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<bbox w="580.0" h="685.0" x="4050.0" y="700.0"/> </glyph> <glyph class="compartment" id="c15_ca15" compartmentRef="c2_ca2"> <label text="Lytic granule"> <bbox w="70.0" h="10.0" x="3638.5" y="6603.397"/> </label> <bbox w="880.0" h="360.0" x="3240.0" y="6280.0"/> </glyph> <glyph class="compartment" id="c16_ca16" compartmentRef="c2_ca2"> <label text="Endoplasmic Reticulum"> <bbox w="110.0" h="10.0" x="2675.5" y="3213.0078"/> </label> <bbox w="360.0" h="270.0" x="2570.0" y="2980.0"/> </glyph> <glyph class="macromolecule" id="s19_sa19" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL6 MODULE:TCR_SIGNALING PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="IL6"/> <bbox w="80.0" h="40.0" x="1890.0" y="5995.0"/> </glyph> <glyph class="macromolecule" id="s27_sa27" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:IL13 PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ</body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="1660.0" y="6170.0"/> </glyph> <glyph class="macromolecule" id="s34_sa865" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="140.0" h="90.0" x="2620.0" y="4570.0"/> <glyph class="unit of information" id="_c2c600ee-9775-4348-a024-d7aa7c918ef1"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2665.0" y="4565.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s35_sa974" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:FOXP3 PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:17449799 In mice, the enzyme is present on virtually all CD4(+)CD25(+) cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation. PMID: 16873067 NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25 Chromatin immunoprecipitation (ChIP) experiments confirmed that NFAT1 and FOXP3 could each occupy the Il2, Ctla4, and Cd25 promoters, both in T cells retrovirally transduced with FOXP3 and in “natural” CD4+CD25+ T regulatory cells that had been expanded with IL-2 PMID:12522256 Foxp3 is known to drive the expression of Treg-associated markers such as CD25, CTLA-4, and GITR PMID:17237765 Foxp3 occupancy and regulation of key target genes during T-cell stimulation</body> </html> </notes> <label text="FOXP3"/> <bbox w="80.0" h="40.0" x="960.0" y="1440.0"/> </glyph> <glyph class="macromolecule" id="s36_sa37" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 MODULE:TCR_SIGNALING HUGO:IL5 PMID:1825141; PMID:2965306 The stacks contact the plasma membrane (Stinchcombe et al., 2006), which would lead to very focused secretion of cytokines. Interleukin 2 (IL2), IL4, IL5, and interferon-g are all secreted in a polarized manner toward the target APC by T-helpers PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ</body> </html> </notes> <label text="IL5"/> <bbox w="80.0" h="40.0" x="1550.0" y="6170.0"/> </glyph> <glyph class="macromolecule" id="s41_sa822" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RELB CASCADE:TCR MODULE:TCR_SIGNALING PMID:21873235 Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. RelB inhibits expression of NF-κB gene targets (IL2) in T cells.</body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="40.0" x="3785.0" y="3950.0"/> </glyph> <glyph class="macromolecule" id="s3448_sa122" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: MODULE:SMAC 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:22437870;PMID:12810107 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 References_end</body> </html> </notes> <label text="CD86"/> <bbox w="80.0" h="40.0" x="2860.0" y="390.0"/> <glyph class="state variable" id="_dfae6344-d1b0-42b6-b562-ad721939fa16"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2855.0" y="405.0"/> </glyph> <glyph class="unit of information" id="_09578e12-310b-4bfb-8031-933b960f73f7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2877.5" y="385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3449_sa124" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS 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:22437870; PMID:12810107 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:18585785, PMID:17629517 human B7-1(CD80) can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. ligation of PD-L1 on T cells by B7-1 inhibits T cell responses in mouse T-cells References_end</body> </html> </notes> <label text="CD80"/> <bbox w="80.0" h="40.0" x="3620.0" y="400.0"/> <glyph class="unit of information" id="_88464a8d-58b3-41fd-a759-1469b2cb75bf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3637.5" y="395.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3436_sa131" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: MODULE:ACTIVATING_CHECKPOINTS 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:11964292, PMID:11698286, PMID: 11207245) PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II ) PMID:17317815 Engagement of CD40 by multimeric CD40L causes redistribution of CD40 to membrane lipid rafts and a conformational change that recruits adapter molecules known as TNF receptor (TNFR)–associated factors (TRAF) to at least two distinct binding sites on the CD40 cytoplasmic tail (67, 68). TRAFs then recruit TRAF-interacting kinases and together influence a number of well-characterized signal transduction pathways, including the nuclear factor-κB, p38/mitogen-activated protein kinase (MAPK), and c-Jun-NH2-kinase (JNK) pathways References_end</body> </html> </notes> <label text="CD40"/> <bbox w="80.0" h="40.0" x="5130.0" y="290.0"/> <glyph class="unit of information" id="_4b5b54e2-0220-4a27-86ba-1b10ca5fa890"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5147.5" y="285.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2081_sa137" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD40LG MODULE:ACTIVATING_CHECKPOINTS CASCADE:AR2A 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.. PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines PMID: 11343122 ICOS co-stimulation induces CD40L expression by T cells</body> </html> </notes> <label text="CD40LG"/> <bbox w="80.0" h="40.0" x="5100.0" y="650.0"/> </glyph> <glyph class="macromolecule" id="s2253_sa139" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFSF9 MODULE:ACTIVATING_CHECKPOINTS 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. PMID:9206996 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.</body> </html> </notes> <label text="TNFSF9"/> <bbox w="80.0" h="40.0" x="5850.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s3452_sa143" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD70 MODULE:ACTIVATING_CHECKPOINTS 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. PMID: 26098609 CD70 is exclusively expressed after immune activation. It is found on activated DCs [15–17,29,30], B cells [25], conventional- and regulatory T cells [15,24,25,31] and NK cells [27]. CD70 expression is highly regulated by antigen, since it is under control of PRRs, T cell and B cell antigen receptors and its expression is further tuned by cytokines such as IL-1α, IL-12, TNFα, prostaglandin E2 and by CD28- and CD40 co-stimulation</body> </html> </notes> <label text="CD70"/> <bbox w="80.0" h="40.0" x="5650.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s2249_sa144" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ICOSLG MODULE:ACTIVATING_CHECKPOINTS 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. PMID:20116985</body> </html> </notes> <label text="ICOSLG"/> <bbox w="80.0" h="40.0" x="5220.0" y="420.0"/> </glyph> <glyph class="complex" id="s2288_csa16" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>NAME:MHC_class_II*:Tumor_antigen_fragment MODULE:DC MODULE:CROSS_ACTIVATION_OF_IMMUNE_CELLS MODULE:ANTIGEN_PRESENTATION_AND_ACTIVATING_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION CASCADE:IL10</body> </html> </notes> <label text="MHC_class_II*:Tumor_antigen_fragment"/> <bbox w="120.0" h="140.0" x="3050.0" y="370.0"/> <glyph class="macromolecule" id="s65_sa158"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: MODULE:SMAC CASCADE:TCR 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="3070.0" y="440.0"/> <glyph class="state variable" id="_dc0f60b4-ab89-4074-8f12-a9826be1499a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3065.0" y="455.0"/> </glyph> <glyph class="unit of information" id="_fda37d9a-bc40-4259-beff-8b2497eea1c5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3087.5" y="435.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s66_sa159"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR PMID:8642276; PMID:24457417 Human tumor antigens could be recognized by T lymphocytes. 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)</body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="3070.0" y="390.0"/> <glyph class="unit of information" id="_c7ec8d1c-eea9-4c02-a964-bce6f696d44b"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3085.0" y="385.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s2372_csa18" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>NAME:MHC_class_I*:B2M:Tumor_antigen_fragment MODULE:DC MODULE:CROSS_ACTIVATION_OF_IMMUNE_CELLS MODULE:ANTIGEN_PRESENTATION_AND_ACTIVATING_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION</body> </html> </notes> <label text="MHC_class_I*:B2M:Tumor_antigen_fragment"/> <bbox w="230.0" h="135.0" x="3235.0" y="372.5"/> <glyph class="macromolecule" id="s2374_sa163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR PMID:8642276; PMID:24457417 Human tumor antigens could be recognized by T lymphocytes. 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)</body> </html> </notes> <label text="Tumor_antigen_fragment"/> <bbox w="80.0" h="40.0" x="3310.0" y="380.0"/> <glyph class="unit of information" id="_3ada6ca1-a796-4518-830f-3f8ae946aeab"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3325.0" y="375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2373_sa164"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:HLA-A HUGO:HLA-B HUGO:HLA-C HUGO:HLA-E HUGO:HLA-F HUGO:HLA-G HUGO:HLA-K HUGO:HLA-L MODULE:SMAC 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.</body> </html> </notes> <label text="MHC_class_I*"/> <bbox w="80.0" h="50.0" x="3255.0" y="427.5"/> <glyph class="unit of information" id="_99af9cbb-bc03-4710-98ff-a1d8739f5078"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3272.5" y="422.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s2375_sa165"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:B2M MODULE:SMAC CASCADE:TCR 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.</body> </html> </notes> <label text="B2M"/> <bbox w="80.0" h="40.0" x="3350.0" y="430.0"/> </glyph> </glyph> <glyph class="complex" id="s2281_csa19" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>NAME:CD40:CD40LG 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.</body> </html> </notes> <label text="CD40:CD40LG"/> <bbox w="100.0" h="130.0" x="4970.0" y="265.0"/> <glyph class="macromolecule" id="s2083_sa166"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: MODULE:ACTIVATING_CHECKPOINTS 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:11964292, PMID:11698286, PMID: 11207245) PMID:17513775 Probably via STAT1(demondrtated for CD40 and CD11c PMID:14764699, and for CD40, CD80, CD86, and MHC II ) PMID:17317815 Engagement of CD40 by multimeric CD40L causes redistribution of CD40 to membrane lipid rafts and a conformational change that recruits adapter molecules known as TNF receptor (TNFR)–associated factors (TRAF) to at least two distinct binding sites on the CD40 cytoplasmic tail (67, 68). TRAFs then recruit TRAF-interacting kinases and together influence a number of well-characterized signal transduction pathways, including the nuclear factor-κB, p38/mitogen-activated protein kinase (MAPK), and c-Jun-NH2-kinase (JNK) pathways References_end</body> </html> </notes> <label text="CD40"/> <bbox w="80.0" h="40.0" x="4980.0" y="275.0"/> <glyph class="unit of information" id="_b63919cf-179f-4f9d-86f3-7aa72e79d07c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4997.5" y="270.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2084_sa167"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD40LG MODULE:ACTIVATING_CHECKPOINTS CASCADE:AR2A 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.. PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines PMID: 11343122 ICOS co-stimulation induces CD40L expression by T cells</body> </html> </notes> <label text="CD40LG"/> <bbox w="80.0" h="40.0" x="4980.0" y="325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2247_sa168" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD274 MODULE:INHIBITING_CHECKPOINTS 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. PMID:18585785; PMID:17629517 human B7-1(CD80) can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. ligation of PD-L1 on T cells by B7-1 inhibits T cell responses in mouse T-cells</body> </html> </notes> <label text="PDL1*"/> <bbox w="80.0" h="40.0" x="1810.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s2248_sa169" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PDCD1LG2 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.</body> </html> </notes> <label text="PDL2*"/> <bbox w="80.0" h="40.0" x="1700.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s2251_sa170" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VTCN1 MODULE:INHIBITING_CHECKPOINTS CASCADE:B4H4 PMID:12818165; PMID:24657487 ; PMID:28325750 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. Receptor for this protein is uknown. B7-H4 expression in tumor tissues from breast, uterus, ovary, colon, and pancreas showed a statistically significant increase in percentage B7-H4 expressed and stage PMID:12818165 By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. It inhibits IL-2, IL-4, IL-10, and IFN-γ secretion from B7-1 costimulated T cells. B7-H4 Inhibits CD28 Costimulation PMID:12818166 the expression of JunB, a component of the AP-1 family induced after T cell activation, was reduced by 49% after B7S1 costimulation. On the other hand, there was little change in c-Jun expression (11% reduction) with B7S1-Ig treatment. JunB has been previously shown to bind to the IL-2 promoter (Boise et al., 1993 and JunB overexpression resulted in greater IL-2 production (our unpublished data). Since JunB is induced after T cell activation (Jain et al., 1995, the mechanism of which is unknown, B7S1 costimulation may result in inefficient JunB induction. PMID:12818166 B7S1(VTCN1) is expressed on professional APC and widely distributed in nonlymphoid tissues. A soluble B7S1-Ig fusion protein binds to activated but not naive T cells. B7S1-Ig inhibits T cell activation and IL-2 production. A monoclonal antibody that blocks binding of B7S1 to its receptor enhances T cell proliferation in vitro and exacerbates experimental autoimmune encephalomyelitis in vivo. PMID:29189263 high levels of B7-H4 expression are inversely correlated with tumor T-cell infiltration and with CD14-labeled macrophages in Ovarian Cancer PMID:28978159 high expression of B7-H4 is a negative correlation with the outcome of cancer patients. PMID:12796776 B7x (VTCN1)is a ligand, although not necessarily the only ligand, for BTLA (idirect data)</body> </html> </notes> <label text="B7H4*"/> <bbox w="80.0" h="40.0" x="1190.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s2252_sa173" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFRSF14 MODULE:INHIBITING_CHECKPOINTS MODULE:ACTIVATING_CHECKPOINTS PMID:18097025 HVEM is expressed in DCs. PMID:18193050 Binding of HVEM to BTLA or CD160 inhibited T cell activation. PMID:20038811 expression of HVEM by melanoma cells PMID:27192566 HVEM expressed in T cells binds to its ligands: LIGHT and LTα expressed on APC to modulate the proliferation and function of effector T cells via TRAF2 and TRAF3 PMID:19332782 The herpesvirus entry mediator (HVEM; TNFRSF14) activates NF-kappaB through the canonical TNF-related cytokine LIGHT, serving as a costimulatory pathway during activation of T cells. HVEM also functions as a ligand for the Ig superfamily members B and T lymphocyte attenuator (BTLA) and CD160, both of which limit inflammatory responses initiated by T cells.</body> </html> </notes> <label text="HVEM*"/> <bbox w="80.0" h="40.0" x="1330.0" y="380.0"/> <glyph class="unit of information" id="_06f763c7-dbda-4953-8452-fed213afb148"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1347.5" y="375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2640_sa174" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LGALS9 MODULE:INHIBITING_CHECKPOINTS 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 PMID:27192565 Tim-3 ligands include soluble ligands (galectin-9 and HMGB1) and cell surface ligands (Ceacam-1 and Phosphatidyl serine [PtdSer]). PMID:16286920 The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Galectin-9 induces TH1 cell death through Tim-3 Galectin-9 eliminates IFN-γ-producing TH1 cells</body> </html> </notes> <label text="LGALS9"/> <bbox w="80.0" h="40.0" x="960.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s69_sa820" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE CASCADE:TCR MODULE:TCR_SIGNALING PMID:12133805</body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="3590.0" y="3605.0"/> <glyph class="state variable" id="_4e42291f-c03c-4349-8355-92a939c3f177"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3585.0" y="3620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s71_sa26" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 MODULE:TCR_SIGNALING HUGO:IL4 PMID:11160275 T cell prolipheration is dependent on IL2 and IL4 IκBα(ΔN) inhibition of the NF-κB/Rel pathway impairs the competence of T cells to respond to IL-4 growth signaling. the inhibitory effects of IκBα(ΔN) on IL-4 signaling pathways include decreased expression of selected target genes such as c-myc, IL4RA and IL2RB PMID:11371360 GADD45B was also highly expressed in TH1 versus TH2 cells the expression of this gene is both upregulated by TCR signaling and IL-12 but repressed by IL-4. PMID:1825141; PMID:2965306 The stacks contact the plasma membrane (Stinchcombe et al., 2006), which would lead to very focused secretion of cytokines. Interleukin 2 (IL2), IL4, IL5, and interferon-g are all secreted in a polarized manner toward the target APC by T-helpers PMID:12818165 By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. It inhibits IL-2, IL-4, IL-10, and IFN-γ secretion from B7-1 costimulated T cells.</body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="1590.0" y="6370.0"/> </glyph> <glyph class="macromolecule" id="s75_sa186" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PDCD1 CASCADE:PD1 CASCADE:TCR PMID:27806234 REW PMID:22437870 PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM SHP-2 is recruited to the PD-1 cytoplasmic tail in absence of receptor ligation ITSM of PD-1 does not recruit SH2D1A PMID:23732914 PD-1 Increases PTEN Phosphatase Activity While Decreasing PTEN Protein Stability by Inhibiting Casein Kinase 2 PMID:28893624 Frequencies of PD-1+ TIGIT+ CD226− CD8+ T cells are increased in AML patients and correlate with poor clinical prognosis. PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="PDCD1"/> <bbox w="80.0" h="50.0" x="1750.0" y="665.0"/> <glyph class="unit of information" id="_42563a79-f108-4914-9d3b-0d88fbcc6ee1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1767.5" y="660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s82_sa194" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 MODULE:INHIBITING_CHECKPOINTS HUGO:BTLA PMID:22437870, PMID:20007250 rew PMID: 12796776 BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation PMID:20038811 BTLA activation inhibits the function of human CD8+ cancer-specific T cells Regulation of proliferation and cytokine production of primary CD8+ T cells depending on BTLA expression and interaction with HVEM.</body> </html> </notes> <label text="BTLA"/> <bbox w="80.0" h="50.0" x="1050.0" y="655.0"/> <glyph class="unit of information" id="_412debb2-3c7e-4476-8171-7f40f949d44a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1067.5" y="650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s84_sa196" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD160 PMID:22437870, PMID:20007250 REW</body> </html> </notes> <label text="CD160"/> <clone/> <bbox w="80.0" h="50.0" x="1210.0" y="665.0"/> <glyph class="unit of information" id="_69ac2a66-1658-4649-9bd9-8bf668249201"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1227.5" y="660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s84_sa197" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD160 PMID:22437870, PMID:20007250 REW</body> </html> </notes> <label text="CD160"/> <clone/> <bbox w="80.0" h="50.0" x="1210.0" y="765.0"/> <glyph class="unit of information" id="_75c13f8c-c34b-4abd-ae76-23a4f21d7b8a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1227.5" y="760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s86_sa198" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 HUGO:LAG3 MODULE:INHIBITING_CHECKPOINTS PMID:22437870; PMID: 28900677 LAG3 was cloned over 20 years ago as a CD4 homologue100, but its function in the immune checkpoint was only defined in 2005 when it was shown to have a role in enhancing the function of TReg cells99,101. LAG3 also inhibits CD8+ effector T cell functions independently of its role on TReg cells The LAG-3 protein (CD223) is expressed on activated T and NK cells 1, 2 and binds to MHC class II molecules with a much higher avidity than CD4 3. On T cells, LAG-3 associates with the TCR/CD3 complex and, like CTLA-4, negatively regulates signal transduction http://www.jimmunol.org/content/198/1_Supplement/150.1 AG-3−/− OT.II cells demonstrated significantly increased basal respiration, spare respiratory capacity, and aerobic glycolysis, as compared to wildtype OT.IIs, indicating an enhanced metabolic profile. PMID:7589152, PMID:15586367; PMID:27192565 The LAG-3 protein (CD223) is expressed on activated T and NK cells 1, 2 and binds to MHC class II molecules with a much higher avidity than CD4 3. On T cells, LAG-3 associates with the TCR/CD3 complex and, like CTLA-4, negatively regulates signal transduction The signaling pathway downstream of Lag-3 responsible for these effects is still not clear. In fact, the cytoplasmic tail of Lag-3 is unique among all known immune receptors. The Lag- 3 cytoplasmic tail has three regions that are conserved between human and mouse. The ﬁrst region contains a serine-phosphorylation site, the second region contains a unique KIEELE motif, and the third region contains glutamic acid-proline (EP) repeats (Workman et al., 2002). Of these three regions, the KIEELE motif has been shown to be essential for the inhibitory function of Lag- 3 in effector CD4+ T cells (Workman et al., 2002); however, the intracellular proteins that bind to this motif have not been identi- ﬁed. Moreover, whether this motif is required for the effects of Lag-3 in Treg cells is not known.</body> </html> </notes> <label text="LAG3"/> <clone/> <bbox w="80.0" h="50.0" x="540.0" y="695.0"/> <glyph class="unit of information" id="_93ebeb06-1020-4bde-9b66-8f7a28a58582"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="557.5" y="690.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s86_sa1264" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 HUGO:LAG3 MODULE:INHIBITING_CHECKPOINTS PMID:22437870; PMID: 28900677 LAG3 was cloned over 20 years ago as a CD4 homologue100, but its function in the immune checkpoint was only defined in 2005 when it was shown to have a role in enhancing the function of TReg cells99,101. LAG3 also inhibits CD8+ effector T cell functions independently of its role on TReg cells The LAG-3 protein (CD223) is expressed on activated T and NK cells 1, 2 and binds to MHC class II molecules with a much higher avidity than CD4 3. On T cells, LAG-3 associates with the TCR/CD3 complex and, like CTLA-4, negatively regulates signal transduction http://www.jimmunol.org/content/198/1_Supplement/150.1 AG-3−/− OT.II cells demonstrated significantly increased basal respiration, spare respiratory capacity, and aerobic glycolysis, as compared to wildtype OT.IIs, indicating an enhanced metabolic profile. PMID:7589152, PMID:15586367; PMID:27192565 The LAG-3 protein (CD223) is expressed on activated T and NK cells 1, 2 and binds to MHC class II molecules with a much higher avidity than CD4 3. On T cells, LAG-3 associates with the TCR/CD3 complex and, like CTLA-4, negatively regulates signal transduction The signaling pathway downstream of Lag-3 responsible for these effects is still not clear. In fact, the cytoplasmic tail of Lag-3 is unique among all known immune receptors. The Lag- 3 cytoplasmic tail has three regions that are conserved between human and mouse. The ﬁrst region contains a serine-phosphorylation site, the second region contains a unique KIEELE motif, and the third region contains glutamic acid-proline (EP) repeats (Workman et al., 2002). Of these three regions, the KIEELE motif has been shown to be essential for the inhibitory function of Lag- 3 in effector CD4+ T cells (Workman et al., 2002); however, the intracellular proteins that bind to this motif have not been identi- ﬁed. Moreover, whether this motif is required for the effects of Lag-3 in Treg cells is not known.</body> </html> </notes> <label text="LAG3"/> <clone/> <bbox w="80.0" h="50.0" x="540.0" y="795.0"/> <glyph class="unit of information" id="_b80167c9-8930-4c53-a46d-5a3172f7c280"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="557.5" y="790.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s87_sa199" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS PMID:22406983 4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on several subsets of activated immune cells. Numerous studies of mouse and human T cells indicate that 4-1BB promotes cellular proliferation, survival, and cytokine production. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. PF-05082566 enhances IL-2 production by primary human T cells and expansion of antigen-specific CD8+ T cells in vitro. PMID:23758787 4-1BB - TRAF1, 2, 3</body> </html> </notes> <label text="TNFRSF9"/> <clone/> <bbox w="80.0" h="50.0" x="5840.0" y="685.0"/> <glyph class="unit of information" id="_4aae574f-8baf-4602-90ab-942122bf4466"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5857.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s87_sa200" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS PMID:22406983 4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on several subsets of activated immune cells. Numerous studies of mouse and human T cells indicate that 4-1BB promotes cellular proliferation, survival, and cytokine production. