0" y="2545.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f75ce7d0-02b0-4a98-a8c4-d4d68c397077"> <bbox w="10.0" h="10.0" x="14660.0" y="2478.75"/> <port id="pr_f75ce7d0-02b0-4a98-a8c4-d4d68c397077_p1" x="14665.0" y="2498.75"/> <port id="pr_f75ce7d0-02b0-4a98-a8c4-d4d68c397077_p2" x="14665.0" y="2468.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_91f2c283-51cb-4b13-aed7-cfb96237ee21"> <bbox w="10.0" h="10.0" x="3615.2695" y="4454.125"/> <port id="pr_91f2c283-51cb-4b13-aed7-cfb96237ee21_p1" x="3620.2695" y="4444.125"/> <port id="pr_91f2c283-51cb-4b13-aed7-cfb96237ee21_p2" x="3620.2695" y="4474.125"/> </glyph> <glyph class="process" orientation="vertical" id="pr_11fe1e29-9aa6-436a-b88b-ed519a8733ea"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12907458, PMID:12907458 STAT3‭ ‬ directly‭ ‬up-regulates‭ ‬BCL3‭ ‬expression downstream of‭ ‬IL10. PMID:15465827 NFkB p50 is needfull for BCL3 expression. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="6338.5938" y="7106.44"/> <port id="pr_a1a0bd14-9703-4905-b5e6-cd347181d575_p1" x="6343.5938" y="7096.44"/> <port id="pr_a1a0bd14-9703-4905-b5e6-cd347181d575_p2" x="6343.5938" y="7126.44"/> </glyph> <glyph class="process" orientation="vertical" id="pr_99fb0be4-9df1-4afb-9d6e-27adf2e3e644"> <bbox w="10.0" h="10.0" x="6338.5938" y="7166.94"/> <port id="pr_99fb0be4-9df1-4afb-9d6e-27adf2e3e644_p1" x="6343.5938" y="7156.94"/> <port id="pr_99fb0be4-9df1-4afb-9d6e-27adf2e3e644_p2" x="6343.5938" y="7186.94"/> </glyph> <glyph class="process" orientation="vertical" id="pr_36e5989f-e055-4876-b4f7-c63130c87a3c"> <bbox w="10.0" h="10.0" x="6206.3184" y="7684.7188"/> <port id="pr_36e5989f-e055-4876-b4f7-c63130c87a3c_p1" x="6211.3184" y="7674.7188"/> <port id="pr_36e5989f-e055-4876-b4f7-c63130c87a3c_p2" x="6211.3184" y="7704.7188"/> </glyph> <glyph class="process" orientation="vertical" id="pr_528474e6-9778-47a1-9c76-71f93fe15289"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:23124025 IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6. IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2398.25" y="3702.0024"/> <port id="pr_528474e6-9778-47a1-9c76-71f93fe15289_p1" x="2403.25" y="3692.0024"/> <port id="pr_528474e6-9778-47a1-9c76-71f93fe15289_p2" x="2403.25" y="3722.0024"/> </glyph> <glyph class="process" orientation="vertical" id="pr_afa796b8-636c-44f5-bbaa-8ac9804b7e4c"> <bbox w="10.0" h="10.0" x="2400.002" y="3762.5024"/> <port id="pr_afa796b8-636c-44f5-bbaa-8ac9804b7e4c_p1" x="2405.002" y="3752.5024"/> <port id="pr_afa796b8-636c-44f5-bbaa-8ac9804b7e4c_p2" x="2405.002" y="3782.5024"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f68a1ba5-70e9-4094-b1f3-485839de5ae7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10432118 Linoleic acid is oxygenated by ALOX15 to 13-HODE which activates PPARG. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2604.75" y="3860.75"/> <port id="pr_f68a1ba5-70e9-4094-b1f3-485839de5ae7_p1" x="2609.75" y="3850.75"/> <port id="pr_f68a1ba5-70e9-4094-b1f3-485839de5ae7_p2" x="2609.75" y="3880.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6cf48583-14eb-4279-b4d9-021d28ac7d5d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10432118 Linoleic acid is oxygenated by ALOX15 to 13-HODE which activates PPARG. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2492.25" y="3821.5"/> <port id="pr_6cf48583-14eb-4279-b4d9-021d28ac7d5d_p1" x="2497.25" y="3811.5"/> <port id="pr_6cf48583-14eb-4279-b4d9-021d28ac7d5d_p2" x="2497.25" y="3841.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_999a887d-ffcf-4ce0-8eae-bdbb0d62c137"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10432118, PMID:21093321 IL4 upregulates expression of PPARG via JAK3/STAT6 pathway References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2607.25" y="3715.0"/> <port id="pr_999a887d-ffcf-4ce0-8eae-bdbb0d62c137_p1" x="2612.25" y="3705.0"/> <port id="pr_999a887d-ffcf-4ce0-8eae-bdbb0d62c137_p2" x="2612.25" y="3735.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_02c041a6-e851-48e8-a28c-5f94a1501e61"> <bbox w="10.0" h="10.0" x="2605.0122" y="3777.0"/> <port id="pr_02c041a6-e851-48e8-a28c-5f94a1501e61_p1" x="2610.0122" y="3767.0"/> <port id="pr_02c041a6-e851-48e8-a28c-5f94a1501e61_p2" x="2610.0122" y="3797.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6749e769-a5cd-479b-a6a0-ac10309fc4a6"> <bbox w="10.0" h="10.0" x="2689.25" y="3969.4287"/> <port id="pr_6749e769-a5cd-479b-a6a0-ac10309fc4a6_p1" x="2679.25" y="3974.4287"/> <port id="pr_6749e769-a5cd-479b-a6a0-ac10309fc4a6_p2" x="2709.25" y="3974.4287"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a8130eb4-7943-4a0a-b9eb-82f29eeacf10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:10432118 ALOX15 activation results in induction of CD36 expression downstream of IL4 and IL13 via PRARG CD36 gene expression is directly controlled by 15-LO expression/activity in IL-13-driven monocytes/macrophages PMID:17681149 STAT6 and PPARγ together upregulate CD36 transcription. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2565.0" y="4620.0"/> <port id="pr_15e284cc-0c1e-4caa-a533-6177309aed3f_p1" x="2570.0" y="4610.0"/> <port id="pr_15e284cc-0c1e-4caa-a533-6177309aed3f_p2" x="2570.0" y="4640.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6e2db37c-bb43-450b-b700-3743dbc678fe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2565.0" y="4815.0"/> <port id="pr_6e2db37c-bb43-450b-b700-3743dbc678fe_p1" x="2555.0" y="4820.0"/> <port id="pr_6e2db37c-bb43-450b-b700-3743dbc678fe_p2" x="2585.0" y="4820.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2b4255df-ea9d-4c84-998c-b532e63786d0"> <bbox w="10.0" h="10.0" x="2565.0" y="4686.25"/> <port id="pr_2b4255df-ea9d-4c84-998c-b532e63786d0_p1" x="2570.0" y="4676.25"/> <port id="pr_2b4255df-ea9d-4c84-998c-b532e63786d0_p2" x="2570.0" y="4706.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ce2dd063-d653-4b0e-a761-d80b2702fcf1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20580461, PMID:19567879 IL4 induces expression of IRF4 probably via STAT6/KDM6B ( Jmjd3) pathway. PMID:20729857 KDM6B ( Jmjd3) demethylates promoter region of IRF4 and upregulates its expression References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2895.0" y="4750.0"/> <port id="pr_ce2dd063-d653-4b0e-a761-d80b2702fcf1_p1" x="2900.0" y="4740.0"/> <port id="pr_ce2dd063-d653-4b0e-a761-d80b2702fcf1_p2" x="2900.0" y="4770.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_facfa292-f6f7-4d78-8863-5f8a68799c5a"> <bbox w="10.0" h="10.0" x="2895.0" y="4801.25"/> <port id="pr_facfa292-f6f7-4d78-8863-5f8a68799c5a_p1" x="2900.0" y="4791.25"/> <port id="pr_facfa292-f6f7-4d78-8863-5f8a68799c5a_p2" x="2900.0" y="4821.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7cb8453e-0a8f-4ec0-8f59-37ba8580f7ba"> <bbox w="10.0" h="10.0" x="3055.0" y="4892.5"/> <port id="pr_7cb8453e-0a8f-4ec0-8f59-37ba8580f7ba_p1" x="3060.0" y="4882.5"/> <port id="pr_7cb8453e-0a8f-4ec0-8f59-37ba8580f7ba_p2" x="3060.0" y="4912.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_541d11ee-e910-448c-b86d-ddd6102ffa2b"> <bbox w="10.0" h="10.0" x="5334.25" y="4737.759"/> <port id="pr_541d11ee-e910-448c-b86d-ddd6102ffa2b_p1" x="5354.25" y="4742.759"/> <port id="pr_541d11ee-e910-448c-b86d-ddd6102ffa2b_p2" x="5324.25" y="4742.759"/> </glyph> <glyph class="process" orientation="vertical" id="pr_23cdc040-2eb9-4910-b679-b6075f249c9a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4355.0" y="3490.0"/> <port id="pr_ff4c3f37-ef36-47ba-97d8-3956d8939454_p1" x="4360.0" y="3480.0"/> <port id="pr_ff4c3f37-ef36-47ba-97d8-3956d8939454_p2" x="4360.0" y="3510.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_f49a3ee8-1fda-4a3d-a692-118bfa3167cc"> <bbox w="10.0" h="10.0" x="4322.0" y="3668.65"/> <port id="pr_f49a3ee8-1fda-4a3d-a692-118bfa3167cc_p1" x="4312.0" y="3673.65"/> <port id="pr_f49a3ee8-1fda-4a3d-a692-118bfa3167cc_p2" x="4342.0" y="3673.65"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_592ccf9f-0ff7-4570-a7c5-9f51a0784155"> <bbox w="10.0" h="10.0" x="4530.5" y="3705.65"/> <port id="pr_592ccf9f-0ff7-4570-a7c5-9f51a0784155_p1" x="4520.5" y="3710.65"/> <port id="pr_592ccf9f-0ff7-4570-a7c5-9f51a0784155_p2" x="4550.5" y="3710.65"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e129858b-1541-45d5-a534-541a3efb0ff7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="10770.0" y="3965.0"/> <port id="pr_e129858b-1541-45d5-a534-541a3efb0ff7_p1" x="10775.0" y="3955.0"/> <port id="pr_e129858b-1541-45d5-a534-541a3efb0ff7_p2" x="10775.0" y="3985.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5a314051-db34-4435-9e81-f6a9245d0688"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="9625.0" y="4035.0"/> <port id="pr_5a314051-db34-4435-9e81-f6a9245d0688_p1" x="9630.0" y="4055.0"/> <port id="pr_5a314051-db34-4435-9e81-f6a9245d0688_p2" x="9630.0" y="4025.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f283d06c-839f-4a88-99f0-d4bc31391b16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. 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xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16327802 IL13 and TNF together (but neither IL-13 nor TNF alone) upregulates TGFB1 expression downstream of IL13RA2. IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. PMID:21372296 HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages via TLR4-dependent mechanisms. 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