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. PF-05082566 enhances IL-2 production by primary human T cells and expansion of antigen-specific CD8+ T cells in vitro. PMID:23758787 4-1BB - TRAF1, 2, 3</body> </html> </notes> <label text="TNFRSF9"/> <clone/> <bbox w="80.0" h="50.0" x="5840.0" y="785.0"/> <glyph class="unit of information" id="_2e68d7f5-8b59-4dde-8455-ef4d7d1b1071"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5857.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s89_sa201" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:CD27 PMID: 26098609 In human, CD27 is exclusively expressed in the lymphoid lineage, in other words, by T, B and NK cells and their immediate precursors. Activated T cells proteolytically shed CD27 from the cell surface, thereby giving rise to circulating soluble CD27 that can serve as a diagnostic marker of T-cell activation [25]. Terminally differentiated effector CD8+ T cells loose CD27, while long-lived central memory cells retain it CD27 ligand CD70 was likewise shown to promote TCR/CD3-induced proliferation of naïve CD4+ and CD8+ human T cells and the generation of effector cells PMID:23758787 CD27 - TRAF2, 3, 5 PMID:18292513 Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells blocking CD27L not only increases FasL expression on CD4+ T cells but also increases antigen-specific CD8+ T cells sensitivity to Fas-mediated apoptosis. PMID:21048108 CD27 signaling upregulated expression of the antiapoptotic Bcl-2 family member Bcl-x(L).</body> </html> </notes> <label text="CD27"/> <clone/> <bbox w="80.0" h="50.0" x="5640.0" y="685.0"/> <glyph class="unit of information" id="_7bdf6192-928c-45dd-a706-a328373ca795"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5657.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s89_sa202" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:CD27 PMID: 26098609 In human, CD27 is exclusively expressed in the lymphoid lineage, in other words, by T, B and NK cells and their immediate precursors. Activated T cells proteolytically shed CD27 from the cell surface, thereby giving rise to circulating soluble CD27 that can serve as a diagnostic marker of T-cell activation [25]. Terminally differentiated effector CD8+ T cells loose CD27, while long-lived central memory cells retain it CD27 ligand CD70 was likewise shown to promote TCR/CD3-induced proliferation of naïve CD4+ and CD8+ human T cells and the generation of effector cells PMID:23758787 CD27 - TRAF2, 3, 5 PMID:18292513 Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells blocking CD27L not only increases FasL expression on CD4+ T cells but also increases antigen-specific CD8+ T cells sensitivity to Fas-mediated apoptosis. PMID:21048108 CD27 signaling upregulated expression of the antiapoptotic Bcl-2 family member Bcl-x(L).</body> </html> </notes> <label text="CD27"/> <clone/> <bbox w="80.0" h="50.0" x="5640.0" y="785.0"/> <glyph class="unit of information" id="_fd14b96a-b5f3-4184-8982-24852beb532a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5657.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s91_sa203" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFRSF4 MODULE:ACTIVATING_CHECKPOINTS PMID:22437870 OX40 PMID:23758787 OX40 - TRAF1, 2, 3, 5, 6 PMID:21074068 Signaling Through OX40 Enhances Antitumor Immunity</body> </html> </notes> <label text="TNFRSF4"/> <clone/> <bbox w="80.0" h="50.0" x="5540.0" y="685.0"/> <glyph class="unit of information" id="_f08658df-59ac-4dc4-9bda-a93f00e1aa58"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5557.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s91_sa205" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFRSF4 MODULE:ACTIVATING_CHECKPOINTS PMID:22437870 OX40 PMID:23758787 OX40 - TRAF1, 2, 3, 5, 6 PMID:21074068 Signaling Through OX40 Enhances Antitumor Immunity</body> </html> </notes> <label text="TNFRSF4"/> <clone/> <bbox w="80.0" h="50.0" x="5540.0" y="785.0"/> <glyph class="unit of information" id="_21078366-6bed-453f-b08c-2d19850e87a5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5557.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s92_sa204" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:TNFSF4 PMID:22437870 OX40L 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.</body> </html> </notes> <label text="TNFSF4"/> <bbox w="80.0" h="40.0" x="5550.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s106_sa218" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD200 PMID:17442942 CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy.</body> </html> </notes> <label text="CD200"/> <bbox w="80.0" h="40.0" x="1440.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s109_sa221" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:NECTIN2 PMID:22285893 CD112 PMID:12913096 Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule (NK model). PMID:19098271 The ligands which are able to trigger CD226-mediated cytotoxicity are two necl and nectin ligands which are CD155 (necl-5) and CD112 (PVRL2, nectin-2), respectively . These ligands have frequently been found to be upregulated on tumour cells. Interestingly, expression of CD155 and CD112 is reportedly regulated through the DNA damage response pathway in response to chemotherapy (NK model). PMID:26755705 CD112 is the ligand for CD112R CD112R, Identification of CD112R as a novel checkpoint for human T cells DCs and the majority of human cancer lines express a putative ligand for CD112R</body> </html> </notes> <label text="NECTIN2"/> <bbox w="80.0" h="40.0" x="470.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s110_sa222" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 MODULE:INHIBITING_CHECKPOINTS PMID:26755705 CD112R, Identification of CD112R as a novel checkpoint for human T cells Signal through CD112R inhibits TCR-mediated signal SHIP was strongly associated with CD112R in untreated Molt4 cells, and pervanadate treatment further increased this interaction (Fig. 2 J). SHP-1 and SHP-2 weakly associated with CD112R in untreated Molt4 cells, but these associations were enhanced greatly upon pervanadate treatment when CD112R was used as a competitor, the CD112–CD226 interaction was significantly inhibited even in a relatively low concentration. Thus, our competition studies indicate that CD112R and CD226 share a common binding site on CD112. CD112 interacts with CD112R to suppress T cell response the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ</body> </html> </notes> <label text="PVRIG"/> <bbox w="80.0" h="50.0" x="350.0" y="710.0"/> <glyph class="state variable" id="_588197be-73f6-4201-a34f-19034d8cb476"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="345.0" y="730.0"/> </glyph> <glyph class="unit of information" id="_9c1afa07-e155-4524-ad67-5b4b59e99fa1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="367.5" y="705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s112_sa224" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TREG CELL:TCD4 HUGO:TIGIT MODULE:INHIBITING_CHECKPOINTS PMID:22285893 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells CD226 and CRTAM promote NK and CD8 T cell function, where as TIGIT has an inhibitory function. PMID:25866972 TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand–expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8+ T cells and CD8+ TILs. PD-1 blockade increases TIGIT expression by NY-ESO-1–specific CD8+ T cells. PMID:27620276 TIGIT is highly upregulated on both CD8+ T cells and regulatory T cells (Treg) in many clinical tumor settings TIGIT blockade has been shown to enhance T-cell function in particular, in combination with other checkpoints such as PD-1 (12), PD-L1 (21, 22), and TIM-3 (23). Although CD155 is considered the dominant ligand for CD226 and TIGIT, CD226 can also interact with CD112 (24), and TIGIT can interact with CD112 and CD113 (25). PMID:26763253 T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. TIGIT+ CD8+ T cells had significantly lower intracellular TNFα, IFNγ, and IL2 compared with TIGIT− CD8+ T cells TIGIT+ CD8+ T cells exhibited significantly higher levels of ki67 expression compared with TIGIT− CD8+ T cells (Supplementary Fig. S2A). Consistently, TIGIT+ CD8+ T cells showed an increased proliferation index in the CFSE assay (Supplementary Fig. S2B). In addition, perforin staining was elevated on TIGIT+ CD8+ T cells (Supplementary Fig. S2C), indicating a stronger killing potential. Thus TIGIT+ CD8+ T cells are functional impaired to some degree by displaying low capacity of cytokine production and high susceptibility to apoptosis, but retaining their capacity for proliferation and potential to kill. PMID:22427644 TIGIT can exert inhibitory regulation by competing with its costimulatory counterpart, CD226, for their common ligand CD155 PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ PMID:28893624 Frequencies of PD-1+ TIGIT+ CD226− CD8+ T cells are increased in AML patients and correlate with poor clinical prognosis.</body> </html> </notes> <label text="TIGIT"/> <clone/> <bbox w="80.0" h="50.0" x="220.0" y="710.0"/> <glyph class="unit of information" id="_4fd5aa3f-8de0-42db-abff-8a0017d84f57"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="237.5" y="705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s112_sa225" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TREG CELL:TCD4 HUGO:TIGIT MODULE:INHIBITING_CHECKPOINTS PMID:22285893 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells CD226 and CRTAM promote NK and CD8 T cell function, where as TIGIT has an inhibitory function. PMID:25866972 TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand–expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8+ T cells and CD8+ TILs. PD-1 blockade increases TIGIT expression by NY-ESO-1–specific CD8+ T cells. PMID:27620276 TIGIT is highly upregulated on both CD8+ T cells and regulatory T cells (Treg) in many clinical tumor settings TIGIT blockade has been shown to enhance T-cell function in particular, in combination with other checkpoints such as PD-1 (12), PD-L1 (21, 22), and TIM-3 (23). Although CD155 is considered the dominant ligand for CD226 and TIGIT, CD226 can also interact with CD112 (24), and TIGIT can interact with CD112 and CD113 (25). PMID:26763253 T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. TIGIT+ CD8+ T cells had significantly lower intracellular TNFα, IFNγ, and IL2 compared with TIGIT− CD8+ T cells TIGIT+ CD8+ T cells exhibited significantly higher levels of ki67 expression compared with TIGIT− CD8+ T cells (Supplementary Fig. S2A). Consistently, TIGIT+ CD8+ T cells showed an increased proliferation index in the CFSE assay (Supplementary Fig. S2B). In addition, perforin staining was elevated on TIGIT+ CD8+ T cells (Supplementary Fig. S2C), indicating a stronger killing potential. Thus TIGIT+ CD8+ T cells are functional impaired to some degree by displaying low capacity of cytokine production and high susceptibility to apoptosis, but retaining their capacity for proliferation and potential to kill. PMID:22427644 TIGIT can exert inhibitory regulation by competing with its costimulatory counterpart, CD226, for their common ligand CD155 PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ PMID:28893624 Frequencies of PD-1+ TIGIT+ CD226− CD8+ T cells are increased in AML patients and correlate with poor clinical prognosis.</body> </html> </notes> <label text="TIGIT"/> <clone/> <bbox w="80.0" h="50.0" x="220.0" y="810.0"/> <glyph class="unit of information" id="_c8447370-dada-40ad-be3a-3a7c433a3b17"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="237.5" y="805.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s119_sa226" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 HUGO:CD96 MODULE:INHIBITING_CHECKPOINTS PMID:22285893; PMID:1313846 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells http://www.ejcancer.com/article/S0959-8049(16)61670-2/abstract Combined inhibition of PD1 and CD96 checkpoints improves survival in a resectable murine model of pancreatic cancer PMID:17971293 The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1 PMID:24658051 CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. CD96 competed with CD226 for ligand binding and dampened the production of IFN-γ by NK cells in vitro and in vivo through direct inhibition. PMID:27620276 CD96 has been shown to be highly expressed in acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL; ref. 29) and myelodysplastic syndromes (33). CD96 has additionally been proposed as a cancer stem cell marker in leukemia PMID:26787820 Treatment with Anti-CD96 mAb Protects against Experimental Lung Metastases NK cells, but not T cells, were critical for the antimetastatic effect</body> </html> </notes> <label text="CD96"/> <clone/> <bbox w="80.0" h="50.0" x="90.0" y="710.0"/> <glyph class="unit of information" id="_81d0258c-5a43-4d74-b34b-2d6c6e543aaa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="107.5" y="705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s119_sa229" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 HUGO:CD96 MODULE:INHIBITING_CHECKPOINTS PMID:22285893; PMID:1313846 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells http://www.ejcancer.com/article/S0959-8049(16)61670-2/abstract Combined inhibition of PD1 and CD96 checkpoints improves survival in a resectable murine model of pancreatic cancer PMID:17971293 The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1 PMID:24658051 CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. CD96 competed with CD226 for ligand binding and dampened the production of IFN-γ by NK cells in vitro and in vivo through direct inhibition. PMID:27620276 CD96 has been shown to be highly expressed in acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL; ref. 29) and myelodysplastic syndromes (33). CD96 has additionally been proposed as a cancer stem cell marker in leukemia PMID:26787820 Treatment with Anti-CD96 mAb Protects against Experimental Lung Metastases NK cells, but not T cells, were critical for the antimetastatic effect</body> </html> </notes> <label text="CD96"/> <clone/> <bbox w="80.0" h="50.0" x="90.0" y="810.0"/> <glyph class="unit of information" id="_1602bce6-0b16-4ac7-b2c8-c535893cdb8f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="107.5" y="805.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s120_sa230" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PVR PMID:22285893 PMID:12913096 Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule(NK model). PMID:19098271 The ligands which are able to trigger CD226-mediated cytotoxicity are two necl and nectin ligands which are CD155 (necl-5) and CD112 (PVRL2, nectin-2), respectively . These ligands have frequently been found to be upregulated on tumour cells. Interestingly, expression of CD155 and CD112 is reportedly regulated through the DNA damage response pathway in response to chemotherapy (NK model).</body> </html> </notes> <label text="PVR"/> <bbox w="80.0" h="40.0" x="140.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s121_sa231" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFSF18 MODULE:ACTIVATING_CHECKPOINTS PMID:22029729 Glucocorticoid-induced TNFR-related (gitr) is a gene coding for a member of the TNF receptor superfamily. GITR activation by its ligand (GITRL) influences the activity of effector and regulatory T cells, thus participating in the development of immune response against tumours and infectious agents, as well as in autoimmune and inflammatory diseases.</body> </html> </notes> <label text="TNFSF18"/> <bbox w="80.0" h="40.0" x="5740.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s122_sa232" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS PMID:16651447 Agonist Anti-GITR Antibody Enhances Vaccine-Induced CD8+ T-Cell Responses and Tumor Immunity in mouse model PMID:24484736 In Tregs, Foxp3 modulates GITR expression: ectopic expression of Foxp3 in initially GITRlo CD4+CD25− cells confers both suppressive activity and high-level GITR expression [17]. In conventional T cells, GITR is reciprocally regulated by classical nuclear factor κB (NF-κB; RelA most critical, but cRel and p50 are also important) and nuclear factor of activated T cells (NFAT), with NF-κB inducing and NFAT repressing GITR expression downstream of TCR signals GITR positively modulates Erk, JNK and p38 mitogen activated protein kinase (MAPK) as well as NF-κB signaling [24,25] to augment cell survival and cytokine production GITR recruits signaling adaptors, TNFR associated factors (TRAFs), of which there are six in mammals, TRAF1-6 (reviewed in [26]). TRAFs 2 and 5 are required downstream of GITR for maximal activation of the MAPK and canonical NF-κB pathways and up-regulation of the anti-apoptotic molecule Bcl-xL PMID:23758787 GITR - TRAF1, 2, 3, 4, 5 PMID:27591414 Rationale for anti-GITR cancer immunotherapy In syngeneic mouse tumour models, GITR modulation shows compelling antitumour activity which is attributed to both its costimulatory role on CD4+ and CD8+ T cells as well as inhibition or depletion of intratumoural Tregs</body> </html> </notes> <label text="TNFRSF18"/> <clone/> <bbox w="80.0" h="50.0" x="5730.0" y="685.0"/> <glyph class="unit of information" id="_ed608fa6-5682-4272-a159-5d8957458187"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5747.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s122_sa233" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS PMID:16651447 Agonist Anti-GITR Antibody Enhances Vaccine-Induced CD8+ T-Cell Responses and Tumor Immunity in mouse model PMID:24484736 In Tregs, Foxp3 modulates GITR expression: ectopic expression of Foxp3 in initially GITRlo CD4+CD25− cells confers both suppressive activity and high-level GITR expression [17]. In conventional T cells, GITR is reciprocally regulated by classical nuclear factor κB (NF-κB; RelA most critical, but cRel and p50 are also important) and nuclear factor of activated T cells (NFAT), with NF-κB inducing and NFAT repressing GITR expression downstream of TCR signals GITR positively modulates Erk, JNK and p38 mitogen activated protein kinase (MAPK) as well as NF-κB signaling [24,25] to augment cell survival and cytokine production GITR recruits signaling adaptors, TNFR associated factors (TRAFs), of which there are six in mammals, TRAF1-6 (reviewed in [26]). TRAFs 2 and 5 are required downstream of GITR for maximal activation of the MAPK and canonical NF-κB pathways and up-regulation of the anti-apoptotic molecule Bcl-xL PMID:23758787 GITR - TRAF1, 2, 3, 4, 5 PMID:27591414 Rationale for anti-GITR cancer immunotherapy In syngeneic mouse tumour models, GITR modulation shows compelling antitumour activity which is attributed to both its costimulatory role on CD4+ and CD8+ T cells as well as inhibition or depletion of intratumoural Tregs</body> </html> </notes> <label text="TNFRSF18"/> <clone/> <bbox w="80.0" h="50.0" x="5731.0" y="785.0"/> <glyph class="unit of information" id="_940e0217-9ed9-4bdb-afa6-90feec281432"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5748.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s124_sa234" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:HHLA2 PMID:25869386; PMID:23784006 HHLA2 is a newly identified B7 family member that modulates T-cell functions through interaction with TMIGD2 and possibly a second receptor, with coinhibition in two studies and costimulation in one study. HHLA2 is expressed on a variety of human cancers, and its coinhibitory function makes it a candidate for cancer immunotherapy.</body> </html> </notes> <label text="HHLA2"/> <bbox w="80.0" h="40.0" x="5970.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s125_sa235" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TMIGD2 MODULE:ACTIVATING_CHECKPOINTS PMID:25869386; PMID:23784006 Concomitant with T cell receptor (TCR) signaling, TMIGD2 on naïve T cells interacts with HHLA2 on APCs and costimulates T cell proliferation and cytokine production via a pathway involving AKT phosphorylation.</body> </html> </notes> <label text="TMIGD2"/> <clone/> <bbox w="80.0" h="50.0" x="5970.0" y="685.0"/> <glyph class="unit of information" id="_121f04f4-bad4-466f-94d7-7d6429c26062"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5987.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s125_sa236" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TMIGD2 MODULE:ACTIVATING_CHECKPOINTS PMID:25869386; PMID:23784006 Concomitant with T cell receptor (TCR) signaling, TMIGD2 on naïve T cells interacts with HHLA2 on APCs and costimulates T cell proliferation and cytokine production via a pathway involving AKT phosphorylation.</body> </html> </notes> <label text="TMIGD2"/> <clone/> <bbox w="80.0" h="50.0" x="5970.0" y="785.0"/> <glyph class="unit of information" id="_4782b9c4-9459-4bde-be76-d74504e4a17a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5987.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s127_sa237" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 HUGO:CD4 CASCADE:TCR PMID:3263576 CD4 and CD8 are cell-surface glycoproteins expressed on mutually exclusive subsets of peripheral T cells. T cells that express CD4 have T-cell antigen receptors that are specific for antigens presented by major histocompatibility complex class II molecules, whereas T cells that express CD8 have receptors specific for antigens presented by MHC class I molecules PMID:10398592 CD4 in immunological synapse</body> </html> </notes> <label text="CD4"/> <bbox w="80.0" h="50.0" x="2990.0" y="720.0"/> <glyph class="unit of information" id="_1be4919a-e203-47e8-b193-691f3ab187f6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3007.5" y="715.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s129_sa239" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD8A HUGO:CD8B CELL:TCD8 CASCADE:TCR PMID:3263576 CD4 and CD8 are cell-surface glycoproteins expressed on mutually exclusive subsets of peripheral T cells. T cells that express CD4 have T-cell antigen receptors that are specific for antigens presented by major histocompatibility complex class II molecules, whereas T cells that express CD8 have receptors specific for antigens presented by MHC class I molecules</body> </html> </notes> <label text="CD8*"/> <bbox w="80.0" h="50.0" x="3670.0" y="725.0"/> <glyph class="unit of information" id="_8822091e-17fb-4eb4-bc79-d33c90efd19a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3687.5" y="720.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s133_sa294" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 HUGO:IL2 MODULE:TCR_SIGNALING CASCADE:AR2A CASCADE:TCR PMID:1825141; PMID:2965306 The stacks contact the plasma membrane (Stinchcombe et al., 2006), which would lead to very focused secretion of cytokines. Interleukin 2 (IL2), IL4, IL5, and interferon-g are all secreted in a polarized manner toward the target APC by T-helpers PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ PMID:18758473 A2A receptor activation inhibits IL2 secretion48 by naive CD4+ T cells thereby reducing their proliferation49 following T-cell receptor stimulation. PMID: 12796776 BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation</body> </html> </notes> <label text="IL2"/> <bbox w="210.0" h="140.0" x="2465.0" y="6110.0"/> </glyph> <glyph class="phenotype" id="s4348_sa244"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:12360211 T cell prolipheration is dependent on NFkB signaling. T cells from transgenic mice that express IBM (a mutant IB that cannot be degradaded) under the control of a T-cell-specific promoter have markedly impaired proliferative responses T cells that express IBM cannot activate signal transducer and activator of transcription 5a (STAT5a), a transcription factor that is required for T-cell proliferation induced by IL-2 and IL-4 (Ref. 76). In addition, the development of CD8+ T-cell responses requires p65 (Ref. 77). Similarly, inhibitors of NF-B activation have been shown to block the maturation of dendritic cells74. The expression of B7-H, a new co-stimulatory homologue of B7-1 (CD80) and B7-2 (CD86), also requires NF-B.</body> </html> </notes> <label text="Tcell_prolipheration"/> <bbox w="340.0" h="155.0" x="1830.0" y="6892.5"/> </glyph> <glyph class="complex" id="s4356_csa21" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:21059766 TCR (T cell receptor) is a cell-surface heterodimer that recognizes antigen peptides bound to major histocompatibility complex proteins (pMHCs) on antigen-presenting cells (APCs). TCR heterodimers associate constitutively with multiple CD3 proteins [γ, δ, ε and ζ] in the T cell membrane for signal transduction. The term ‘TCR’ is sometimes applied to this larger complex. All CD3 subunits in the complex contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domains, whose phosphorylation leads to signaling downstream of TCR triggering The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:23886063 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta</body> </html> </notes> <label text="s4356"/> <bbox w="115.0" h="187.5" x="3352.5" y="751.25"/> <glyph class="macromolecule" id="s5065_sa248"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD247 CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is lolalized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:11353765 Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="3370.0" y="820.0"/> <glyph class="state variable" id="_328605fa-f14b-4026-af09-d7c59f3d13a4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3445.0" y="841.46893"/> </glyph> <glyph class="state variable" id="_77e2f7ad-5532-4787-a964-6361c8aa3f63"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3365.0" y="840.0"/> </glyph> <glyph class="unit of information" id="_088d1ef9-e24a-43d7-848e-2578cfe5a075"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3387.5" y="815.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5066_sa606"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRA HUGO:TRB CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)].</body> </html> </notes> <label text="alpha_/beta_TCR*"/> <bbox w="80.0" h="50.0" x="3370.0" y="760.0"/> <glyph class="unit of information" id="_1f915886-4610-4eca-b3c2-f5deafec8034"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3387.5" y="755.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5067_sa752"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD3E HUGO:CD3G HUGO:CD3D CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse.</body> </html> </notes> <label text="CD3*"/> <bbox w="80.0" h="50.0" x="3370.0" y="870.0"/> <glyph class="state variable" id="_c61ed948-dcb2-4c68-825f-5cf7eaa0f7ad"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3365.0" y="890.0"/> </glyph> <glyph class="unit of information" id="_b2a1c3e4-4c88-436d-9741-2a6427894649"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3387.5" y="865.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4357_csa22" compartmentRef="c8_ca8"> <label text="s4357"/> <bbox w="100.0" h="120.0" x="3180.0" y="755.0"/> <glyph class="macromolecule" id="s4358_sa240"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 HUGO:CD4 CASCADE:TCR PMID:3263576 CD4 and CD8 are cell-surface glycoproteins expressed on mutually exclusive subsets of peripheral T cells. T cells that express CD4 have T-cell antigen receptors that are specific for antigens presented by major histocompatibility complex class II molecules, whereas T cells that express CD8 have receptors specific for antigens presented by MHC class I molecules PMID:10398592 CD4 in immunological synapse</body> </html> </notes> <label text="CD4"/> <bbox w="80.0" h="50.0" x="3190.0" y="760.0"/> <glyph class="unit of information" id="_e95263f6-ed1a-4706-b5b5-0ffd4614ecd4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3207.5" y="755.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5811_sa1006"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LCK CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508;PMID:21127503 Lck (lymphocyte-specific tyrosine-protein kinase) is a membrane-tethered kinase that phosphorylates tyrosine residues in the ITAMs in the TCR–CD3 complex. Doubly phosphorylated ITAMs are the docking sites for ZAP70 and other TCR signaling-associated proteins. Lck is often associated with the CD4 or CD8 co-receptors, which might potentiate its activity by bringing it into the proximity of the CD3 chains PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function</body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="3190.0" y="825.0"/> <glyph class="state variable" id="_969d54e5-dde1-4e6a-9505-05ffae9eb36e"> <state value="" variable="Y505"/> <bbox w="30.0" h="10.0" x="3175.0" y="825.4865"/> </glyph> <glyph class="state variable" id="_71a15a22-e57b-491c-8f08-d8db96532981"> <state value="P" variable="Y394"/> <bbox w="35.0" h="10.0" x="3252.5" y="859.638"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4360_csa23" compartmentRef="c8_ca8"> <label text="s4360"/> <bbox w="100.0" h="120.0" x="3530.0" y="755.0"/> <glyph class="macromolecule" id="s4361_sa241"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD8A HUGO:CD8B CELL:TCD8 CASCADE:TCR PMID:3263576 CD4 and CD8 are cell-surface glycoproteins expressed on mutually exclusive subsets of peripheral T cells. T cells that express CD4 have T-cell antigen receptors that are specific for antigens presented by major histocompatibility complex class II molecules, whereas T cells that express CD8 have receptors specific for antigens presented by MHC class I molecules</body> </html> </notes> <label text="CD8*"/> <bbox w="80.0" h="50.0" x="3540.0" y="770.0"/> <glyph class="unit of information" id="_836c8c95-86e3-4f0c-9c3a-0eb7d8e17645"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3557.5" y="765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5304_sa1007"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LCK CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508;PMID:21127503 Lck (lymphocyte-specific tyrosine-protein kinase) is a membrane-tethered kinase that phosphorylates tyrosine residues in the ITAMs in the TCR–CD3 complex. Doubly phosphorylated ITAMs are the docking sites for ZAP70 and other TCR signaling-associated proteins. Lck is often associated with the CD4 or CD8 co-receptors, which might potentiate its activity by bringing it into the proximity of the CD3 chains PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function</body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="3540.0" y="815.0"/> <glyph class="state variable" id="_4415ab06-c68f-4fc1-800f-b417abc43e00"> <state value="" variable="Y505"/> <bbox w="30.0" h="10.0" x="3525.0" y="815.4865"/> </glyph> <glyph class="state variable" id="_b724ee57-4bf4-47c7-a8fe-dfb25d1172b0"> <state value="P" variable="Y394"/> <bbox w="35.0" h="10.0" x="3602.5" y="849.638"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4407_sa297" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL22 MODULE:TCR_SIGNALING PMID:18329370 loss of Crtam resulted in decreased secretion of IFNg(a TH1-associated cytokine) as well as IL22 and IL17 (TH17-associated cytokines).</body> </html> </notes> <label text="IL22"/> <bbox w="80.0" h="40.0" x="1720.0" y="6370.0"/> </glyph> <glyph class="macromolecule" id="s4410_sa1002" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IFNG CELL:TCD4 CASCADE:TCR MODULE:TCR_SIGNALING CASCADE:AR2A MODULE:TH1 PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:1825141; PMID:2965306 The stacks contact the plasma membrane (Stinchcombe et al., 2006), which would lead to very focused secretion of cytokines. Interleukin 2 (IL2), IL4, IL5, and interferon-g are all secreted in a polarized manner toward the target APC by T-helpers PMID:24658051 CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. CD96 competed with CD226 for ligand binding and dampened the production of IFN-γ by NK cells in vitro and in vivo through direct inhibition. PMID:15811952 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM Stimulation of a human polyclonal T-cell line with PMA/ionomycin induced expression of CRTAM on CD8+ T cells after 4 hours of stimulation CRTAM expression on NK cells and CD8+ T cells is tightly regulated by NK cell–activating receptors and T-cell receptor (TCR) triggering, respectively. Necl-2–CRTAM interaction leads to strong IFN-γ secretion by CD8+ T cells. PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ PMID:16286920; PMID:20819927 Galectin-9 via TIM3 eliminates IFN-γ-producing TH1 cells PMID:12818165 By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. It inhibits IL-2, IL-4, IL-10, and IFN-γ secretion from B7-1 costimulated T cells. PMID:15634932 A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. PMID:20038811 IFNG as well as TNF secretion was reduced when melanoma cell lines expressed HVEM (Figure (Figure6,6, C and D). This inhibition correlated significantly with percentages of T cells expressing BTLA (Figure (Figure6E).6E).</body> </html> </notes> <label text="IFNG"/> <bbox w="80.0" h="40.0" x="2030.0" y="6370.0"/> </glyph> <glyph class="macromolecule" id="s4414_sa306" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS HUGO:TBX21 PMID:17440449 rew PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection.</body> </html> </notes> <label text="TBX21"/> <bbox w="80.0" h="40.0" x="700.0" y="1260.0"/> </glyph> <glyph class="macromolecule" id="s867_sa439" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRIP10 MODULE:TCR_SIGNALING 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. PMID:10713100 Cdc42-interacting protein 4 mediates binding of the Wiskott-Aldrich syndrome protein to microtubules. (COS7 model) PMID:15541654 Involvement of the Wiskott-Aldrich syndrome protein and other actin regulatory adaptors in T cell activation</body> </html> </notes> <label text="TRIP10"/> <bbox w="80.0" h="40.0" x="5000.0" y="5710.0"/> </glyph> <glyph class="macromolecule" id="s4213_sa1190" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PXN CASCADE:TCR MODULE:TCR_SIGNALING PMID:22043013 Paxillin associates with the microtubule cytoskeleton and the immunological synapse of CTL through its leucine-aspartic acid domains and contributes to microtubule organizing center reorientation. LFA-1 or CD3 engagement alone was insufficient for paxillin recruitment because there was no paxillin accumulation at the site of CTL contact with anti-LFA-1- or anti-CD3-coated beads. In contrast, paxillin accumulation was detected when beads coated with both anti-CD3 and anti-LFA-1 were bound to CTL, suggesting that signals from both the TCR and LFA-1 are required for paxillin accumulation. Paxillin was shown to be phosphorylated downstream of ERK, paxillin was demonstrated to be a direct target of ERK phosphorylation PMID:29021139 Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors</body> </html> </notes> <label text="PXN"/> <bbox w="80.0" h="40.0" x="4920.0" y="5355.0"/> <glyph class="state variable" id="_fdc52d47-e98b-49c0-baf5-3679e1806943"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4915.0" y="5370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1189_sa443" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL2 MODULE:TCR_SIGNALING PMID:21383498 IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.</body> </html> </notes> <label text="WASF2"/> <bbox w="80.0" h="40.0" x="5230.0" y="4975.0"/> <glyph class="state variable" id="_312c8f3f-b712-4017-ba2c-2d3978511086"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5225.0" y="4990.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1668_sa444" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL2 MODULE:TCR_SIGNALING PMID:21383498 IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.</body> </html> </notes> <label text="WASF2"/> <bbox w="80.0" h="40.0" x="5230.0" y="5065.0"/> <glyph class="state variable" id="_986fefac-ef58-49d1-9b5d-b23218386c80"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5222.5" y="5080.0"/> </glyph> </glyph> <glyph class="phenotype" id="s2418_sa454" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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. PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="Actin polymerization"/> <bbox w="160.0" h="35.0" x="5070.0" y="6497.5"/> </glyph> <glyph class="macromolecule" id="s865_sa455" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="4570.0" y="3735.0"/> <glyph class="state variable" id="_59782d54-907f-4216-8262-6c8b1c9c2490"> <state value="" variable="Tyr291"/> <bbox w="40.0" h="10.0" x="4550.0" y="3730.3296"/> </glyph> </glyph> <glyph class="macromolecule" id="s1705_sa457" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="4570.0" y="3855.0"/> <glyph class="state variable" id="_b9b72691-b221-45c3-a2ab-75178bc97aae"> <state value="P" variable="Tyr291"/> <bbox w="45.0" h="10.0" x="4547.5" y="3850.3296"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1168_sa462" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRF1 MODULE:TCR_SIGNALING PMID:19380804 Activated CD8+ T cells rapidly up-regulate perforin.</body> </html> </notes> <label text="PRF1"/> <bbox w="90.0" h="25.0" x="3865.0" y="6147.5"/> <glyph class="unit of information" id="_83b6dead-cdd9-4ac2-aa54-a45f6e8dd762"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3900.0" y="6142.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1119_sa463" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMB MODULE:TCR_SIGNALING 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..</body> </html> </notes> <label text="GZMB"/> <bbox w="90.0" h="25.0" x="3745.0" y="6147.5"/> <glyph class="unit of information" id="_1d44abe4-ceef-4281-8a4a-6aa490d36e44"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3780.0" y="6142.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1171_sa464" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMB MODULE:TCR_SIGNALING PMID:24973821 mTOR has positive influence on GZMA level in the NK cells.</body> </html> </notes> <label text="GZMA"/> <bbox w="90.0" h="25.0" x="3625.0" y="6147.5"/> <glyph class="unit of information" id="_ecd4c61a-6399-4a5b-9ae8-4e4f597d1f18"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3660.0" y="6142.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s919_sa474" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYH9 MODULE:TCR_SIGNALING CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Three genes encode mammalian non-muscle myosin II heavy chains, referred to as MyH9 {http://www.signaling-gateway.org/molecule/query?afcsid=A004003}, MyH10 and MyH14 (refs. 21, 22)21, 22. Of these three isoforms, only MyH9 is dominant in T cells Myosin IIA was rapidly activated upon TCR engagement and its activity was essential for centripetal movement of TCR microclusters. Additionally, both immunological synapse stability and signaling downstream of TCR required intact myosin IIA.</body> </html> </notes> <label text="MYH9"/> <bbox w="80.0" h="40.0" x="4940.0" y="3625.0"/> </glyph> <glyph class="macromolecule multimer" id="s3777_sa475" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYH9 MODULE:TCR_SIGNALING CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Three genes encode mammalian non-muscle myosin II heavy chains, referred to as MyH9 {http://www.signaling-gateway.org/molecule/query?afcsid=A004003}, MyH10 and MyH14 (refs. 21, 22)21, 22. Of these three isoforms, only MyH9 is dominant in T cells Myosin IIA was rapidly activated upon TCR engagement and its activity was essential for centripetal movement of TCR microclusters. Additionally, both immunological synapse stability and signaling downstream of TCR required intact myosin IIA.</body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="5109.5" y="3627.0"/> <glyph class="unit of information" id="_604666ba-f1f2-4bd4-9d5e-7fb99695f262"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5142.5" y="3622.0"/> </glyph> </glyph> <glyph class="phenotype" id="s837_sa485"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:20439993</body> </html> </notes> <label text="Granules exocytosis"/> <bbox w="160.0" h="45.0" x="4280.0" y="6947.5"/> </glyph> <glyph class="macromolecule" id="s3776_sa487" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL9, HUGO:MYL12A HUGO:MYL12B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5302.5" y="3710.0"/> <glyph class="state variable" id="_b5799882-4c2a-4cea-adb3-beb4a9a91364"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5297.5" y="3725.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3775_sa488" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL6, HUGO:MYL6B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5302.5" y="3640.0"/> </glyph> <glyph class="macromolecule" id="s3794_sa489" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYLK HUGO:MYLK2 MODULE:TCR_SIGNALING CASCADE:TCR PMID:19349987 Both ROCK and MLCK phosphorylate and activate MLC and both ML7 and Y27632 inhibited phosphorylation of MLC during T cell stimulation with soluble TCR antibody PMID:27241914 Ca2+-dependent calmodulin signaling leads to MLCK activation and, subsequently, pulling forces. Indeed, loss of calmodulin leads to unresponsiveness in T cells (Lin et al., 2005). Our experiments perturbing Ca2+ entry showed that at low Ca2+ levels, the magnitude of the pull force became more dependent on integrated Ca2+ concentration. The etiology of this Ca2+ threshold is as yet unknown, and could be caused by calmodulin. Probably via CAMK PMID:19349987 Ca2+ signaling requires myosin IIA activity</body> </html> </notes> <label text="MLCK*"/> <bbox w="80.0" h="40.0" x="5342.5" y="3865.0"/> <glyph class="state variable" id="_89080dc2-3f7d-48ed-8748-c170bb011e5f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5337.5" y="3880.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3786_sa490" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYLK HUGO:MYLK2 MODULE:TCR_SIGNALING CASCADE:TCR PMID:19349987 Both ROCK and MLCK phosphorylate and activate MLC and both ML7 and Y27632 inhibited phosphorylation of MLC during T cell stimulation with soluble TCR antibody PMID:27241914 Ca2+-dependent calmodulin signaling leads to MLCK activation and, subsequently, pulling forces. Indeed, loss of calmodulin leads to unresponsiveness in T cells (Lin et al., 2005). Our experiments perturbing Ca2+ entry showed that at low Ca2+ levels, the magnitude of the pull force became more dependent on integrated Ca2+ concentration. The etiology of this Ca2+ threshold is as yet unknown, and could be caused by calmodulin. Probably via CAMK PMID:19349987 Ca2+ signaling requires myosin IIA activity</body> </html> </notes> <label text="MLCK*"/> <bbox w="80.0" h="40.0" x="5343.5" y="3955.0"/> <glyph class="state variable" id="_4cebe1de-5c73-46c0-b2ae-d5393f9be5eb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5336.0" y="3970.0"/> </glyph> </glyph> <glyph class="complex" id="s808_csa43" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:NKG2D MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS PMID:24655141; PMID:17006514 REW</body> </html> </notes> <label text="MTOC"/> <bbox w="211.25" h="256.25" x="4479.375" y="4506.875"/> <glyph class="macromolecule" id="s818_sa491"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBG1 HUGO:TUBG2 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="Tubulin-γ*"/> <bbox w="80.0" h="40.0" x="4590.625" y="4523.125"/> </glyph> <glyph class="macromolecule" id="s819_sa492"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP2 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP2"/> <bbox w="80.0" h="40.0" x="4500.625" y="4523.125"/> </glyph> <glyph class="macromolecule" id="s820_sa493"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP3 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP3"/> <bbox w="80.0" h="40.0" x="4500.625" y="4563.125"/> </glyph> <glyph class="macromolecule" id="s821_sa494"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP4 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP4"/> <bbox w="80.0" h="40.0" x="4500.625" y="4603.125"/> </glyph> <glyph class="macromolecule" id="s822_sa495"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP5 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP5"/> <bbox w="80.0" h="40.0" x="4590.625" y="4563.125"/> </glyph> <glyph class="macromolecule" id="s823_sa496"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP6 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP6"/> <bbox w="80.0" h="40.0" x="4590.625" y="4603.125"/> </glyph> <glyph class="macromolecule" id="s816_sa497"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBA1A HGNC:20766 ENTREZ:7846 UNIPROT:Q71U36 GENECARDS:TUBA1A REACTOME:191692 KEGG:7846 ATLASONC:GC_TUBA1A WIKI:TUBA1A SwissProt:Q71U36 HUGO:TUBA1B HGNC:18809 ENTREZ:10376 UNIPROT:P68363 GENECARDS:TUBA1B REACTOME:191693 KEGG:10376 ATLASONC:GC_TUBA1B WIKI:TUBA1B SwissProt:P68363 HUGO:TUBA1C HGNC:20768 ENTREZ:84790 UNIPROT:Q9BQE3 GENECARDS:TUBA1C REACTOME:65667 KEGG:84790 ATLASONC:GC_TUBA1C WIKI:TUBA1C SwissProt:Q9BQE3 tubulin, alpha 3c HUGO:TUBA3C HGNC:12408 ENTREZ:7278 UNIPROT:Q13748 GENECARDS:TUBA3C REACTOME:154750 KEGG:7278 WIKI:TUBA3C SwissProt: Q13748 HUGO:TUBA3D HGNC:24071 ENTREZ:113457 UNIPROT:Q13748 GENECARDS:TUBA3D REACTOME:154750 KEGG:113457 WIKI:TUBA3D tubulin, alpha 3e HUGO:TUBA3E HGNC:20765 ENTREZ:112714 UNIPROT:Q6PEY2 GENECARDS:TUBA3E WIKI:TUBA3E SwissProt:Q6PEY2 HUGO:TUBA4A HGNC:12407 ENTREZ:7277 UNIPROT:P68366 GENECARDS:TUBA4A REACTOME:191690 KEGG:7277 ATLASONC:GC_TUBA4A WIKI:TUBA4A SwissProt: P68366 HUGO:TUBA8 HGNC:12410 ENTREZ:51807 UNIPROT:Q9NY65 GENECARDS:TUBA8 KEGG:51807 WIKI:TUBA8 SwissProt:Q9NY65 MODULE:TCR_SIGNALING PMID:18287025</body> </html> </notes> <label text="Tubulin-α*"/> <bbox w="80.0" h="40.0" x="4496.875" y="4683.125"/> </glyph> <glyph class="macromolecule" id="s817_sa498"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBB HUGO:TUBB1 HUGO:TUBB2A HUGO:TUBB2B HUGO:TUBB2C HUGO:TUBB3 HUGO:TUBB4 HUGO:TUBB4Q HUGO:TUBB6 MODULE:TCR_SIGNALING PMID:18287025</body> </html> </notes> <label text="Tubulin-β*"/> <bbox w="80.0" h="40.0" x="4580.625" y="4683.125"/> </glyph> </glyph> <glyph class="complex" id="s879_csa44" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:MACROPHAGE CASCADE:CR3 CASCADE:Fc_gamma_RII MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:PHAGOCYTOSIS 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:17306570 Arp2/3 Complex-Dependent F-Actin Polymerization Does Not Control MTOC Polarity, but Regulates Integrins and TCR Internalization</body> </html> </notes> <label text="Arp2/3"/> <bbox w="190.0" h="210.0" x="4857.5" y="4385.0"/> <glyph class="macromolecule" id="s947_sa499"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC3 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC3"/> <bbox w="80.0" h="40.0" x="4952.5" y="4400.0"/> </glyph> <glyph class="macromolecule" id="s948_sa500"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC4 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC4"/> <bbox w="80.0" h="40.0" x="4952.5" y="4440.0"/> </glyph> <glyph class="macromolecule" id="s1693_sa501"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC5 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC5"/> <bbox w="80.0" h="40.0" x="4952.5" y="4480.0"/> </glyph> <glyph class="macromolecule" id="s3805_sa502"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ACTR3 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ACTR3"/> <bbox w="80.0" h="40.0" x="4862.5" y="4520.0"/> </glyph> <glyph class="macromolecule" id="s3804_sa503"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ACTR2 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ACTR2"/> <bbox w="80.0" h="40.0" x="4862.5" y="4480.0"/> </glyph> <glyph class="macromolecule" id="s3803_sa504"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC2 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC2"/> <bbox w="80.0" h="40.0" x="4862.5" y="4440.0"/> </glyph> <glyph class="macromolecule" id="s3802_sa505"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC1A HUGO:ARPC1B MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC1*"/> <bbox w="80.0" h="40.0" x="4862.5" y="4400.0"/> </glyph> </glyph> <glyph class="complex" id="s894_csa45" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:MACROPHAGE MODULE:NK CASCADE:CR3 CASCADE:Fc_gamma_RII MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:PHAGOCYTOSIS 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:14707117; PMID:15541654 TCR-induced synapse formation is markedly reduced in Fyn-deficient mice and WASp capacity to trigger Arp 2/3-mediated actin polymerization in vitro is enhanced by Fyn and abrogated by PTP-PEST PMID:17306570 Arp2/3 Complex-Dependent F-Actin Polymerization Does Not Control MTOC Polarity, but Regulates Integrins and TCR Internalization</body> </html> </notes> <label text="Arp2/3"/> <bbox w="220.0" h="205.0" x="4650.0" y="4982.5"/> <glyph class="macromolecule" id="s1690_sa506"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ACTR2 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ACTR2"/> <bbox w="80.0" h="40.0" x="4660.0" y="5075.0"/> </glyph> <glyph class="macromolecule" id="s895_sa507"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ACTR3 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ACTR3"/> <bbox w="80.0" h="40.0" x="4660.0" y="5117.5"/> </glyph> <glyph class="macromolecule" id="s1689_sa508"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC2 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC2"/> <bbox w="80.0" h="40.0" x="4660.0" y="5037.5"/> </glyph> <glyph class="macromolecule" id="s1688_sa509"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC1A HUGO:ARPC1B MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC1*"/> <bbox w="80.0" h="40.0" x="4660.0" y="4997.5"/> </glyph> <glyph class="macromolecule" id="s3801_sa510"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC3 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC3"/> <bbox w="80.0" h="40.0" x="4760.0" y="4997.5"/> </glyph> <glyph class="macromolecule" id="s3800_sa511"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC4 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC4"/> <bbox w="80.0" h="40.0" x="4760.0" y="5045.0"/> </glyph> <glyph class="macromolecule" id="s901_sa512"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ARPC5 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="ARPC5"/> <bbox w="80.0" h="40.0" x="4760.0" y="5077.5"/> </glyph> <glyph class="macromolecule" id="s1687_sa513"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="4760.0" y="5117.5"/> <glyph class="state variable" id="_554d566d-4aae-4615-9fbd-d22217967404"> <state value="P" variable="Tyr291"/> <bbox w="45.0" h="10.0" x="4737.5" y="5112.8296"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s868_csa47" compartmentRef="c2_ca2"> <label text="s868"/> <bbox w="105.0" h="140.0" x="4987.5" y="5985.0"/> <glyph class="macromolecule" id="s1691_sa523"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="4997.5" y="6045.0"/> <glyph class="state variable" id="_5dbe3e95-ca2d-4c49-8cda-ae7f24e07e81"> <state value="P" variable="Tyr291"/> <bbox w="45.0" h="10.0" x="4975.0" y="6040.3296"/> </glyph> </glyph> <glyph class="macromolecule" id="s1692_sa524"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRIP10 MODULE:TCR_SIGNALING 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. PMID:10713100 Cdc42-interacting protein 4 mediates binding of the Wiskott-Aldrich syndrome protein to microtubules. (COS7 model) PMID:15541654 Involvement of the Wiskott-Aldrich syndrome protein and other actin regulatory adaptors in T cell activation</body> </html> </notes> <label text="TRIP10"/> <bbox w="80.0" h="40.0" x="5000.0" y="5995.0"/> </glyph> </glyph> <glyph class="complex" id="s912_csa55" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:NK CASCADE:KIR2DL1 MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:PHAGOCYTOSIS PMID:16606694 WIPF1 forms complex with WASP. Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor</body> </html> </notes> <label text="WASP*:WIPF1"/> <bbox w="110.0" h="140.0" x="4877.5" y="3947.5"/> <glyph class="macromolecule" id="s913_sa539"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WIPF1 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="4897.5" y="4017.5"/> <glyph class="state variable" id="_031e1422-c1e4-439c-ba4a-6b4ce2b772ed"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4892.5" y="4032.4683"/> </glyph> </glyph> <glyph class="macromolecule" id="s914_sa540"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="4897.5" y="3957.5"/> <glyph class="state variable" id="_05457fb8-8ec5-4147-ab72-842d3a6575b3"> <state value="P" variable="Tyr291"/> <bbox w="45.0" h="10.0" x="4875.0" y="3952.8296"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s920_csa56" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:KIR2DL1 MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:PHAGOCYTOSIS PMID:16606694 Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. 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.</body> </html> </notes> <label text="WASP*:WIPF1"/> <bbox w="110.0" h="140.0" x="4977.5" y="4180.0"/> <glyph class="macromolecule" id="s921_sa541"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="4990.0" y="4190.0"/> <glyph class="state variable" id="_fa16d7e5-a0a3-459f-9602-c5f685500e3f"> <state value="P" variable="Tyr291"/> <bbox w="45.0" h="10.0" x="4967.5" y="4185.3296"/> </glyph> </glyph> <glyph class="macromolecule" id="s922_sa542"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WIPF1 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="4990.0" y="4240.0"/> <glyph class="state variable" id="_598710f4-d5dd-456d-bfff-62a1b9f4f20a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4982.5" y="4254.9683"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3787_csa57" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:PHAGOCYTOSIS PMID:16606694 Protein kinase C-theta mediates phosphorylation of WIPF1 downstream of NK activation. Inhibitory signaling from KIR2DL1 receptor. Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. 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.</body> </html> </notes> <label text="WASP*:WIPF1"/> <bbox w="122.5" h="305.0" x="5341.25" y="4367.5"/> <glyph class="macromolecule" id="s3788_sa543"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WAS MODULE:TCR_SIGNALING PMID:11520460 Cdc42 and WASP are critical regulators of actin polymerization whose function during T cell signaling is poorly understood. WASP also localized to the T cell:APC contact site in an antigen-dependent manner. Surprisingly, WASP localization was independent of the Cdc42 binding domain but required the proline-rich domain. PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="5356.25" y="4552.5"/> <glyph class="state variable" id="_86e962a3-e4f6-4bf8-be0f-4ec042a0a0cc"> <state value="" variable="Tyr291"/> <bbox w="40.0" h="10.0" x="5336.25" y="4547.8296"/> </glyph> </glyph> <glyph class="macromolecule" id="s3789_sa544"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WIPF1 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="5353.75" y="4597.5"/> <glyph class="state variable" id="_f6c6fa73-6921-4600-81d0-fcd2c22cd6ea"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5346.25" y="4612.4683"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s5838_sa545"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYH9 MODULE:TCR_SIGNALING CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Three genes encode mammalian non-muscle myosin II heavy chains, referred to as MyH9 {http://www.signaling-gateway.org/molecule/query?afcsid=A004003}, MyH10 and MyH14 (refs. 21, 22)21, 22. Of these three isoforms, only MyH9 is dominant in T cells Myosin IIA was rapidly activated upon TCR engagement and its activity was essential for centripetal movement of TCR microclusters. Additionally, both immunological synapse stability and signaling downstream of TCR required intact myosin IIA.</body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="5354.5" y="4377.0"/> <glyph class="unit of information" id="_bd676837-13db-419b-b6b0-3dc178c01616"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5387.5" y="4372.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5837_sa546"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL6, HUGO:MYL6B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5357.5" y="4460.0"/> </glyph> <glyph class="macromolecule" id="s5836_sa547"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL9, HUGO:MYL12A HUGO:MYL12B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5357.5" y="4420.0"/> <glyph class="state variable" id="_dd900016-5066-4ecc-85ca-78171ddbdc3d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5350.0" y="4435.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3778_csa58" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:MACROPHAGE MODULE:TUMOR_KILLING MODULE:EFFECTOR_ACTIVATION MODULE:LYTIC_GRANULES_EXOCYTOSIS MODULE:PHAGOCYTOSIS 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.</body> </html> </notes> <label text="MYOSIN_IIA"/> <bbox w="100.0" h="170.0" x="5163.5" y="3770.0"/> <glyph class="macromolecule multimer" id="s3779_sa548"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYH9 MODULE:TCR_SIGNALING CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Three genes encode mammalian non-muscle myosin II heavy chains, referred to as MyH9 {http://www.signaling-gateway.org/molecule/query?afcsid=A004003}, MyH10 and MyH14 (refs. 21, 22)21, 22. Of these three isoforms, only MyH9 is dominant in T cells Myosin IIA was rapidly activated upon TCR engagement and its activity was essential for centripetal movement of TCR microclusters. Additionally, both immunological synapse stability and signaling downstream of TCR required intact myosin IIA.</body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="5164.5" y="3777.0"/> <glyph class="unit of information" id="_fd2d43dc-e32d-47b5-83d1-2883271649fd"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5197.5" y="3772.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3781_sa549"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL6, HUGO:MYL6B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5173.5" y="3830.0"/> </glyph> <glyph class="macromolecule" id="s3780_sa550"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL9, HUGO:MYL12A HUGO:MYL12B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5173.5" y="3870.0"/> <glyph class="state variable" id="_1c6d51b8-eaa3-456b-a62a-1be3050ca811"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5168.5" y="3885.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3782_csa59" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE: depletion of NMII (nonmuscle myosin II) reduced CTL-mediated cytotoxicity, implying that myosin-dependent forces contribute to mechanopotentiation during target cell killing. PMID:19349987 Myosin IIA is activated during T cell stimulation</body> </html> </notes> <label text="MYOSIN_IIA"/> <bbox w="100.0" h="170.0" x="5162.5" y="4335.0"/> <glyph class="macromolecule multimer" id="s3783_sa551"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYH9 MODULE:TCR_SIGNALING CASCADE:CR3 PMID:16606694 Phosphorylated WIPF1 provides recruitment of of F-actin and MYH9 (myosin IIA) to multiprotein WASP :WIPF1 complexs. PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Three genes encode mammalian non-muscle myosin II heavy chains, referred to as MyH9 {http://www.signaling-gateway.org/molecule/query?afcsid=A004003}, MyH10 and MyH14 (refs. 21, 22)21, 22. Of these three isoforms, only MyH9 is dominant in T cells Myosin IIA was rapidly activated upon TCR engagement and its activity was essential for centripetal movement of TCR microclusters. Additionally, both immunological synapse stability and signaling downstream of TCR required intact myosin IIA.</body> </html> </notes> <label text="MYH9"/> <bbox w="86.0" h="46.0" x="5169.5" y="4342.0"/> <glyph class="unit of information" id="_48bc8dc6-9501-44d6-90aa-d291aef9631e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5202.5" y="4337.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3784_sa552"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL6, HUGO:MYL6B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5172.5" y="4390.0"/> </glyph> <glyph class="macromolecule" id="s3785_sa553"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MYL9, HUGO:MYL12A HUGO:MYL12B MODULE:TCR_SIGNALING 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 PMID:19349987 T cell antigen receptor signaling and immunological synapse stability require myosin IIA.</body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="5172.5" y="4435.0"/> <glyph class="state variable" id="_75402f96-37ac-4fc4-b845-afcd4d79cddd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5165.0" y="4450.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4849_sa607" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:SPN MODULE:SMAC PMID:23886063;PMID:23620508 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). SPN (CD43) https://link.springer.com/referenceworkentry/10.1007%2F978-3-319-67199-4_523 CD43 engagement in human T cells induces its association to the Src family kinases Lck and Fyn, through the interaction of their SH3 domains and the proline-rich region of CD43. This then leads to the phosphorylation of the CD3 ζ chain and the assembly of macromolecular complexes that include adaptor proteins such as Shc, Grb2, SLP-76, and the guanine exchange factor Vav. These signaling complexes promote ERK1/2 MAPK activation, leading to regulation of actin cytoskeleton and a positive feedback loop for Lck signaling as a result of an ERK1/2-dependent serine phosphorylation of Lck, which inhibits its association to the phosphatase SHP-1. CD43 engagement also induces calcium fluxes and PKC activation, necessary for Cbl serine phosphorylation and its interaction with 14-3-3. Moreover, T-cell pre-stimulation by the CD43 co-receptor molecule before TCR engagement inhibits the TCR-dependent c-Cbl tyrosine phosphorylation and interaction with the adapter molecule Crk-L, and promotes Cbl-b ubiquitination and degradation in a PKC θ-dependent manner.</body> </html> </notes> <label text="SPN"/> <bbox w="80.0" h="50.0" x="4760.0" y="885.0"/> <glyph class="unit of information" id="_03d0799e-4c94-4d42-ac3d-71cda1a3f9fa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4777.5" y="880.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4851_sa610" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD2 MODULE:ACTIVATING_CHECKPOINTS PMID:23886063 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal link er proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2 PMID:19398758 The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells the binding of CD58 to CD2, even in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR(cis interaction) PMID: 15331323 CD2-CD48 interactions promote interleukin-2 and interferon-gamma synthesis by stabilizing cytokine mRNA (trans interaction)</body> </html> </notes> <label text="CD2"/> <bbox w="80.0" h="50.0" x="4180.0" y="735.0"/> <glyph class="unit of information" id="_40f8134d-82c8-45a2-9a10-65692f8efbac"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4197.5" y="730.0"/> </glyph> </glyph> <glyph class="complex" id="s990_csa63" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:23886063; PMID:9738502 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:10591186; PMID:14676297 LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. CD226 (DNAM-1) Is Involved in Lymphocyte Function–associated Antigen 1 Costimulatory Signal for Naive T Cell Differentiation and Proliferation Upon antigen recognition by the T cell receptor, lymphocyte function–associated antigen 1 (LFA-1) physically associates with the leukocyte adhesion molecule CD226 (DNAM-1) and the protein tyrosine kinase Fyn. proliferation induced by LFA-1 costimulatory signal was suppressed in mutant (Y-F322) CD226-transduced naive CD4+ and CD8+ T cells in the absence of IL-2. These results suggest that CD226 is involved in LFA-1–mediated costimulatory signals for triggering naive T cell differentiation and proliferation. PMID:24337740 DNAM-1 interacts with LFA-1, a critical molecule for immunological synapse formation between T cells and APCs, and for cytotoxic killing of target cells. Mice that lack DNAM-1 display abnormal T cell responses and antitumor activity; DNAM-1 deficiency results in reduced proliferation of CD8+ T cells after Ag presentation and impaired cytotoxic activity. We also demonstrate that DNAM-1–deficient T cells show reduced conjugations with tumor cells and decreased recruitment of both LFA-1 and lipid rafts to the immunological synapse, which correlates with reduced tumor cell killing in vitro. This synapse defect may explain why DNAM-1–deficient mice cannot clear tumors in vivo, and highlights the importance of DNAM-1 and the immunological synapse in T cell–mediated antitumor immunity.</body> </html> </notes> <label text="LFA1"/> <bbox w="100.0" h="130.0" x="4320.0" y="730.0"/> <glyph class="macromolecule" id="s4854_sa611"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITGB2 MODULE:SMAC PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="4330.0" y="735.0"/> <glyph class="unit of information" id="_c7910de4-cebf-4579-86e6-7fa53984afca"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4347.5" y="730.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4855_sa612"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITGAL MODULE:SMAC PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="4330.0" y="785.0"/> <glyph class="unit of information" id="_566bf89f-5e70-40f0-b99c-1c89000219b2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4347.5" y="780.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4852_sa614" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:TLN1 PMID:23886063; PMID:9738502 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="TLN1"/> <clone/> <bbox w="80.0" h="40.0" x="4330.0" y="1010.0"/> </glyph> <glyph class="macromolecule" id="s4852_sa1250" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:TLN1 PMID:23886063; PMID:9738502 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="TLN1"/> <clone/> <bbox w="80.0" h="40.0" x="4330.0" y="1130.0"/> </glyph> <glyph class="complex" id="s4857_csa64" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:23886063 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells PMID:12616499 Vav1 transduces TCR signals required for LFA-1 function and cell polarization at the immunological synapse. Vav1 is required for TCR-induced activation of LFA-1</body> </html> </notes> <label text="LFA1"/> <bbox w="120.0" h="275.0" x="4470.0" y="797.5"/> <glyph class="macromolecule" id="s4859_sa615"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITGB2 MODULE:SMAC PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="4490.0" y="852.5"/> <glyph class="unit of information" id="_38fba0ee-4294-4efc-9a12-edd5dffa0bb6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4507.5" y="847.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4858_sa616"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITGAL MODULE:SMAC PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="4490.0" y="902.5"/> <glyph class="unit of information" id="_88d81202-dbc1-46c6-910a-3e6e6c99b8e5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4507.5" y="897.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4856_sa617"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 ------ HUGO:ICAM1 MODULE:SMAC 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</body> </html> </notes> <label text="ICAM1"/> <bbox w="80.0" h="40.0" x="4490.0" y="807.5"/> </glyph> <glyph class="macromolecule" id="s4879_sa633"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:TLN1 PMID:23886063; PMID:9738502 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:2150484 LFA-1 associates with talin, but not with PKC , in activated T cells</body> </html> </notes> <label text="TLN1"/> <bbox w="80.0" h="40.0" x="4490.0" y="962.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4864_sa623" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD58 PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2</body> </html> </notes> <label text="CD58"/> <bbox w="80.0" h="50.0" x="4230.0" y="435.0"/> <glyph class="unit of information" id="_3d23999e-b208-44d1-9f3a-e423ce38db73"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4247.5" y="430.0"/> </glyph> </glyph> <glyph class="complex" id="s4865_csa65" compartmentRef="c9_ca9"> <label text="s4865"/> <bbox w="100.0" h="120.0" x="4230.0" y="870.0"/> <glyph class="macromolecule" id="s4866_sa624"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD2 MODULE:ACTIVATING_CHECKPOINTS PMID:23886063 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal link er proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2 PMID:19398758 The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells the binding of CD58 to CD2, even in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR(cis interaction) PMID: 15331323 CD2-CD48 interactions promote interleukin-2 and interferon-gamma synthesis by stabilizing cytokine mRNA (trans interaction)</body> </html> </notes> <label text="CD2"/> <bbox w="80.0" h="50.0" x="4240.0" y="925.0"/> <glyph class="unit of information" id="_ad96005c-e7b3-40e5-a69b-af1187343537"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4257.5" y="920.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4867_sa625"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD58 PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2</body> </html> </notes> <label text="CD58"/> <bbox w="80.0" h="50.0" x="4240.0" y="875.0"/> <glyph class="unit of information" id="_1a6e2b2b-5975-4b59-a466-1a730bcdaa21"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4257.5" y="870.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4872_sa188" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD28 CASCADE:TCR CASCADE:B4H4 MODULE:SMAC MODULE:TCR_SIGNALING PMID:22437870 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:22437870 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:1313950 Costimulatory signaling by CD28 has been described as critical for the enhancement of T cell proliferation</body> </html> </notes> <label text="CD28"/> <bbox w="80.0" h="50.0" x="1215.0" y="937.5"/> <glyph class="state variable" id="_bcd63292-7874-4082-b43e-48b9fc6cd51f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1210.0" y="957.5"/> </glyph> <glyph class="unit of information" id="_ce2c5e72-ed1e-492c-90d8-fa9f11ab4f5e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1232.5" y="932.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4874_sa608" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD44 PMID:23886063; PMID:23620508 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:22566907 CD44-dependent adhesion mechanisms are important for the mobilization of effector T cells to sites of infection and inflammation. can also cooperate with LFA-1 during T cell recruitment</body> </html> </notes> <label text="CD44"/> <clone/> <bbox w="80.0" h="50.0" x="4751.0" y="805.0"/> <glyph class="unit of information" id="_b6b2cee6-c6fb-4829-b320-baa85175b5a7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4768.5" y="800.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4874_sa1384" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD44 PMID:23886063; PMID:23620508 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:22566907 CD44-dependent adhesion mechanisms are important for the mobilization of effector T cells to sites of infection and inflammation. can also cooperate with LFA-1 during T cell recruitment</body> </html> </notes> <label text="CD44"/> <clone/> <bbox w="80.0" h="50.0" x="4751.0" y="735.0"/> <glyph class="unit of information" id="_15cc4099-fd98-492f-88ea-35fa386ff04a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4768.5" y="730.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4875_sa445" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 GENECARDS:ACTA1 REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 GENECARDS:ACTA2 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 GENECARDS:ACTB REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 GENECARDS:ACTC1 REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 GENECARDS:ACTG1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 MODULE:TCR_SIGNALING PMID:18802007 Disruption of actin polymerization inhibits the up-regulation of surface MHCII in a dose-dependent manner in DC. CASCADE:TCR CASCADE:CD226 PMID:23620508 Actin regulation by TCR PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="130.0" h="50.0" x="5085.0" y="6290.0"/> </glyph> <glyph class="macromolecule multimer" id="s4876_sa446" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ACTA1 HGNC:129 ENTREZ:58 UNIPROT:P68133 GENECARDS:ACTA1 REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 HUGO:ACTA2 HGNC:130 ENTREZ:59 UNIPROT:P62736 GENECARDS:ACTA2 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 HUGO:ACTB HGNC:132 ENTREZ:60 UNIPROT:P60709 GENECARDS:ACTB REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB HUGO:ACTC1 HGNC:143 ENTREZ:70 UNIPROT:P68032 GENECARDS:ACTC1 REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 HUGO:ACTG1 HGNC:144 ENTREZ:71 UNIPROT:P63261 GENECARDS:ACTG1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 MODULE:TCR_SIGNALING PMID:18802007 Disruption of actin polymerization inhibits the up-regulation of surface MHCII in a dose-dependent manner in DC. CASCADE:TCR CASCADE:CD226 PMID:23620508 Actin regulation by TCR PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="136.0" h="56.0" x="5082.0" y="6397.0"/> <glyph class="unit of information" id="_e2e94b89-9e31-4263-b620-f038353236cb"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5140.0" y="6392.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s744_sa639" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="PIP2*"/> <bbox w="70.0" h="25.0" x="4515.0" y="2157.5"/> </glyph> <glyph class="simple chemical" id="s1866_sa640" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING PMID:15817676; PMID:25456276 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)</body> </html> </notes> <label text="PtdIns(4)-P"/> <bbox w="70.0" h="25.0" x="4515.0" y="2037.5"/> </glyph> <glyph class="simple chemical" id="s745_sa642" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:12670391 PI3K in T cells Ligation of the T cell receptor for antigen (TCR) and/or costimulatory receptor CD28 results in rapid activation of phosphoinositide-3 kinase (PI-3 kinase). The primary mechanism for class IA PI-3 kinase activation by tyrosine kinase-coupled receptors is recruitment of the p85/p110 heterodimer to phosphorylated tyrosine kinase receptors via interaction of p85 Src homology 2 (SH2) domain(s) with phosphotyrosine moieties on the receptors Products of the PI-3 kinases discussed here include phosphatidylinositol 3,4-bisphosphate (PI-3,4P2) and phosphatidylinositol 3,4,5-trisphosphate (PI-3,4,5P3 or PIP3). PMID:11526404 Inhibition of PI3K leads to a reduction in TCR-induced Vav phosphorylation</body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="4535.0" y="2352.5"/> </glyph> <glyph class="macromolecule" id="s1114_sa646" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PDK1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:19122654 ;PMID:15802604 TCR-CD28–mediated NF-κB activation requires PDK1 PDK1 and PKC-θ also localized together at the immunological synapse following stimulation of primary CD4+ T cells recruitment of PDK1 and PKC-θ can occur independently; that is, treatment with anti-CD3 alone led to PKC-θ recruitment, whereas treatment with anti-CD28 alone led to PDK1 recruitment The protein kinase PDK1 is considered essential for PKCθ activation as PDK1-deficient Jurkat and primary CD4 T cells show a defect in PKCθ phosphorylation and NF-κB activation. PDK1 bound to PKC-θ in primary T cells (Supplementary Fig. 9) and Jurkat T cells16 (Fig. 4c). Moreover, PDK1 can induce weak PKC-θ phosphorylation in vitro, which is associated with the relatively weak binding between these proteins in in vitro conditions.</body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="4910.0" y="1655.0"/> </glyph> <glyph class="complex" id="s1115_csa68" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNG MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s1115"/> <bbox w="100.0" h="120.0" x="5030.0" y="1805.0"/> <glyph class="macromolecule" id="s1116_sa658"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PDK1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:19122654 ;PMID:15802604 TCR-CD28–mediated NF-κB activation requires PDK1 PDK1 and PKC-θ also localized together at the immunological synapse following stimulation of primary CD4+ T cells recruitment of PDK1 and PKC-θ can occur independently; that is, treatment with anti-CD3 alone led to PKC-θ recruitment, whereas treatment with anti-CD28 alone led to PDK1 recruitment The protein kinase PDK1 is considered essential for PKCθ activation as PDK1-deficient Jurkat and primary CD4 T cells show a defect in PKCθ phosphorylation and NF-κB activation. PDK1 bound to PKC-θ in primary T cells (Supplementary Fig. 9) and Jurkat T cells16 (Fig. 4c). Moreover, PDK1 can induce weak PKC-θ phosphorylation in vitro, which is associated with the relatively weak binding between these proteins in in vitro conditions.</body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="5040.0" y="1815.0"/> </glyph> <glyph class="simple chemical" id="s3588_sa659"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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="5045.0" y="1872.5"/> </glyph> </glyph> <glyph class="complex" id="s1172_csa69" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL15 CASCADE:CSF2 MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway.</body> </html> </notes> <label text="TSC1:TSC2"/> <bbox w="100.0" h="140.0" x="4690.0" y="2780.0"/> <glyph class="macromolecule" id="s1173_sa660"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TSC1 MODULE:TCR_SIGNALING CASCADE:TCR PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway.</body> </html> </notes> <label text="TSC1"/> <bbox w="80.0" h="40.0" x="4700.0" y="2800.0"/> </glyph> <glyph class="macromolecule" id="s1174_sa661"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TSC2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway.</body> </html> </notes> <label text="TSC2"/> <bbox w="80.0" h="40.0" x="4700.0" y="2850.0"/> <glyph class="state variable" id="_91fdef49-3548-47ff-b66c-0c24949fb109"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4695.0" y="2865.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1185_csa70" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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.</body> </html> </notes> <label text="TSC1:TSC2"/> <bbox w="100.0" h="140.0" x="5010.0" y="2785.0"/> <glyph class="macromolecule" id="s1186_sa662"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TSC1 MODULE:TCR_SIGNALING CASCADE:TCR PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway.</body> </html> </notes> <label text="TSC1"/> <bbox w="80.0" h="40.0" x="5020.0" y="2800.0"/> </glyph> <glyph class="macromolecule" id="s1187_sa663"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TSC2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12906785, PMID:19022819 AKT activates Rapamycin associated protein FRAP2 ( mTOR ) probably through Tuberin/GTP-binding protein Ras homolog enriched in brain ( RHEB ) pathway.</body> </html> </notes> <label text="TSC2"/> <bbox w="80.0" h="40.0" x="5020.0" y="2845.0"/> <glyph class="state variable" id="_fc630f4b-251b-4c8d-802f-f7c8251a098a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5012.5" y="2860.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1178_csa71" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:DC MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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.</body> </html> </notes> <label text="s1178"/> <bbox w="100.0" h="120.0" x="4780.0" y="3035.0"/> <glyph class="macromolecule" id="s1175_sa664"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:HREB MODULE:TCR_SIGNALING CASCADE:TCR 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:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="RHEB"/> <bbox w="80.0" h="40.0" x="4790.0" y="3045.0"/> </glyph> <glyph class="simple chemical" id="s1180_sa665"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="4795.0" y="3097.5"/> </glyph> </glyph> <glyph class="complex" id="s1176_csa72" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:DC MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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.</body> </html> </notes> <label text="s1176"/> <bbox w="100.0" h="120.0" x="5030.0" y="3035.0"/> <glyph class="macromolecule" id="s1177_sa666"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:HREB MODULE:TCR_SIGNALING CASCADE:TCR 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:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="RHEB"/> <bbox w="80.0" h="40.0" x="5040.0" y="3040.0"/> </glyph> <glyph class="simple chemical" id="s1179_sa667"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <bbox w="70.0" h="25.0" x="5045.0" y="3097.5"/> </glyph> </glyph> <glyph class="complex" id="s4068_csa73" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="mTORC1*"/> <bbox w="210.0" h="210.0" x="4975.0" y="3220.0"/> <glyph class="macromolecule" id="s2257_sa668"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MTOR CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells. two mTOR-dependent pathways that can negatively regulate FoxP3 expression whose loss may explain the increased FoxP3 expression in mTOR null T cells. First, HIF1α is induced by mTORC1 and has been shown to directly bind to FoxP3 protein and promote its ubiquitination and degradation (Dang et al., 2011). Second, the Foxo transcription factors directly bind to and transactivate the FoxP3 promoter, and they are inactivated in an mTORC2-dependent manner following phosphorylation by doubly phosphorylated activated AKT, leading to nuclear export of the Foxos [reviewed in Coffer and Burgering (2004)].</body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="4990.0" y="3345.0"/> <glyph class="state variable" id="_05dffd87-7e54-4d23-99be-b43f8cea8d1c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4985.0" y="3360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5844_sa669"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RPTOR CASCADE:TCR 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="RPTOR"/> <bbox w="80.0" h="40.0" x="4990.0" y="3285.0"/> </glyph> <glyph class="macromolecule" id="s1978_sa670"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MLST8 CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="5080.0" y="3285.0"/> </glyph> <glyph class="macromolecule" id="s1979_sa671"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DEPTOR CASCADE:TCR 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="DEPTOR"/> <bbox w="80.0" h="40.0" x="5080.0" y="3345.0"/> </glyph> <glyph class="macromolecule" id="s1980_sa672"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:AKT1S1 CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="PRAS40*"/> <bbox w="80.0" h="40.0" x="5080.0" y="3235.0"/> </glyph> </glyph> <glyph class="complex" id="s4077_csa74" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="mTORC1*"/> <bbox w="210.0" h="210.0" x="4685.0" y="3220.0"/> <glyph class="macromolecule" id="s4082_sa673"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MTOR CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells. two mTOR-dependent pathways that can negatively regulate FoxP3 expression whose loss may explain the increased FoxP3 expression in mTOR null T cells. First, HIF1α is induced by mTORC1 and has been shown to directly bind to FoxP3 protein and promote its ubiquitination and degradation (Dang et al., 2011). Second, the Foxo transcription factors directly bind to and transactivate the FoxP3 promoter, and they are inactivated in an mTORC2-dependent manner following phosphorylation by doubly phosphorylated activated AKT, leading to nuclear export of the Foxos [reviewed in Coffer and Burgering (2004)].</body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="4705.0" y="3350.0"/> <glyph class="state variable" id="_cbc59d6d-ad30-498b-8280-460097721aa8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4697.5" y="3365.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4078_sa674"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RPTOR CASCADE:TCR 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="RPTOR"/> <bbox w="80.0" h="40.0" x="4700.0" y="3295.0"/> </glyph> <glyph class="macromolecule" id="s4079_sa675"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MLST8 MODULE:NK MODULE:DC MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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 ----- content merged by Celldesigner to SBGN-ML translation ------ HUGO:MLST8 CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="4790.0" y="3295.0"/> </glyph> <glyph class="macromolecule" id="s4080_sa676"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DEPTOR CASCADE:TCR 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="DEPTOR"/> <bbox w="80.0" h="40.0" x="4800.0" y="3345.0"/> </glyph> <glyph class="macromolecule" id="s4081_sa677"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:AKT1S1 CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="PRAS40*"/> <bbox w="80.0" h="40.0" x="4795.0" y="3240.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5023_sa1026" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LCP2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:23620508 LCP2(SLP76) SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa, also known as LCP2), an adaptor that mediates interactions between a host of proteins, including LAT and the actin-regulatory proteins Nck and Vav1. SLP-76 is activated through phosphorylation by Lck and ZAP70 as well as through TCR-independent pathways PMID:12640133 the induced Gab2 potentially competes with SLP-76 for Gads binding, and this may play a role in the efficient negative regulation of TCR signaling through Gab2. PMID:24584089 CD6, which is expressed on the surface of T cells, is also phosphorylated by Zap70 regardless of the presence of Lat. CD6 nucleates the assembly of a signalosome that also involves SLP-76 and probably accounts for the many TCR-induced tyrosine-phosphorylated species that remain in the absence of Lat CD6–SLP-76 association requires Zap70 SLP-76 associates with CD6 in a Lat-independent manner. PMID:21536650 Lat-bound SLP-76 also interacts with Nck and with Vav1 to promote reorganization of the actin cytoskeleton PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation</body> </html> </notes> <label text="LCP2"/> <bbox w="80.0" h="40.0" x="2480.0" y="1940.0"/> <glyph class="state variable" id="_5fbc2203-acfe-429f-9ca9-ad8a6b0e645e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2475.0" y="1955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5026_sa681" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:GRAP2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. GRAP2 (GADS, GRPL) PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:10209041 GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76.</body> </html> </notes> <label text="GRAP2"/> <bbox w="80.0" h="40.0" x="3990.0" y="1830.0"/> </glyph> <glyph class="macromolecule" id="s5028_sa189" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD28 CASCADE:TCR CASCADE:B4H4 MODULE:SMAC MODULE:TCR_SIGNALING PMID:22437870 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:22437870 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:1313950 Costimulatory signaling by CD28 has been described as critical for the enhancement of T cell proliferation</body> </html> </notes> <label text="CD28"/> <bbox w="80.0" h="50.0" x="3900.0" y="845.0"/> <glyph class="state variable" id="_d5c8ba8f-80ea-49cc-bbba-5a0623c512d9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3892.5" y="865.0"/> </glyph> <glyph class="unit of information" id="_e43f2f2e-cfb3-4d04-9ac3-0445ef36305c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3917.5" y="840.0"/> </glyph> </glyph> <glyph class="complex" id="s5029_csa75" compartmentRef="c2_ca2"> <label text="s5029"/> <bbox w="200.0" h="150.0" x="4210.0" y="1655.0"/> <glyph class="macromolecule" id="s5032_sa685"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:GRB2 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="4320.0" y="1730.0"/> </glyph> <glyph class="macromolecule" id="s5033_sa688"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:GRAP2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. GRAP2 (GADS, GRPL) PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:10209041 GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76.</body> </html> </notes> <label text="GRAP2"/> <bbox w="80.0" h="40.0" x="4320.0" y="1670.0"/> </glyph> <glyph class="macromolecule" id="s5034_sa689"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD28 CASCADE:TCR CASCADE:B4H4 MODULE:SMAC MODULE:TCR_SIGNALING PMID:22437870 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:22437870 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:1313950 Costimulatory signaling by CD28 has been described as critical for the enhancement of T cell proliferation</body> </html> </notes> <label text="CD28"/> <bbox w="80.0" h="50.0" x="4230.0" y="1670.0"/> <glyph class="state variable" id="_c47c106f-65e6-4d48-82e0-0b8f09c4f76f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4222.5" y="1690.0"/> </glyph> <glyph class="unit of information" id="_dade22d4-3c3d-4a98-8e1f-eda552c5d537"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4247.5" y="1665.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4291_sa690" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITPR1 HGNC:6180 ENTREZ:3708 UNIPROT:Q14643 GENECARDS:ITPR1 REACTOME:405731 KEGG:3708 ATLASONC:GC_ITPR1 WIKI:ITPR1 HUGO:ITPR2 HGNC:6181 ENTREZ:3709 UNIPROT:Q14571 GENECARDS:ITPR2 REACTOME:405722 KEGG:3709 ATLASONC:GC_ITPR2 WIKI:ITPR2 HUGO:ITPR3 HGNC:6182 ENTREZ:3710 UNIPROT:Q14573 GENECARDS:ITPR3 REACTOME:57433 KEGG:3710 ATLASONC:GC_ITPR3 WIKI:ITPR3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT.</body> </html> </notes> <label text="IP3R*"/> <bbox w="80.0" h="50.0" x="2610.0" y="2855.0"/> <glyph class="unit of information" id="_3b450758-9bb9-432e-883e-e01e4971a4c1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2627.5" y="2850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2455_sa692" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>calmodulin 1 (phosphorylase kinase, delta) CALML2 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 2 (phosphorylase kinase, delta) HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 3 (phosphorylase kinase, delta) HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 CASCADE:TCR MODULE:TCR_SIGNALING 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) ). </body> </html> </notes> <label text="Calmodulin*"/> <bbox w="80.0" h="40.0" x="2550.0" y="3425.0"/> </glyph> <glyph class="simple chemical" id="s406_sa694" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING PMID:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 PMID:25456276 Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. The exception is T-cell receptor activation, which is linked to PLCG1, not PLCG2. PLCγ enzymes are mainly activated through tyrosine phosphorylation by receptor and non-receptor kinases. As in all other PLC families, the main signaling output is generation of the second messengers inositol 1,4,5- trisphosphate (IP3, or InsP3) and diacylglycerol (DAG), from phosphatidylinositol 4,5- bisphosphate (PIP2, or PtdIns(4,5)P2). The released IP3 binds to IP3 receptors on the endoplasmic reticulum resulting in Ca2+ release into the cytoplasm. D</body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="3515.0" y="2397.5"/> </glyph> <glyph class="simple chemical" id="s397_sa695" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING PMID:25456276 Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. The exception is T-cell receptor activation, which is linked to PLCG1, not PLCG2. PLCγ enzymes are mainly activated through tyrosine phosphorylation by receptor and non-receptor kinases. As in all other PLC families, the main signaling output is generation of the second messengers inositol 1,4,5- trisphosphate (IP3, or InsP3) and diacylglycerol (DAG), from phosphatidylinositol 4,5- bisphosphate (PIP2, or PtdIns(4,5)P2). The released IP3 binds to IP3 receptors on the endoplasmic reticulum resulting in Ca2+ release into the cytoplasm.</body> </html> </notes> <label text="IP3"/> <bbox w="70.0" h="25.0" x="2895.0" y="2947.5"/> </glyph> <glyph class="macromolecule" id="s396_sa1023" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PLCG1 MODULE:TCR_SIGNALING CASCADE:CD226 CASCADE:TCR PMID:1712101; PMID:25456276 Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. The exception is T-cell receptor activation, which is linked to PLCG1, not PLCG2. PLCγ enzymes are mainly activated through tyrosine phosphorylation by receptor and non-receptor kinases. As in all other PLC families, the main signaling output is generation of the second messengers inositol 1,4,5- trisphosphate (IP3, or InsP3) and diacylglycerol (DAG), from phosphatidylinositol 4,5- bisphosphate (PIP2, or PtdIns(4,5)P2). The released IP3 binds to IP3 receptors on the endoplasmic reticulum resulting in Ca2+ release into the cytoplasm. D PMID:10811803; PMID:9846483 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. LAT Is Required for TCR-Mediated Activation of PLCγ1 and the Ras Pathways. PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. Tec family kinases directly activate PLCγ1 and regulate Ca2+ responses in immune cells AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release. PMID:14764585; PMID:11994416 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="3670.0" y="1870.0"/> <glyph class="state variable" id="_76f9a36d-04c8-4bba-8e24-ada238c25f5f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3665.0" y="1885.0"/> </glyph> </glyph> <glyph class="complex" id="s632_csa76" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:MACROPHAGE PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13.</body> </html> </notes> <label text="IP3:IP3R*"/> <bbox w="86.0" h="115.0" x="2647.0" y="3042.5"/> <glyph class="macromolecule" id="s404_sa701"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITPR1 HGNC:6180 ENTREZ:3708 UNIPROT:Q14643 GENECARDS:ITPR1 REACTOME:405731 KEGG:3708 ATLASONC:GC_ITPR1 WIKI:ITPR1 HUGO:ITPR2 HGNC:6181 ENTREZ:3709 UNIPROT:Q14571 GENECARDS:ITPR2 REACTOME:405722 KEGG:3709 ATLASONC:GC_ITPR2 WIKI:ITPR2 HUGO:ITPR3 HGNC:6182 ENTREZ:3710 UNIPROT:Q14573 GENECARDS:ITPR3 REACTOME:57433 KEGG:3710 ATLASONC:GC_ITPR3 WIKI:ITPR3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT.</body> </html> </notes> <label text="IP3R*"/> <bbox w="80.0" h="50.0" x="2650.0" y="3095.0"/> <glyph class="unit of information" id="_5ffd5c09-0849-40d8-abd8-caf9f8c617f4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2667.5" y="3090.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s403_sa702"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING</body> </html> </notes> <label text="IP3"/> <bbox w="70.0" h="25.0" x="2654.125" y="3064.0"/> </glyph> </glyph> <glyph class="complex" id="s1817_csa77" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR 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) ). </body> </html> </notes> <label text="s1817"/> <bbox w="100.0" h="120.0" x="2320.0" y="4055.0"/> <glyph class="macromolecule" id="s2473_sa703"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>calmodulin 1 (phosphorylase kinase, delta) CALML2 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 2 (phosphorylase kinase, delta) HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 3 (phosphorylase kinase, delta) HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 CASCADE:TCR MODULE:TCR_SIGNALING 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) ). </body> </html> </notes> <label text="Calmodulin*"/> <bbox w="80.0" h="40.0" x="2330.0" y="4065.0"/> </glyph> <glyph class="simple chemical" id="s2474_sa704"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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="2357.5" y="4122.5"/> </glyph> </glyph> <glyph class="complex" id="s1823_csa78" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR 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:9510155 calcineurin inhibitor FK506 also reduced CD3/CD28-induced production of IL-3, IL-4, IL-10, TNF-α, and IL-6 but augmented that of GM-CSF, IL-5, IFN-γ, and IL-13. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation Vav2 Functions Upstream of Cn to Inhibit TCR-induced NF-AT Activation</body> </html> </notes> <label text="s1823"/> <bbox w="180.0" h="140.0" x="2040.0" y="4525.0"/> <glyph class="simple chemical" id="s1824_sa705"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:Fc_gamma_RIII MODULE:TCR MODULE:TCR_SIGNALING PMID:19349987 Ca2+ signaling requires myosin IIA activity</body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="2167.5" y="4602.5"/> </glyph> <glyph class="macromolecule" id="s1825_sa706"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>calmodulin 1 (phosphorylase kinase, delta) CALML2 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 2 (phosphorylase kinase, delta) HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 calmodulin 3 (phosphorylase kinase, delta) HUGO:CALM3 HGNC:1449 ENTREZ:808 UNIPROT:P62158 GENECARDS:CALM3 REACTOME:51306 KEGG:808 ATLASONC:GC_CALM3 WIKI:CALM3 HUGO:CALM1 HGNC:1442 ENTREZ:801 UNIPROT:P62158 GENECARDS:CALM1 REACTOME:51306 KEGG:801 ATLASONC:GC_CALM1 WIKI:CALM1 HUGO:CALM2 HGNC:1445 ENTREZ:805 UNIPROT:P62158 GENECARDS:CALM2 REACTOME:51306 KEGG:805 WIKI:CALM2 CASCADE:TCR MODULE:TCR_SIGNALING 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) ). </body> </html> </notes> <label text="Calmodulin*"/> <bbox w="80.0" h="40.0" x="2140.0" y="4545.0"/> </glyph> <glyph class="macromolecule" id="s2472_sa707"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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)" HUGO:PPP3CA HGNC:9314 ENTREZ:5530 UNIPROT:Q08209 GENECARDS:PPP3CA 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)" HUGO:PPP3CB HGNC:9315 ENTREZ:5532 UNIPROT:P16298 GENECARDS:PPP3CB 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)" HUGO:PPP3CC HGNC:9316 ENTREZ:5533 UNIPROT:P48454 GENECARDS:PPP3CC REACTOME:61114 KEGG:5533 ATLASONC:GC_PPP3CC WIKI:PPP3CC CASCADE:TCR MODULE:TCR_SIGNALING 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:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10.</body> </html> </notes> <label text="CNA*"/> <bbox w="80.0" h="40.0" x="2050.0" y="4545.0"/> </glyph> <glyph class="macromolecule" id="s1828_sa708"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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" HUGO:PPP3R1 HGNC:9317 ENTREZ:5534 UNIPROT:P63098 GENECARDS:PPP3R1 REACTOME:51292 KEGG:5534 ATLASONC:GC_PPP3R1 WIKI:PPP3R1 protein phosphatase 3, regulatory subunit B, beta HUGO:PPP3PR2 GENECARDS:PPP3PR2 WIKI:PPP3PR2 HUGO:PPP3R2 HGNC:9318 ENTREZ:5535 UNIPROT:Q96LZ3 GENECARDS:PPP3R2 KEGG:5535 ATLASONC:GC_PPP3R2 WIKI:PPP3R2 CASCADE:TCR MODULE:TCR_SIGNALING 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:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10.</body> </html> </notes> <label text="CNB*"/> <bbox w="80.0" h="40.0" x="2050.0" y="4595.0"/> </glyph> </glyph> <glyph class="complex" id="s1822_csa79" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR 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) ). </body> </html> </notes> <label text="s1822"/> <bbox w="100.0" h="120.0" x="2640.0" y="3805.0"/> <glyph class="macromolecule" id="s3590_sa709"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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)" HUGO:PPP3CA HGNC:9314 ENTREZ:5530 UNIPROT:Q08209 GENECARDS:PPP3CA 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)" HUGO:PPP3CB HGNC:9315 ENTREZ:5532 UNIPROT:P16298 GENECARDS:PPP3CB 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)" HUGO:PPP3CC HGNC:9316 ENTREZ:5533 UNIPROT:P48454 GENECARDS:PPP3CC REACTOME:61114 KEGG:5533 ATLASONC:GC_PPP3CC WIKI:PPP3CC CASCADE:TCR MODULE:TCR_SIGNALING 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:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10.</body> </html> </notes> <label text="CNA*"/> <bbox w="80.0" h="40.0" x="2650.0" y="3815.0"/> </glyph> <glyph class="macromolecule" id="s3591_sa710"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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" HUGO:PPP3R1 HGNC:9317 ENTREZ:5534 UNIPROT:P63098 GENECARDS:PPP3R1 REACTOME:51292 KEGG:5534 ATLASONC:GC_PPP3R1 WIKI:PPP3R1 protein phosphatase 3, regulatory subunit B, beta HUGO:PPP3PR2 GENECARDS:PPP3PR2 WIKI:PPP3PR2 HUGO:PPP3R2 HGNC:9318 ENTREZ:5535 UNIPROT:Q96LZ3 GENECARDS:PPP3R2 KEGG:5535 ATLASONC:GC_PPP3R2 WIKI:PPP3R2 CASCADE:TCR MODULE:TCR_SIGNALING 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:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10.</body> </html> </notes> <label text="CNB*"/> <bbox w="80.0" h="40.0" x="2650.0" y="3865.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s787_sa713" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:VAV1 MODULE:TCR_SIGNALING PMID:10714681 PKCθ is regulated by Vav1, a guanine nucleotide exchange factor for Rac and Cdc42 that plays an important role in T cell development and activation46. Thus, a dominant negative PKCθ mutant blocked a number of growth signals, which are normally induced by overexpression of Vav1, namely, activation of JNK, the IL-2 gene promoter and NFAT or AP-1 reporter genes. Conversely, a dominant negative Vav1 mutant did not significantly inhibit the same signaling events induced by a constitutively active PKCθ mutant46, tentatively placing PKCθ downstream of Vav1 in these growth signaling pathways. Vav promoted PKCθ translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCθ to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production. PMID:25539813 Vav1 is the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions. PMID:12186560 Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. PMID:11754814 CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. PMID:10849438; PMID:10077632 ;PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function Tyrosine-phosphorylated Vav1 as a Point of Integration for T-cell Receptor- and CD28-mediated Activation of JNK, p38, and Interleukin-2 Transcription Vav1 is phosphorylated probably by Lck. The Rho-family GTP exchange factor Vav is a critical transducer of T cell receptor signals to the calcium, ERK, and NF-κB pathways PMID:10898494 Vav-induced NFAT activation involves a MEK/ERK pathway 3 Vav functions upstream of Ras in the NFAT activation pathway Ras function is required for Vav-induced ERK activation Vav up-regulates the expression of CD69 via a Ras-dependent, but Rac-independent, PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. Vav1 Transduces TCR Signals to Ras and ERK via PLC and DAG Defective TCR-induced DAG Production in Vav1-deficient Cells Defective phosphorylation of PKCθ and PKD in Vav1–/– thymocytes. Vav1 Is Required for TCR-induced Translocation of Ras-GRP1 in Vav1–/– cells, whereasGrb2 was constitutively associated with Sos1 and Sos2, there was very little or no inducible association with LAT. Taken together these results show that in Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:11994416 Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways PMID:10646608 Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b Cbl-b negatively regulates Vav1 tyrosine phosphorylation. Probably downstream of PI3K) PMID:11526404 inhibition of PI3K leads to a reduction in TCR-induced Vav phosphorylation PMID:12616499 Vav1 transduces TCR signals required for LFA-1 function and cell polarization at the immunological synapse. Vav1 is required for TCR-induced activation of LFA-1 Vav1 is required for TCR-induced polarization of the MTOC PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="2030.0" y="2360.0"/> <glyph class="state variable" id="_c6cb2f03-495c-4e72-8bde-d9bec6313be0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2022.5" y="2375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s758_sa714" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:VAV1 MODULE:TCR_SIGNALING PMID:10714681 PKCθ is regulated by Vav1, a guanine nucleotide exchange factor for Rac and Cdc42 that plays an important role in T cell development and activation46. Thus, a dominant negative PKCθ mutant blocked a number of growth signals, which are normally induced by overexpression of Vav1, namely, activation of JNK, the IL-2 gene promoter and NFAT or AP-1 reporter genes. Conversely, a dominant negative Vav1 mutant did not significantly inhibit the same signaling events induced by a constitutively active PKCθ mutant46, tentatively placing PKCθ downstream of Vav1 in these growth signaling pathways. Vav promoted PKCθ translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCθ to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production. PMID:25539813 Vav1 is the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions. PMID:12186560 Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. PMID:11754814 CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. PMID:10849438; PMID:10077632 ;PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function Tyrosine-phosphorylated Vav1 as a Point of Integration for T-cell Receptor- and CD28-mediated Activation of JNK, p38, and Interleukin-2 Transcription Vav1 is phosphorylated probably by Lck. The Rho-family GTP exchange factor Vav is a critical transducer of T cell receptor signals to the calcium, ERK, and NF-κB pathways PMID:10898494 Vav-induced NFAT activation involves a MEK/ERK pathway 3 Vav functions upstream of Ras in the NFAT activation pathway Ras function is required for Vav-induced ERK activation Vav up-regulates the expression of CD69 via a Ras-dependent, but Rac-independent, PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. Vav1 Transduces TCR Signals to Ras and ERK via PLC and DAG Defective TCR-induced DAG Production in Vav1-deficient Cells Defective phosphorylation of PKCθ and PKD in Vav1–/– thymocytes. Vav1 Is Required for TCR-induced Translocation of Ras-GRP1 in Vav1–/– cells, whereasGrb2 was constitutively associated with Sos1 and Sos2, there was very little or no inducible association with LAT. Taken together these results show that in Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:11994416 Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways PMID:10646608 Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b Cbl-b negatively regulates Vav1 tyrosine phosphorylation. Probably downstream of PI3K) PMID:11526404 inhibition of PI3K leads to a reduction in TCR-induced Vav phosphorylation PMID:12616499 Vav1 transduces TCR signals required for LFA-1 function and cell polarization at the immunological synapse. Vav1 is required for TCR-induced activation of LFA-1 Vav1 is required for TCR-induced polarization of the MTOC PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="2030.0" y="2170.0"/> <glyph class="state variable" id="_e8c5a0cb-1761-4d4b-95a3-5ed25b803cd6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2025.0" y="2185.0"/> </glyph> </glyph> <glyph class="complex" id="s5037_csa80" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 MODULE:DC MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s94"/> <bbox w="90.0" h="105.0" x="1695.0" y="2562.5"/> <glyph class="simple chemical" id="s2985_sa715"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="1710.0" y="2615.0"/> </glyph> <glyph class="macromolecule" id="s3772_sa716"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RAC1 HUGO:RAC2 CASCADE:TCR MODULE:TCR_SIGNALING MODULE:TH1 PMID:10714681 PKCθ is regulated by Vav1, a guanine nucleotide exchange factor for Rac and Cdc42 that plays an important role in T cell development and activation46. Thus, a dominant negative PKCθ mutant blocked a number of growth signals, which are normally induced by overexpression of Vav1, namely, activation of JNK, the IL-2 gene promoter and NFAT or AP-1 reporter genes. Conversely, a dominant negative Vav1 mutant did not significantly inhibit the same signaling events induced by a constitutively active PKCθ mutant46, tentatively placing PKCθ downstream of Vav1 in these growth signaling pathways. Vav promoted PKCθ translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCθ to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production. PMID:15184873 The action of Vav and Rac1 proteins on RasGRP1 is specifically dependent on PLCG activity The effect of the Vav/Rac pathway on RasGRP1 is independent of the kinase activity of PI3-K Vav and Rac1 proteins promote constitutive tyrosine phosphorylation and increased membrane localization of PLC- in Jurkat cells The interaction between Vav and RasGRP1 results in enhanced activation of Ras- and Rac-dependent biological responses Rac2 was found to be specifically expressed in TH1 cells, and overexpression of Rac2 in T cells seems to drive TH1 differentiation (Li et al., 2000).</body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="1700.0" y="2565.0"/> </glyph> </glyph> <glyph class="complex" id="s5038_csa81" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:INTEGRIN_A4B1 CASCADE:INTEGRIN_A5B1 CASCADE:INTEGRIN_AVB5 MODULE:DC MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s94"/> <bbox w="100.0" h="110.0" x="1450.0" y="2560.0"/> <glyph class="simple chemical" id="s5040_sa717"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="1468.75" y="2611.875"/> </glyph> <glyph class="macromolecule" id="s3771_sa718"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RAC1 HUGO:RAC2 CASCADE:TCR MODULE:TCR_SIGNALING MODULE:TH1 PMID:10714681 PKCθ is regulated by Vav1, a guanine nucleotide exchange factor for Rac and Cdc42 that plays an important role in T cell development and activation46. Thus, a dominant negative PKCθ mutant blocked a number of growth signals, which are normally induced by overexpression of Vav1, namely, activation of JNK, the IL-2 gene promoter and NFAT or AP-1 reporter genes. Conversely, a dominant negative Vav1 mutant did not significantly inhibit the same signaling events induced by a constitutively active PKCθ mutant46, tentatively placing PKCθ downstream of Vav1 in these growth signaling pathways. Vav promoted PKCθ translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCθ to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production. PMID:15184873 The action of Vav and Rac1 proteins on RasGRP1 is specifically dependent on PLCG activity The effect of the Vav/Rac pathway on RasGRP1 is independent of the kinase activity of PI3-K Vav and Rac1 proteins promote constitutive tyrosine phosphorylation and increased membrane localization of PLC- in Jurkat cells The interaction between Vav and RasGRP1 results in enhanced activation of Ras- and Rac-dependent biological responses Rac2 was found to be specifically expressed in TH1 cells, and overexpression of Rac2 in T cells seems to drive TH1 differentiation (Li et al., 2000).</body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="1460.0" y="2565.0"/> </glyph> </glyph> <glyph class="complex" id="s5042_csa82" compartmentRef="c2_ca2"> <label text="s5042"/> <bbox w="100.0" h="120.0" x="3890.0" y="1980.0"/> <glyph class="macromolecule" id="s5041_sa719"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 MODULE:SMAC MODULE:TCR_SIGNALING HUGO:PRKCQ CASCADE:TCR PMID:23433459 PKCtheta in tregs. PMID:23886063; PMID:9738502 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta PMID:17544292 ; PMID:23433459 Protein kinase C theta (PKCtheta): a key player in T cell life and death. Mutation of the PKCθ gene leads to impaired receptor-induced stimulation of the transcription factors AP-1, NF-κB and NFAT, which results in defective T cell activation, and to aberrant expression of apoptosis-related proteins, resulting in poor T cell survival. Furthermore, PKCθ-deficient mice display defects in the differentiation of T helper subsets, particularly in Th2 and Th17-mediated inflammatory responses. The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation PMID: 10746729 The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:15536066 Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. PMID:10652356 The C2-like domain contains a tyrosine residue (Tyr-90), which is phosphorylated by the T cell tyrosine kinase Lck PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner PKCθ was required for the survival of both activated CD4 and CD8+ T cells</body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="3900.0" y="1990.0"/> <glyph class="state variable" id="_f4dced03-0e2a-41cf-98b1-571a65e8ebb9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3895.0" y="2005.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s5043_sa720"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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="3905.0" y="2047.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1831_sa726" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 CASCADE:TCR MODULE:TCR_SIGNALING PMID:11148124 NFAT is activated in T-cells downstream of TCR signaling PMID:8068174 NF-ATp cooperates with Fos- and Jun-family proteins to mediate transcription of the interleukin 2 gene PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation (robably via RAS) Vav2 Functions Upstream of Cn to Inhibit TCR-induced NF-AT Activation PMID:10898494 The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation PMID:19836308; PMID:11406367 GSK3 inactivates NFATc by phosphorylation-dependent stimulation of NFATc nuclear export</body> </html> </notes> <label text="NFAT*"/> <bbox w="80.0" h="40.0" x="2120.0" y="5215.0"/> <glyph class="state variable" id="_d23bfe6b-cdd3-4168-af70-66bf17ccd4a5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2112.5" y="5230.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1834_sa727" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="NFAT*"/> <bbox w="90.0" h="25.0" x="2285.0" y="5122.5"/> <glyph class="unit of information" id="_5213dbf7-526a-4394-97b2-74a62bef07d9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2320.0" y="5117.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1833_sa728" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 MODULE:TCR_SIGNALING 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) ). </body> </html> </notes> <label text="NFAT*"/> <bbox w="70.0" h="25.0" x="2295.0" y="5062.5"/> </glyph> <glyph class="macromolecule" id="s1829_sa729" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 HUGO:NFATC1 HGNC:7775 ENTREZ:4772 UNIPROT:O95644 GENECARDS:NFATC1 REACTOME:60119 KEGG:4772 ATLASONC:GC_NFATC1 WIKI:NFATC1 nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 3 HUGO:NFATC3 HGNC:7777 ENTREZ:4775 UNIPROT:Q12968 GENECARDS:NFATC3 REACTOME:60123 KEGG:4775 ATLASONC:GC_NFATC3 WIKI:NFATC3 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 NF-ATP, NFAT1, NFATp HUGO:NFATC2 HGNC:7776 ENTREZ:4773 UNIPROT:Q13469 GENECARDS:NFATC2 REACTOME:60121 KEGG:4773 ATLASONC:NFATC2ID44004ch20q13 WIKI:NFATC2 NF-ATC, NFAT2, NFATc nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 NFAT3 HUGO:NFATC4 HGNC:7778 ENTREZ:4776 UNIPROT:Q14934 GENECARDS:NFATC4 KEGG:4776 ATLASONC:GC_NFATC4 WIKI:NFATC4 UNIIPROT:Q149934 nuclear factor of activated T-cells 5, tonicity-responsive NFAT5 HUGO:NFAT5 HGNC:7774 ENTREZ:10725 UNIPROT:O94916 GENECARDS:NFAT5 KEGG:10725 ATLASONC:GC_NFAT5 WIKI:NFAT5 CASCADE:TCR MODULE:TCR_SIGNALING PMID:11148124 NFAT is activated in T-cells downstream of TCR signaling PMID:8068174 NF-ATp cooperates with Fos- and Jun-family proteins to mediate transcription of the interleukin 2 gene PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation (robably via RAS) Vav2 Functions Upstream of Cn to Inhibit TCR-induced NF-AT Activation PMID:10898494 The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation PMID:19836308; PMID:11406367 GSK3 inactivates NFATc by phosphorylation-dependent stimulation of NFATc nuclear export</body> </html> </notes> <label text="NFAT*"/> <bbox w="230.0" h="150.0" x="2345.0" y="5190.0"/> <glyph class="state variable" id="_98f25b06-4ad0-4726-8e57-525ae9d2f27c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2340.0" y="5260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5053_sa732" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GSK3B HUGO:GSK3A CELL:TCD4 CELL:TCD8 CASCADE:TCR MODULE:CHEKPOINTS MODULE:TCR_SIGNALING PMID:19836308 CD28 stimulation inhibits GSK3 by increasing inhibitory serine phosphorylation mediated by the phosphatidylinositol 3-kinase (PI3K) pathway, but independently of the guanine nucleotide exchange factor Vav-1 [25]. By inhibiting GSK3, CD28 relieves inhibition of nuclear factor of activated T cells (NFAT), thus providing a mechanism by which cells can monitor receptor occupancy to maintain T-cell responses Maintenance of GSK3 inhibition is critical for CD4+ and CD8+ T-cell survival after activation GSK3 inhibition increased the production of anti-inflammatory IL-10 by memory CD4+ T cells T-cell migration across endothelial cell barriers separating blood from tissue is critical for accessing targets and failure to clear pathogens can result from blocked migration, for example, due to a lack of necessary recognition molecules. T-cell motility is promoted by the chemokine CXCL12, which inhibits GSK3-mediated phosphorylation of CRMP2 mitogenic stimulation of T lymphocytes causes rapid activation of protein synthesis, in part due to increased expression of many translational components such as the initiation factor eIF2B. eIF2B is phosphorylated by GSK3, which inhibits nucleotide exchange, and this inhibition is released by TCR activation-induced inhibition of GSK3 PMID:19836308 GSK3 inactivates NFATc by phosphorylation-dependent stimulation of NFATc nuclear export PMID:26885856 TCR and CD28 phosphorylate and inactivate GSK-3 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID:23732914 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β</body> </html> </notes> <label text="GSK3*"/> <bbox w="80.0" h="40.0" x="4460.0" y="3495.0"/> <glyph class="state variable" id="_ef9eec94-f0f3-44dd-86d0-b7029c994cbe"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4455.0" y="3510.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s742_sa740" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:16713974 TLR2 activates (induses phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. ----- content merged by Celldesigner to SBGN-ML translation ------ HUGO:MAPK8 HGNC:6881 ENTREZ:5599 UNIPROT:P45983 GENECARDS:MAPK8 REACTOME:59293 KEGG:5599 ATLASONC:JNK1ID196 WIKI:MAPK8 mitogen-activated protein kinase 9 HUGO:MAPK9 HGNC:6886 ENTREZ:5601 UNIPROT:P45984 GENECARDS:MAPK9 REACTOME:59295 KEGG:5601 ATLASONC:JNK2ID426 WIKI:MAPK9 mitogen-activated protein kinase 10 HUGO:MAPK10 HGNC:6872 ENTREZ:5602 UNIPROT:P53779 GENECARDS:MAPK10 REACTOME:59297 KEGG:5602 ATLASONC:JNK3ID427 WIKI:MAPK10 CASCADE:TCR MODULE:TCR_SIGNALING MODULE:TH1 PMID:10849438 Tyrosine-phosphorylated Vav1 as a Point of Integration for T-cell Receptor- and CD28-mediated Activation of JNK, p38, and Interleukin-2 Transcription PMID:11371360, PMID:8205621 p38 and JNK pathways are very important for the responses of TH1 effector cells (Lu et al., 1999; Rincon et al., 1998; Yang et al., 1998). The p38 kinase can be activated efficiently in TH1 effector cells but not in TH2 effector cells; blocking the pathway inhibits and agonists of the pathway potentiate TH1 responses References_end</body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="1470.0" y="4375.0"/> <glyph class="state variable" id="_d340b8b8-bf5a-420b-8585-32420d9c5a89"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1465.0" y="4390.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4197_sa741" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAPK8 HGNC:6881 ENTREZ:5599 UNIPROT:P45983 GENECARDS:MAPK8 REACTOME:59293 KEGG:5599 ATLASONC:JNK1ID196 WIKI:MAPK8 mitogen-activated protein kinase 9 HUGO:MAPK9 HGNC:6886 ENTREZ:5601 UNIPROT:P45984 GENECARDS:MAPK9 REACTOME:59295 KEGG:5601 ATLASONC:JNK2ID426 WIKI:MAPK9 mitogen-activated protein kinase 10 HUGO:MAPK10 HGNC:6872 ENTREZ:5602 UNIPROT:P53779 GENECARDS:MAPK10 REACTOME:59297 KEGG:5602 ATLASONC:JNK3ID427 WIKI:MAPK10 CASCADE:TCR MODULE:TCR_SIGNALING MODULE:TH1 PMID:10849438 Tyrosine-phosphorylated Vav1 as a Point of Integration for T-cell Receptor- and CD28-mediated Activation of JNK, p38, and Interleukin-2 Transcription PMID:11371360, PMID:8205621 p38 and JNK pathways are very important for the responses of TH1 effector cells (Lu et al., 1999; Rincon et al., 1998; Yang et al., 1998). The p38 kinase can be activated efficiently in TH1 effector cells but not in TH2 effector cells; blocking the pathway inhibits and agonists of the pathway potentiate TH1 responses References_end</body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="1470.0" y="4475.0"/> <glyph class="state variable" id="_be2ac3d6-e522-45a9-a395-a4bef7c1b664"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1462.5" y="4490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4039_sa742" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MODULE:TCELL MODULE:TCR_SIGNALING CADCADE:TCR Maps_Modules_end References_begin: PMID:11148124 JNK/AP1 signaling is activated in T-cells downstream of TCR signaling PMID:15214048; PMID:10807788; PMID:24027568 AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release. probably via RAS/ERK pathway PMID: 11262396 We examined whether Vav2 overexpression results in stimulation of c-fos SRE transcriptional activity. We transfected Jurkat-TAg cells with Myc-tagged Vav1 or Vav2 along with a luciferase reporter driven by SRE-binding sequences. Similarly both Vav1 and Vav2 induced a marked increase of either the basal or TCR-stimulated activities of SRE reporter plasmid References_end PMID:12818166 the expression of JunB, a component of the AP-1 family induced after T cell activation, was reduced by 49% after B7S1 costimulation. On the other hand, there was little change in c-Jun expression (11% reduction) with B7S1-Ig treatment. JunB has been previously shown to bind to the IL-2 promoter (Boise et al., 1993 and JunB overexpression resulted in greater IL-2 production (our unpublished data). Since JunB is induced after T cell activation (Jain et al., 1995, the mechanism of which is unknown, B7S1 costimulation may result in inefficient JunB induction.</body> </html> </notes> <label text="AP1*"/> <bbox w="80.0" h="40.0" x="1690.0" y="4705.0"/> <glyph class="state variable" id="_f0eabe57-da61-4764-b13e-ae75fc173eff"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1685.0" y="4720.0"/> </glyph> </glyph> <glyph class="phenotype" id="s5058_sa744" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Following engagement by B7, human CD28 binds Vav1 that in turn favors the recruitment of PIP5Kα and PIP5Kβ. PIP5Kα generates PIP2 that favors the recruitment of the WASP/Cdc42/ARP2/3 complex, which, in turn, promotes actin polymerization. PIP5Kβ mediates the recruitment of filamin-A (FLN-A) and lipid rafts to the T:APC contact zone. (B) Upon TCR recognition of peptide–MHC complexes presented on the surface of APCs, Lck and Fyn phosphorylate CD3 and ζ chains, which bind ZAP-70. ZAP-70 phosphorylates LAT that in turn binds PLC-γ1. CD28 mediates the recruitment of Vav-associated PIP5Kα that generates PIP2. PLC-γ1 hydrolyzes PIP2 in IP3 and DAG. IP3 induces the activation of Ca2+/calcineurin (CN) and NF-AT. CD28 also binds class 1A PI3K that phosphorylates PIP2 and generates PIP3 that favors the recruitment and activation of Akt. Akt cooperates with DAG to activate PKCθ/CARMA1/Bcl10/MALT1 complex and NF-κB. PMID: 19132916 rew PMID:17544292 Recent studies have indicated several potential candidate substrates of PKCθ. The PKCθ-mediated phosphorylation of SPAK41 and CARMA152, which is required for proper activation of the AP-1 and NF-κB signaling pathways, respectively, in T cells, has been discussed earlier. The first PKCθ substrate to be identified was moesin53, a member of the ezrin-radixin-moesin (ERM) family of cytoskeletal proteins, which serve to link intracellular signaling proteins to the actin cytoskeleton. Interaction of ERM proteins with actin is regulated by phosphorylation of a conserved Thr residue near their C-terminus, and that conserved residue (Thr-558) was found to be phosphorylated by PKCθ53. Of interest, other tested PKC enzymes did not phosphorylate moesin53. However, it is not clear whether PKCθ phosphorylates moesin (or other ERM proteins) in intact T cells and, if so, whether other kinases can phosphorylate ERM proteins. The biological role of moesin phosphorylation in the context of T cell activation is not clear, but it may be involved in remodeling of the actin cytoskeleton, which occurs following the interaction of an Ag-specific T cells with an APC and the organization of the IS, given the findings that upon assembly of the IS, ERM proteins translocate to the T cell membrane at a site opposite the IS54-56. PKCθ may potentially regulate actin cytoskeleton remodeling in Ag-stimulated T cells by phosphorylating another substrate, i.e., WASP-interacting protein (WIP)57. Actin polymerization following TCR engagement is dependent on Wiskott-Aldrich syndrome protein (WASP), which is one of the effectors of the small GTPase Cdc42, and is critical for T cell activation58. WIP associates with WASP and thereby inhibits its Cdc42-mediated activation. TCR engagement was found to lead to PKCθ-dependent phosphorylation of WIP, most likely on Ser-488, resulting in dissociation of WIP from WASP and, consequently, WASP activation57. The importance of PKCθ for WIP phosphorylation was evident from the finding that WIP phosphorylation was largely impaired in PKCθ−/− T cells57.</body> </html> </notes> <label text="Cytoskeleton_remodeling"/> <bbox w="180.0" h="55.0" x="4520.0" y="5937.5"/> </glyph> <glyph class="macromolecule" id="s3597_sa746" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K4 CASCADE:TCR MODULE:TCR_SIGNALING PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK3 and MKK6 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3 Baseline phosphorylation of MKK4 did not increase with anti-CD3 stimulation PMID: 9294148 SEK1 (MAP2K4) has a role in CD28-mediated costimulation for proliferation and IL-2 production in peripheral T cells</body> </html> </notes> <label text="MAP2K4"/> <bbox w="80.0" h="40.0" x="1439.0" y="3865.0"/> <glyph class="state variable" id="_11598572-1928-4981-9996-f397166ac351"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1434.0" y="3880.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3598_sa748" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K4 CASCADE:TCR MODULE:TCR_SIGNALING PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK3 and MKK6 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3 Baseline phosphorylation of MKK4 did not increase with anti-CD3 stimulation PMID: 9294148 SEK1 (MAP2K4) has a role in CD28-mediated costimulation for proliferation and IL-2 production in peripheral T cells</body> </html> </notes> <label text="MAP2K4"/> <bbox w="80.0" h="40.0" x="1440.0" y="3965.0"/> <glyph class="state variable" id="_018090d6-1bc3-46ba-8834-31c61cd9a1bd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1432.5" y="3980.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4850_sa609" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PTPRC CASCADE:TCR MODULE:SMAC PMID:23886063; PMID:23620508; For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal linker proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PTPRC (CD45) PMID:23620508 In the resting state, the T cell receptor (TCR)–CD3 complex is primarily monomeric or forms very transient small aggregates. Phosphatase activity dominates and the level of TCR–CD3 immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation is low. b | TCR engagement with peptide–MHC complex leads to segregation of the TCR–CD3 complex from phosphatases such as CD45, as well as aggregation and conformational change in the TCR–CD3 cytoplasmic domains. PMID:19290918; PMID:12414720 the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation</body> </html> </notes> <label text="PTPRC"/> <bbox w="80.0" h="50.0" x="4761.0" y="970.0"/> <glyph class="unit of information" id="_d59ac308-c4da-4682-94cb-6ce9b59e7865"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4778.5" y="965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5062_sa751" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FYN CASCADE:TCR MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells PMID:10648627 Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="2940.0" y="885.0"/> <glyph class="state variable" id="_b4635b45-ac66-4508-99ef-8bac2b1b59bf"> <state value="" variable="Y417"/> <bbox w="30.0" h="10.0" x="3005.0" y="918.2294"/> </glyph> <glyph class="state variable" id="_6b9ff448-d577-493c-97e9-099f75d5fff6"> <state value="P" variable="Y528"/> <bbox w="35.0" h="10.0" x="2925.946" y="880.0"/> </glyph> </glyph> <glyph class="complex" id="s5072_csa84" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:23886063 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta</body> </html> </notes> <label text="s4356"/> <bbox w="120.0" h="163.75" x="3350.0" y="1043.125"/> <glyph class="macromolecule" id="s5074_sa753"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD247 CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is lolalized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:11353765 Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="3370.0" y="1088.125"/> <glyph class="state variable" id="_2d02c629-23f5-4f94-9b98-9e71fce8f94c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3445.0" y="1109.5939"/> </glyph> <glyph class="state variable" id="_60cf8761-abde-4b13-8120-fc52ab83d74b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3362.5" y="1108.125"/> </glyph> <glyph class="unit of information" id="_ee361ad7-5afe-4989-84a4-00baa2e30f66"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3387.5" y="1083.125"/> </glyph> </glyph> <glyph class="macromolecule" id="s5073_sa754"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRA HUGO:TRB CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)].</body> </html> </notes> <label text="alpha_/beta_TCR*"/> <bbox w="80.0" h="50.0" x="3370.0" y="1048.125"/> <glyph class="unit of information" id="_c0418d46-bd5b-4a4d-b3d5-fce8683130af"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3387.5" y="1043.125"/> </glyph> </glyph> <glyph class="macromolecule" id="s5075_sa755"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD3E HUGO:CD3G HUGO:CD3D CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse.</body> </html> </notes> <label text="CD3*"/> <bbox w="80.0" h="50.0" x="3370.0" y="1138.125"/> <glyph class="state variable" id="_ce8a3072-4776-47a7-bd17-d2c10ee0269f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3362.5" y="1158.125"/> </glyph> <glyph class="unit of information" id="_a27592cf-ff9b-4bbd-bafe-1dc1e7eb3f75"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3387.5" y="1133.125"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5076_sa1143" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRAT1 CASCADE:TCR MODULE:SMAC PMID:20828560 In T cells, a dimer of the TCR interacting molecule (TRIM) is also part of the receptor complex (Fig. 1a). However, it is not known what percentage of TCRs contain TRIM. TRIM-deficient mice produce a functional, surface-expressed TCR, demonstrating that TRIM is dispensable for a functional TCR in vivo PMID: 9687533 TRAT1 (TRIM)after T cell activation, TRIM becomes rapidly phosphorylated on tyrosine residues and then associates with the 85-kD regulatory subunit of PI3-kinase via an YxxM motif. Thus, TRIM represents a TCR-associated transmembrane adaptor protein which is likely involved in targeting of intracellular signaling proteins to the plasma membrane after triggering of the TCR. TRIM becomes tyrosine phosphorylated by lck and fyn but not by ZAP70. In addition, concomitant expression of lck and ZAP70 does not induce higher levels of TRIM tyrosine phosphorylation than expression of lck alone. Also, coexpression of TRIM and Syk in COS cells did not result in tyrosine phosphorylation of TRIM (not shown). These data indicate that TRIM could represent a protein that is preferentially phosphorylated by tyrosine kinases of the src family. To further substantiate this assumption, TCR-mediated tyrosine phosphorylation of TRIM was analyzed in wild-type Jurkat cells and in a Jurkat variant lacking expression of both ZAP70 and Syk tyrosine kinases (P116 cells [12]). As shown in Fig. Fig.1010 C, TRIM becomes strongly tyrosine phosphorylated in P116 cells after engagement of the TCR or upon Pervanadate stimulation. In addition, preincubation of P116 cells with the recently described inhibitor for src-kinases, PP1 (15), completely abrogates TCR-mediated tyrosine phosphorylation of TRIM. Thus, tyrosine phosphorylation of TRIM can occur independently of expression of members of the Syk family PTKs and can be prevented by an inhibitor with a proposed specificity for src-kinases.</body> </html> </notes> <label text="TRAT1"/> <bbox w="80.0" h="40.0" x="3580.0" y="1055.0"/> <glyph class="state variable" id="_dc25a6d1-172e-4734-b126-e13e37c794f6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3575.0" y="1070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5077_sa757" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CARD11 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12356734 CARD11(CARMA1) mediates NF-kappaB activation by alphaCD3/alphaCD28 cross-linking. CARD11 functions upstream of the IKK complex. wild‐type CARD11 co‐precipitating with endogenous Bcl10 CARMA1 only expresses in lymphocytes PMID:20685844 CARMA1, a critical target of PKCθ phosphorylation, resides in lymphocytes in an inactive state. Extensive CARMA1 mutagenesis data suggest that this inactive state is maintained by intramolecular interactions that prevent the CARMA1 CARD from interacting with the CARD of BCL10 12 and 13. PKCθ phosphorylates human CARMA1 at three serine residues, S552, S645 and S637 (S564, S657, S649 in mice) PMID:11356195; PMID: 17052756; PMID:21199863 CARMA1 induces BCL10 phosphorylation via CaMKII PMID:16809782;PMID:17052756 In the immune synapse, CaMKII phosphorylates Carma1 on Ser109 and the phosphorylation increases the interaction between Carma1 and Bcl10. Carma1/Bcl10/Malt1 complex induces NF-κB activation (Sun et al., 2004). Accordingly based on the findings in the present study, CaMKII phosphorylates Bcl10 on Ser138 while IKKβ phosphorylates residues Ser134, 136, 138, 141 and 144 (Wegener et al., 2006). Phosphorylation of Bcl10 disrupts Bcl10/Malt1 association (Wegener et al., 2006), and attenuates NF-κB activation. PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKKα/β phosphorylation in the TCR signaling pathway. PKCθ, TAK1, and IKK assemble into a complex in a signal‐dependent but CARMA1‐independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKCθ–TAK1–IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKKα/β in a CARMA1‐independent manner, and, together with CARMA1‐dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF‐κB in antigen receptor signaling pathways CARMA1 is essential for the ubiquitination of NEMO NEMO, but not its ubiquitination, is required for IKKα/β phosphorylation</body> </html> </notes> <label text="CARD11"/> <bbox w="80.0" h="40.0" x="4070.0" y="3405.0"/> <glyph class="state variable" id="_0aceaf1e-4f97-4ff5-bb91-2b4d94d12934"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4065.0" y="3420.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5079_sa760" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:MALT1 MODULE:TCR_SIGNALING PMID:21873235 Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA- or c-Rel–containing NF-κB complexes. PMID:18264101 MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, PMID:17948050 TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKgamma.</body> </html> </notes> <label text="MALT1"/> <bbox w="80.0" h="40.0" x="3710.0" y="3415.0"/> <glyph class="state variable" id="_602a26c7-fe24-451b-987e-5087052efb39"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3705.0" y="3430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5080_sa762" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAPK3 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 GENECARDS:MAPK3 KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 HUGO:MAPK1 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 GENECARDS:MAPK1 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 CASCADE:TCR CASCADE:CD226 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:10807788 RAS/ERK signaling upregulates IL2 expression, probably via AP-1 PMID:9510155 MEK1 inhibitor PD98059 inhibited TNF-α, IL-3, granulocyte-macrophage (GM)-CSF, IFN-γ, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation PMID:10898494 The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK both the phosphorylation of ERK and the activation of Ras were reduced by treatment with U73122 (PLCG inhibitor) to a level similar to that observed in Vav1–/– cells In contrast to the effects of U73122, treatment of wild-type DP thymocytes with BAPTA, which blocks the intracellular calcium flux by chelating Ca2+, had no effect on TCR-induced ERK phosphorylatio PMID:22043013 Paxillin was shown to be phosphorylated downstream of ERK, PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="2133.245" y="3833.5"/> <glyph class="state variable" id="_0ef0d7ca-6ad2-4555-9a1e-da09a937f703"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2125.745" y="3848.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s93_sa763" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K1 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 GENECARDS:MAP2K1 REACTOME:59503 KEGG:5604 ATLASONC:GC_MAP2K1 WIKI:MAP2K1 HUGO:MAP2K2 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 GENECARDS:MAP2K2 REACTOME:59505 KEGG:5605 ATLASONC:GC_MAP2K2 WIKI:MAP2K2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:9510155 MEK1 inhibitor PD98059 inhibited TNF-α, IL-3, granulocyte-macrophage (GM)-CSF, IFN-γ, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK1 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3</body> </html> </notes> <label text="MEK*"/> <bbox w="80.0" h="40.0" x="2146.5" y="3153.0"/> <glyph class="state variable" id="_dee558df-f858-4caf-8bf1-4125e30ddf7b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2139.0" y="3167.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s5081_sa764" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAPK3 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 GENECARDS:MAPK3 KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 HUGO:MAPK1 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 GENECARDS:MAPK1 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 CASCADE:TCR CASCADE:CD226 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:10807788 RAS/ERK signaling upregulates IL2 expression, probably via AP-1 PMID:9510155 MEK1 inhibitor PD98059 inhibited TNF-α, IL-3, granulocyte-macrophage (GM)-CSF, IFN-γ, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation PMID:10898494 The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK both the phosphorylation of ERK and the activation of Ras were reduced by treatment with U73122 (PLCG inhibitor) to a level similar to that observed in Vav1–/– cells In contrast to the effects of U73122, treatment of wild-type DP thymocytes with BAPTA, which blocks the intracellular calcium flux by chelating Ca2+, had no effect on TCR-induced ERK phosphorylatio PMID:22043013 Paxillin was shown to be phosphorylated downstream of ERK, PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="2130.0" y="3735.0"/> <glyph class="state variable" id="_bc2bc37e-d4cb-47dc-aabc-661007d54fac"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2125.0" y="3750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s90_sa768" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K1 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 GENECARDS:MAP2K1 REACTOME:59503 KEGG:5604 ATLASONC:GC_MAP2K1 WIKI:MAP2K1 HUGO:MAP2K2 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 GENECARDS:MAP2K2 REACTOME:59505 KEGG:5605 ATLASONC:GC_MAP2K2 WIKI:MAP2K2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:9510155 MEK1 inhibitor PD98059 inhibited TNF-α, IL-3, granulocyte-macrophage (GM)-CSF, IFN-γ, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK1 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3</body> </html> </notes> <label text="MEK*"/> <bbox w="80.0" h="40.0" x="2150.0" y="3035.0"/> <glyph class="state variable" id="_c047dac9-76b4-4e79-9614-a3f58b1f38bc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2145.0" y="3049.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s1856_sa769" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RAF1 MODULE:TCR_SIGNALING CASCADE:TCR PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK</body> </html> </notes> <label text="RAF1"/> <bbox w="80.0" h="40.0" x="2430.0" y="2915.0"/> <glyph class="state variable" id="_ff5e06e4-4321-4179-99d6-b8710e88d414"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2422.5" y="2930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2440_sa771" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RAF1 MODULE:TCR_SIGNALING CASCADE:TCR PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK</body> </html> </notes> <label text="RAF1"/> <bbox w="80.0" h="40.0" x="2430.0" y="2815.0"/> <glyph class="state variable" id="_70ccf3af-4649-471c-b012-5a5f1491df47"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2425.0" y="2830.0"/> </glyph> </glyph> <glyph class="complex" id="s2460_csa85" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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.</body> </html> </notes> <label text="s1852"/> <bbox w="100.0" h="120.0" x="2870.0" y="2615.0"/> <glyph class="simple chemical" id="s2485_sa781"> <label text="GDP"/> <bbox w="70.0" h="25.0" x="2885.0" y="2672.5"/> </glyph> <glyph class="macromolecule" id="s5390_sa1077"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:HRAS MODULE:TCR_SIGNALING CASCADE:TCR PMID:16102570; PMID:9846483 "LAT signalosome" links the TCR to the main intracellular signalling pathways that regulate T-cell development and T-cell function. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:7510700 A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells. PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK</body> </html> </notes> <label text="HRAS"/> <bbox w="80.0" h="40.0" x="2880.0" y="2625.0"/> </glyph> </glyph> <glyph class="complex" id="s1849_csa87" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:NK CASCADE:Fc_gamma_RIII MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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.</body> </html> </notes> <label text="s1849"/> <bbox w="100.0" h="120.0" x="2650.0" y="2616.0"/> <glyph class="simple chemical" id="s1850_sa784"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="2665.0" y="2673.5"/> </glyph> <glyph class="macromolecule" id="s2469_sa785"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:HRAS MODULE:TCR_SIGNALING CASCADE:TCR PMID:16102570; PMID:9846483 "LAT signalosome" links the TCR to the main intracellular signalling pathways that regulate T-cell development and T-cell function. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:7510700 A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells. PMID:24027568 Ras·GTP is a potent signaling hub, connecting to many downstream effector molecules like RAF, PI3K, and RalGDS. The best-characterized signaling cascade is the Ras·GTP-RAF-MEK-ERK pathway The physiological significance of biochemical signals transduced by an intact Ras-RAF-MEK-ERK pathway in lymphocytes was subsequently shown through transgenic expression of mutant Ras- and MEK-alleles in thymocytes; PMID:14764585 Vav1 Is Required for TCR-induced Activation of Ras, B-Raf, MEK, and ERK</body> </html> </notes> <label text="HRAS"/> <bbox w="80.0" h="40.0" x="2660.0" y="2626.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s134_sa787" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: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: CASCADE:TCR CASCADE:IL18 CASCADE:IL12 MODULE:TCR_SIGNALING MOGULE:TH1 Maps_Modules_end References_begin: PMID:10395678 TCR and CD28 Are Coupled Via ZAP-70 to the Activation of the Vav/Rac-1-/PAK-1/p38 MAPK Signaling Pathway PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:16799472 GADD45 inhibited p38 activated by ZAP70 (that is, through phosphorylation of Tyr323) but not by MKK6 (that is, through phosphorylation of Thr180 and Tyr182). PMID:24104473 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 p38 and JNK pathways are very important for the responses of TH1 effector cells (Lu et al., 1999; Rincon et al., 1998; Yang et al., 1998). The p38 kinase can be activated efficiently in TH1 effector cells but not in TH2 effector cells; blocking the pathway inhibits and agonists of the pathway potentiate TH1 responses PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent References_end</body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="1910.0" y="3825.0"/> <glyph class="state variable" id="_05d4645a-2264-4684-a388-e727ae01a13f"> <state value="" variable="Tyr180"/> <bbox w="40.0" h="10.0" x="1967.3706" y="3820.0"/> </glyph> <glyph class="state variable" id="_c5f7f250-b0b6-4173-80a0-a105e69728b6"> <state value="P" variable="Tyr323"/> <bbox w="45.0" h="10.0" x="1888.0948" y="3820.0"/> </glyph> <glyph class="state variable" id="_1ebd115a-a244-46c2-b27d-447c646857eb"> <state value="" variable="TYR182"/> <bbox w="40.0" h="10.0" x="1966.3782" y="3860.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5082_sa788" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: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: CASCADE:TCR CASCADE:IL18 CASCADE:IL12 MODULE:TCR_SIGNALING MOGULE:TH1 Maps_Modules_end References_begin: PMID:10395678 TCR and CD28 Are Coupled Via ZAP-70 to the Activation of the Vav/Rac-1-/PAK-1/p38 MAPK Signaling Pathway PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:16799472 GADD45 inhibited p38 activated by ZAP70 (that is, through phosphorylation of Tyr323) but not by MKK6 (that is, through phosphorylation of Thr180 and Tyr182). PMID:24104473 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 p38 and JNK pathways are very important for the responses of TH1 effector cells (Lu et al., 1999; Rincon et al., 1998; Yang et al., 1998). The p38 kinase can be activated efficiently in TH1 effector cells but not in TH2 effector cells; blocking the pathway inhibits and agonists of the pathway potentiate TH1 responses PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent References_end</body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="1570.0" y="3815.0"/> <glyph class="state variable" id="_55663179-3f1e-44ff-bf94-ee3edff3f3e5"> <state value="" variable="Tyr180"/> <bbox w="40.0" h="10.0" x="1627.3706" y="3810.0"/> </glyph> <glyph class="state variable" id="_4442b54d-a807-4543-a9d4-074b120a4127"> <state value="" variable="Tyr323"/> <bbox w="40.0" h="10.0" x="1550.5948" y="3810.0"/> </glyph> <glyph class="state variable" id="_0d920f10-b35a-4c71-bdcd-baafc2d315b6"> <state value="" variable="TYR182"/> <bbox w="40.0" h="10.0" x="1626.3782" y="3850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5083_sa796" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PTEN CASCADE:TCR CASCADE:PD1 MODULE:TCR_SIGNALING PMID:16982858 An additional level of regulation is provided by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (13), which does not act on PI3K directly, but rather dephosphorylates PIP3 on the 3′ position to regenerate PIP2, thus limiting the amount of available PI3K product PTEN-deficient CD4+ T cells are hyperresponsive to TCR stimulation. Augmented response of PTENΔT T cells is correlated with enhanced activation of the PI3K pathway PTEN regulates anergy induction in vitro and in vivo PMID:23732914 during T cell receptor (TCR)/CD3- and CD28-mediated stimulation, PTEN is phosphorylated by casein kinase 2 (CK2) in the Ser380-Thr382-Thr383 cluster within the C-terminal regulatory domain, which stabilizes PTEN, resulting in increased protein abundance but suppressed PTEN phosphatase activity. PD-1 inhibited the stabilizing phosphorylation of the Ser380-Thr382-Thr383 cluster within the C-terminal domain of PTEN, thereby resulting in ubiquitin-dependent degradation and diminished abundance of PTEN protein but increased PTEN phosphatase activity.</body> </html> </notes> <label text="PTEN"/> <bbox w="80.0" h="40.0" x="4770.0" y="1835.0"/> <glyph class="state variable" id="_acef9eeb-df25-4b0b-b858-2eeb66b344b0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4765.0" y="1850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5084_sa797" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CSK MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues PMID:10790433 PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. PMID:12485116 REW PMID:11181701 Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion.</body> </html> </notes> <label text="CSK"/> <bbox w="80.0" h="40.0" x="2210.0" y="1305.0"/> <glyph class="state variable" id="_8b321f73-4f60-4fdd-b025-74a7287b66db"> <state value="" variable="S364"/> <bbox w="30.0" h="10.0" x="2195.0" y="1302.4022"/> </glyph> </glyph> <glyph class="macromolecule" id="s5086_sa801" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PAG1 PMID:10790433 PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells</body> </html> </notes> <label text="PAG1"/> <bbox w="80.0" h="40.0" x="2460.0" y="1295.0"/> <glyph class="state variable" id="_8c87a8c0-8d7e-4878-985a-95d728ffa7b6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2455.0" y="1310.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5088_sa799" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PAG1 PMID:10790433 PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells</body> </html> </notes> <label text="PAG1"/> <bbox w="80.0" h="40.0" x="2460.0" y="1085.0"/> <glyph class="state variable" id="_09b4a0be-f57e-460b-926b-6f71d9e5c8eb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2452.5" y="1100.0"/> </glyph> </glyph> <glyph class="complex" id="s5091_csa88" compartmentRef="c2_ca2"> <label text="s5091"/> <bbox w="100.0" h="120.0" x="2360.0" y="1155.0"/> <glyph class="macromolecule" id="s5092_sa802"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PAG1 PMID:10790433 PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells</body> </html> </notes> <label text="PAG1"/> <bbox w="80.0" h="40.0" x="2370.0" y="1165.0"/> <glyph class="state variable" id="_ab7bcb38-08e2-40ba-8d35-dab6c98fcd57"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2362.5" y="1180.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5093_sa803"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CSK MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues PMID:10790433 PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. PMID:12485116 REW PMID:11181701 Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion.</body> </html> </notes> <label text="CSK"/> <bbox w="80.0" h="40.0" x="2370.0" y="1205.0"/> <glyph class="state variable" id="_556162e6-212c-48af-8614-baed5cf89d61"> <state value="" variable="S364"/> <bbox w="30.0" h="10.0" x="2355.0" y="1202.4022"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5097_csa89" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:23886063 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta</body> </html> </notes> <label text="s4356"/> <bbox w="118.75" h="210.0" x="3240.625" y="1267.0"/> <glyph class="macromolecule" id="s5098_sa806"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRA HUGO:TRB CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)].</body> </html> </notes> <label text="alpha_/beta_TCR*"/> <bbox w="80.0" h="50.0" x="3259.375" y="1272.0"/> <glyph class="unit of information" id="_1736df49-239d-4187-8631-67032bdd84b1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3276.875" y="1267.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5100_sa807"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD3E HUGO:CD3G HUGO:CD3D CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse.</body> </html> </notes> <label text="CD3*"/> <bbox w="80.0" h="50.0" x="3259.375" y="1352.0"/> <glyph class="state variable" id="_e22cb3fc-dc9c-42ad-8ffa-298435a68848"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3251.875" y="1372.0"/> </glyph> <glyph class="unit of information" id="_b7a85d94-21e1-4099-9e09-43bfc13f0b41"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3276.875" y="1347.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5099_sa808"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD247 CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is lolalized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:11353765 Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="3259.375" y="1312.0"/> <glyph class="state variable" id="_3fcc317a-c8a9-4c54-8d39-dc6b6633aea2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3334.375" y="1333.4689"/> </glyph> <glyph class="state variable" id="_60afcae7-7dfe-411e-8e11-c5493403d810"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3251.875" y="1332.0"/> </glyph> <glyph class="unit of information" id="_6617f734-e1e6-4621-a5d8-a6e9c5b574bb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3276.875" y="1307.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5101_sa809"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ZAP70 CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508 ZAP70 (ζ-chain-associated protein of 70 kDa) is a tyrosine-protein kinase from the Syk family that docks at phosphorylated ITAMs of the TCR. Docking, subsequent phosphorylation by Lck and trans-autophosphorylation all increase kinase activity. ZAP70 phosphorylates a number of signaling proteins, including LAT and SLP-76 PMID:7600293; PMID:8642247 ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta TCR ligation promotes a large increase in the tyrosine phosphorylation of ZAP-70 by Lck PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:12415267 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. c-Cbl was highly expressed in thymocytes, whereas Cbl-b was preferentially expressed in mature T cells. In the TCR signaling pathway, c-Cbl inhibits ZAP-70 activation in thymocytes PMID:17371980 AR2A agonist ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="3260.0" y="1412.0"/> <glyph class="state variable" id="_b772fb04-82bc-4e36-a1a8-4c64e9cbaaf4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3255.0" y="1427.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5102_csa90" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:23886063 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta</body> </html> </notes> <label text="s4356"/> <bbox w="118.75" h="210.0" x="3470.625" y="1267.0"/> <glyph class="macromolecule" id="s5103_sa810"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRA HUGO:TRB CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)].</body> </html> </notes> <label text="alpha_/beta_TCR*"/> <bbox w="80.0" h="50.0" x="3489.375" y="1272.0"/> <glyph class="unit of information" id="_d6dc4c74-acef-4c5c-aa92-b08d9d316fbb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3506.875" y="1267.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5104_sa811"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD3E HUGO:CD3G HUGO:CD3D CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse.</body> </html> </notes> <label text="CD3*"/> <bbox w="80.0" h="50.0" x="3489.375" y="1352.0"/> <glyph class="state variable" id="_09e4e5db-b9d6-4a58-a542-4884b5b0b651"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3481.875" y="1372.0"/> </glyph> <glyph class="unit of information" id="_257924e4-c3a0-4a35-9e6e-c2525d8a86b7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3506.875" y="1347.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5105_sa812"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD247 CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is lolalized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:11353765 Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="3489.375" y="1312.0"/> <glyph class="state variable" id="_9ebb3480-49af-4c2e-958f-348945d445b4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3564.375" y="1333.4689"/> </glyph> <glyph class="state variable" id="_4a111ccb-8474-491d-aa47-4d523d2f1228"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3481.875" y="1332.0"/> </glyph> <glyph class="unit of information" id="_cc606094-0d98-45ee-be2b-e62b14af3f94"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3506.875" y="1307.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5106_sa813"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ZAP70 CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508 ZAP70 (ζ-chain-associated protein of 70 kDa) is a tyrosine-protein kinase from the Syk family that docks at phosphorylated ITAMs of the TCR. Docking, subsequent phosphorylation by Lck and trans-autophosphorylation all increase kinase activity. ZAP70 phosphorylates a number of signaling proteins, including LAT and SLP-76 PMID:7600293; PMID:8642247 ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta TCR ligation promotes a large increase in the tyrosine phosphorylation of ZAP-70 by Lck PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:12415267 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. c-Cbl was highly expressed in thymocytes, whereas Cbl-b was preferentially expressed in mature T cells. In the TCR signaling pathway, c-Cbl inhibits ZAP-70 activation in thymocytes PMID:17371980 AR2A agonist ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="3489.375" y="1417.0"/> <glyph class="state variable" id="_cb82b991-e66d-4578-b321-26614971d3db"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3481.875" y="1432.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5109_sa758" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CARD11 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12356734 CARD11(CARMA1) mediates NF-kappaB activation by alphaCD3/alphaCD28 cross-linking. CARD11 functions upstream of the IKK complex. wild‐type CARD11 co‐precipitating with endogenous Bcl10 CARMA1 only expresses in lymphocytes PMID:20685844 CARMA1, a critical target of PKCθ phosphorylation, resides in lymphocytes in an inactive state. Extensive CARMA1 mutagenesis data suggest that this inactive state is maintained by intramolecular interactions that prevent the CARMA1 CARD from interacting with the CARD of BCL10 12 and 13. PKCθ phosphorylates human CARMA1 at three serine residues, S552, S645 and S637 (S564, S657, S649 in mice) PMID:11356195; PMID: 17052756; PMID:21199863 CARMA1 induces BCL10 phosphorylation via CaMKII PMID:16809782;PMID:17052756 In the immune synapse, CaMKII phosphorylates Carma1 on Ser109 and the phosphorylation increases the interaction between Carma1 and Bcl10. Carma1/Bcl10/Malt1 complex induces NF-κB activation (Sun et al., 2004). Accordingly based on the findings in the present study, CaMKII phosphorylates Bcl10 on Ser138 while IKKβ phosphorylates residues Ser134, 136, 138, 141 and 144 (Wegener et al., 2006). Phosphorylation of Bcl10 disrupts Bcl10/Malt1 association (Wegener et al., 2006), and attenuates NF-κB activation. PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKKα/β phosphorylation in the TCR signaling pathway. PKCθ, TAK1, and IKK assemble into a complex in a signal‐dependent but CARMA1‐independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKCθ–TAK1–IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKKα/β in a CARMA1‐independent manner, and, together with CARMA1‐dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF‐κB in antigen receptor signaling pathways CARMA1 is essential for the ubiquitination of NEMO NEMO, but not its ubiquitination, is required for IKKα/β phosphorylation</body> </html> </notes> <label text="CARD11"/> <bbox w="80.0" h="40.0" x="4070.0" y="3505.0"/> <glyph class="state variable" id="_57ccd372-27e4-4bd0-8f3a-42fd68ddebde"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4062.5" y="3520.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5110_sa814" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP4K3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:21983831 GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation he kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells.</body> </html> </notes> <label text="MAP4K3"/> <bbox w="80.0" h="40.0" x="4110.0" y="1970.0"/> <glyph class="state variable" id="_3e1d7b7a-b10a-4e18-b6a8-edf47671fcf1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4105.0" y="1985.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5111_sa815" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP4K3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:21983831 GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation he kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells.</body> </html> </notes> <label text="MAP4K3"/> <bbox w="80.0" h="40.0" x="4110.0" y="1900.0"/> <glyph class="state variable" id="_03f2248e-8904-40e4-9dbf-9933260cb574"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4102.5" y="1915.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3464_sa823" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:REL CASCADE:TCR MODULE:TCR_SIGNALING PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter</body> </html> </notes> <label text="cREL*"/> <bbox w="80.0" h="40.0" x="3250.0" y="3950.0"/> </glyph> <glyph class="complex" id="s647_csa91" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: NAME:CHUK:IKBKG:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION CASCADE:IL13 GASCADE: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="3390.0" y="2983.0"/> <glyph class="macromolecule" id="s5114_sa830"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IKBKG Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 References_end</body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="3400.0" y="2995.0"/> <glyph class="state variable" id="_44cceddc-1af0-48bc-9538-8df89526d27c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3475.0" y="3010.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3611_sa831"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation (phosphorylation)of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway References_end</body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="3400.0" y="3035.0"/> <glyph class="state variable" id="_0fdb5e03-0e4a-4c34-a8c3-26cf00d40ce8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3395.0" y="3050.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3610_sa832"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 NFkB downstream of CD28 PMID: 16970925 The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. PMID:15536066 TCR/CD28 costimulation induces IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, and PKC is required for IkappaBalpha and IkappaBepsilon but not IkappaBbeta degradation. PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase. References_end</body> </html> </notes> <label text="IKKα*"/> <bbox w="80.0" h="40.0" x="3401.0" y="3080.0"/> <glyph class="state variable" id="_e2b54f55-6f61-4c79-9650-22ca1bbd99fe"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3396.0" y="3095.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5115_csa92" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: NAME:CHUK:IKBKG:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:DC MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION CASCADE:IL13 GASCADE:VEGFA CASCADE:STING CASCADE:TLR2_4 CASCADE:IL2 CASCADE:CSF2 CASCADE:TNF Maps_Modules_end References_begin: complex PMID:12133805 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:19302050 NFkB in immune cells review. References_end</body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="3390.0" y="3303.0"/> <glyph class="macromolecule" id="s650_sa833"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation (phosphorylation)of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway References_end</body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="3400.0" y="3355.0"/> <glyph class="state variable" id="_92f90ced-e16d-488d-a045-c4d80660e992"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3392.5" y="3370.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s649_sa834"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IKBKG Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 References_end</body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="3398.0" y="3310.0"/> <glyph class="state variable" id="_fe0dd2e1-178d-4d75-87e1-812fff106fa8"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="3468.0" y="3325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s58_sa835"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 NFkB downstream of CD28 PMID: 16970925 The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. PMID:15536066 TCR/CD28 costimulation induces IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, and PKC is required for IkappaBalpha and IkappaBepsilon but not IkappaBbeta degradation. PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase. References_end</body> </html> </notes> <label text="IKKα*"/> <bbox w="80.0" h="40.0" x="3400.0" y="3405.0"/> <glyph class="state variable" id="_d7b81e7f-6277-45c4-9ea1-0d1599411ece"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3395.0" y="3420.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s29_csa93" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s29"/> <bbox w="105.0" h="155.0" x="3735.0" y="4135.0"/> <glyph class="macromolecule" id="s2292_sa836"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RELB CASCADE:TCR MODULE:TCR_SIGNALING PMID:21873235 Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. RelB inhibits expression of NF-κB gene targets (IL2) in T cells.</body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="40.0" x="3745.0" y="4190.0"/> </glyph> <glyph class="macromolecule" id="s3507_sa837"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3750.0" y="4230.0"/> <glyph class="unit of information" id="_80bde876-ad5d-4ce9-90fa-9f86899642bd"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3765.0" y="4225.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3490_sa838"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE CASCADE:TCR MODULE:TCR_SIGNALING PMID:12133805</body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="3750.0" y="4150.0"/> <glyph class="state variable" id="_d1718e38-b0e5-4cde-8adc-0d098d628a6c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3745.0" y="4165.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3488_csa94" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s35"/> <bbox w="110.0" h="150.0" x="3145.0" y="4137.5"/> <glyph class="macromolecule" id="s5840_sa839"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3155.0" y="4227.5"/> <glyph class="unit of information" id="_0571f36b-f10f-4e51-81c3-16cbaae1e138"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3170.0" y="4222.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s3506_sa840"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:REL CASCADE:TCR MODULE:TCR_SIGNALING PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter</body> </html> </notes> <label text="cREL*"/> <bbox w="80.0" h="40.0" x="3155.0" y="4187.5"/> </glyph> <glyph class="macromolecule" id="s5841_sa841"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE CASCADE:TCR MODULE:TCR_SIGNALING PMID:12133805</body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="3155.0" y="4147.5"/> <glyph class="state variable" id="_f0687356-63c8-4a5b-bb95-56cc957032d7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3150.0" y="4162.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s32_csa95" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s32"/> <bbox w="107.5" h="160.0" x="3736.25" y="4355.0"/> <glyph class="macromolecule" id="s5120_sa842"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3750.0" y="4450.0"/> <glyph class="unit of information" id="_afdfebd6-1a00-4335-9c02-8c642beb342b"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3765.0" y="4445.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5121_sa843"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RELB CASCADE:TCR MODULE:TCR_SIGNALING PMID:21873235 Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. 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PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3157.5" y="4452.5"/> <glyph class="unit of information" id="_ca3ae17b-70b5-48ac-bb5a-985a2f4ba6b4"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3172.5" y="4447.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s43_sa846"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:REL CASCADE:TCR MODULE:TCR_SIGNALING PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter</body> </html> </notes> <label text="cREL*"/> <bbox w="80.0" h="40.0" x="3157.5" y="4412.5"/> </glyph> <glyph class="macromolecule" id="s5839_sa847"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE CASCADE:TCR MODULE:TCR_SIGNALING PMID:12133805</body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="3157.5" y="4362.5"/> <glyph class="state variable" id="_5613386d-4a67-45de-af11-dc412aaa71f2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3150.0" y="4377.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3499_csa97" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION 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</body> </html> </notes> <label text="s2440"/> <bbox w="110.0" h="130.0" x="3755.0" y="4650.0"/> <glyph class="macromolecule" id="s2441_sa848"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RELB CASCADE:TCR MODULE:TCR_SIGNALING PMID:21873235 Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. 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PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="81.25" h="46.0" x="3763.75" y="4660.0"/> <glyph class="unit of information" id="_9d23b1c3-70bd-4264-ba2e-420f7446aac0"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3779.375" y="4655.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3498_csa98" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s2447"/> <bbox w="100.0" h="120.0" x="3180.0" y="4675.0"/> <glyph class="macromolecule" id="s3515_sa850"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:REL CASCADE:TCR MODULE:TCR_SIGNALING PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter</body> </html> </notes> <label text="cREL*"/> <bbox w="80.0" h="40.0" x="3190.0" y="4685.0"/> </glyph> <glyph class="macromolecule" id="s3526_sa851"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. 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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 . 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PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="118.5" h="66.5" x="3470.75" y="4719.0"/> <glyph class="unit of information" id="_98c8f06e-dd35-4191-b6e1-ac01729e8134"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3505.0" y="4714.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5124_sa853"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:RELA Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. 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PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="3380.0" y="4205.0"/> </glyph> <glyph class="macromolecule" id="s5843_sa855"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. 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PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="3390.0" y="4425.0"/> </glyph> <glyph class="macromolecule" id="s5842_sa858"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3390.0" y="4455.0"/> <glyph class="unit of information" id="_9c7a38d8-aad7-4f18-a548-f13715c98aeb"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3405.0" y="4450.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3511_sa859"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE CASCADE:TCR MODULE:TCR_SIGNALING PMID:12133805</body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="3386.5" y="4374.5"/> <glyph class="state variable" id="_97dbf378-e37a-401b-a2f1-89d925c5ea78"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3379.0" y="4389.5"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s3474_sa864" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKB1 MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION MODULE: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 ()</body> </html> </notes> <label text="NFKB1_p105*"/> <bbox w="130.0" h="80.0" x="2615.0" y="4405.0"/> <glyph class="state variable" id="_05965bbc-27c9-48a2-8c27-fe4af4e27cef"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2610.0" y="4440.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s546_sa866" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="141.5" h="141.5" x="2619.25" y="4704.25"/> <glyph class="unit of information" id="_7c224603-5530-42d4-8a41-7630c326f60a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2680.0" y="4699.25"/> </glyph> <glyph class="unit of information" id="_bbf21206-d749-441f-b922-b56b826da3d3"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2665.0" y="4699.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s5127_sa867" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKBIA HUGO:NFKBIB HUGO:NFKBIE CASCADE:TCR MODULE:TCR_SIGNALING PMID:12133805</body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="2940.0" y="4585.0"/> <glyph class="state variable" id="_32512c73-c65a-4d61-aece-46d0169149cf"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2932.5" y="4600.0"/> </glyph> </glyph> <glyph class="source and sink" id="s5128_sa868" compartmentRef="c2_ca2"> <label text="sa867_degraded"/> <bbox w="30.0" h="30.0" x="2835.0" y="4590.0"/> </glyph> <glyph class="nucleic acid feature" id="s5130_sa870" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:AR2A HUGO:IL2 MODULE:TCR_SIGNALING PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID: 16920910 A2AAR agonists decreased the stability of proinflammatory cytokine IL-2 and IFN-γ mRNA.</body> </html> </notes> <label text="IL2"/> <bbox w="245.0" h="112.5" x="2447.5" y="6323.75"/> <glyph class="unit of information" id="_fa99b979-b7b2-43f1-96df-8cc22833e9d2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2560.0" y="6318.75"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5131_sa871" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:AR2A HUGO:IL2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. Yarilin IL2 expression downstream of CD28 IL2 expression is akey result of CD4 cells activation, it needs NFkB, AP1 and NF-AT transcription factors PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis PMID:12818166 the expression of JunB, a component of the AP-1 family induced after T cell activation, was reduced by 49% after B7S1 costimulation. On the other hand, there was little change in c-Jun expression (11% reduction) with B7S1-Ig treatment. JunB has been previously shown to bind to the IL-2 promoter (Boise et al., 1993 and JunB overexpression resulted in greater IL-2 production (our unpublished data). Since JunB is induced after T cell activation (Jain et al., 1995, the mechanism of which is unknown, B7S1 costimulation may result in inefficient JunB induction.</body> </html> </notes> <label text="IL2"/> <bbox w="195.0" h="152.5" x="2462.5" y="6493.75"/> </glyph> <glyph class="nucleic acid feature" id="s5132_sa872" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:IL2RA PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. CELL:TREG PMID: 15032588 CD25 is a marker of TREG PMID:16799562 Thymic generation of Treg cells requires TAK1 Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA</body> </html> </notes> <label text="IL2RA"/> <bbox w="197.5" h="156.25" x="2762.5" y="6490.0"/> </glyph> <glyph class="nucleic acid feature" id="s5133_sa873" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG HUGO:IL2RA MODULE:TCR_SIGNALING PMID: 15032588 CD25 is a marker of TREG PMID:16799562 Thymic generation of Treg cells requires TAK1 Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA PMID:10221648 c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells. The IL-2Rα promoter contains an NF-κB/Rel regulatory element. Impaired IL-2Rα expression in c-Rel-deficient T lymphocytes and impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor.</body> </html> </notes> <label text="IL2RA"/> <bbox w="212.5" h="111.25" x="2753.75" y="6324.375"/> <glyph class="unit of information" id="_d7caf6cc-fa73-49d0-b994-cd189d12f171"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2850.0" y="6319.375"/> </glyph> </glyph> <glyph class="macromolecule" id="s5135_sa874" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HIGO:IL2RA CELL:TREG MODULE:TCR_SIGNALING PMID: 15032588 CD25 is a marker of TREG PMID:16799562 Thymic generation of Treg cells requires TAK1 Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA PMID:10820393, PMID:24829413 The IL-2R is composed of three different subunits, IL-2R alpha (CD25), IL-2/15R beta (CD122) and gamma (CD131) PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines</body> </html> </notes> <label text="IL2RA"/> <bbox w="190.0" h="145.0" x="2765.0" y="6107.5"/> <glyph class="unit of information" id="_2e456778-d9a9-4c22-8696-fc913d6f572a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2837.5" y="6102.5"/> </glyph> </glyph> <glyph class="source and sink" id="s5136_sa876" compartmentRef="c2_ca2"> <label text="sa822_degraded"/> <bbox w="30.0" h="30.0" x="3935.0" y="4170.0"/> </glyph> <glyph class="macromolecule" id="s5137_sa940" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:BCL10 MODULE:TCR_SIGNALING PMID:18264101 Lymphocyte activation induces a smaller Bcl-10 isoform downstream of CD3 and CD28 Formation of the faster migrating Bcl-10 isoform depends on its recruitment by CARMA1 and on the formation of CARMA1 oligomers. activation of the NF-B pathway by antigen-presenting cells or by drugs that mimic the antigen receptor signal does not require MALT1-dependent cleavage of Bcl-10 but most likely depends on other MALT1 substrates. After activation with either anti-CD3 and anti-CD28 or PMA, cells expressing the R228G mutant had less adhesion to fibronectin than did cells expressing wild-type Bcl-10 (. In Jurkat T cells, adhesion to the 1 ligand fibronectin is mediated mainly by the integrin a4b1, with a minor contribution from a5b1) MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, In the CARMA1–Bcl-10–MALT1 signaling complex, Bcl-10 acts as an adaptor protein that binds, through its caspase-recruitment domain (CARD), to the CARD motif of CARMA1 (refs. 6,7,8,9,10,11,12); this interaction leads to the recruitment of MALT1 and/or the stabilization of the MALT1-CARMA1 interaction13, 14, 15. The formation of the CARMA1–Bcl-10–MALT1 complex is central to antigen receptor–mediated activation of the NF-B pathway and thereby controls the antigen receptor–induced expression and secretion of cytokines that are essential for lymphocyte proliferation PMID:11356195; PMID:17052756 CARMA1 induces BCL10 phosphorylation (data from non immune cells) Phosphorylation of Bcl10 at S138 Negatively Regulates T-Cell Receptor-Mediated NF-κB Activation. CaMKII phosphorylates Bcl10 on Ser138. Furthermore, a CaMKII inhibitor, KN93, and CaMKII siRNA substantially reduce Bcl10 phosphorylation induced by phorbol myristate acetate/ionomycin. S138A mutation prolongs Bcl10-induced NF-κB activation, suggesting that Bcl10 phosphorylation is involved in attenuation of NF-κB activation. Phosphorylation of Bcl10, especially at Ser138, has been linked to a signal-induced degradation of Bcl10. PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10. PMID:17462996 Bcl-10 links MALT1 to the active caspase complex in effector T cells.</body> </html> </notes> <label text="BCL10"/> <bbox w="80.0" h="40.0" x="3950.0" y="3645.0"/> <glyph class="state variable" id="_e6d67087-0751-4c89-9c07-f8beb30c5d8b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3945.0" y="3660.0"/> </glyph> </glyph> <glyph class="complex" id="s5141_csa103" compartmentRef="c8_ca8"> <label text="s5042"/> <bbox w="100.0" h="120.0" x="3900.0" y="995.0"/> <glyph class="simple chemical" id="s5142_sa882"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC CASCADE:IFNAB 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="3915.0" y="1062.5"/> </glyph> <glyph class="macromolecule" id="s5143_sa883"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 MODULE:SMAC MODULE:TCR_SIGNALING HUGO:PRKCQ CASCADE:TCR PMID:23433459 PKCtheta in tregs. PMID:23886063; PMID:9738502 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta PMID:17544292 ; PMID:23433459 Protein kinase C theta (PKCtheta): a key player in T cell life and death. Mutation of the PKCθ gene leads to impaired receptor-induced stimulation of the transcription factors AP-1, NF-κB and NFAT, which results in defective T cell activation, and to aberrant expression of apoptosis-related proteins, resulting in poor T cell survival. Furthermore, PKCθ-deficient mice display defects in the differentiation of T helper subsets, particularly in Th2 and Th17-mediated inflammatory responses. The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation PMID: 10746729 The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:15536066 Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. PMID:10652356 The C2-like domain contains a tyrosine residue (Tyr-90), which is phosphorylated by the T cell tyrosine kinase Lck PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner PKCθ was required for the survival of both activated CD4 and CD8+ T cells</body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="3910.0" y="1005.0"/> <glyph class="state variable" id="_c7b5f110-bf62-45a7-a48d-306b6e32b95e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3902.5" y="1020.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5147_sa886" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:BCL10 MODULE:TCR_SIGNALING PMID:18264101 Lymphocyte activation induces a smaller Bcl-10 isoform downstream of CD3 and CD28 Formation of the faster migrating Bcl-10 isoform depends on its recruitment by CARMA1 and on the formation of CARMA1 oligomers. activation of the NF-B pathway by antigen-presenting cells or by drugs that mimic the antigen receptor signal does not require MALT1-dependent cleavage of Bcl-10 but most likely depends on other MALT1 substrates. After activation with either anti-CD3 and anti-CD28 or PMA, cells expressing the R228G mutant had less adhesion to fibronectin than did cells expressing wild-type Bcl-10 (. In Jurkat T cells, adhesion to the 1 ligand fibronectin is mediated mainly by the integrin a4b1, with a minor contribution from a5b1)</body> </html> </notes> <label text="BCL10*"/> <bbox w="80.0" h="40.0" x="4140.0" y="2900.0"/> <glyph class="unit of information" id="_eb99d254-7de7-4e06-beff-b68cab4e69ff"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4155.0" y="2895.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s652_sa892" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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:MAP3K7 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING CELL:TREG Maps_Modules_end References_begin: PMID: 15125833 The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. PMID:24403530 the activation of MKK4 and IKK is inhibited by DUSP14; thus, DUSP14 may function upstream of both MKK4 and IKK upon T cell activation The phosphorylation levels of the TAB1–TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IKK, but not ERK, activation of DUSP14-deficient T cells was attenuated by TAB1 shRNA knockdown PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKKα/β phosphorylation in the TCR signaling pathway. PKCθ, TAK1, and IKK assemble into a complex in a signal‐dependent but CARMA1‐independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKCθ–TAK1–IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKKα/β in a CARMA1‐independent manner, and, together with CARMA1‐dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF‐κB in antigen receptor signaling pathways PMID:22941947 TAK1 can also activate MKK4/7 and MKK3/6, resulting in the activation of JNK and p38, respectively. PMID:16799562 Thymic generation of Treg cells requires TAK1 Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA IL-7-mediated T cell survival depends on TAK1 TAK1 is required for TCR-mediated cellular responses and NF-B and Jnk activation in mature thymocytes. TCR-induced Jnk but not NF-B in effector T cells requires TAK1 TAK1 is essential for IL-2-, IL-7- and IL-15-mediated p38 activation in effector T cells. PMID:17363905 TAK1 is essential for JNK and NF-κB activation during TCR signaling in primary T cells PMID:20164171 a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C-theta. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKgamma. Thus, distinct sites within ADAP control two key activation responses that are required for NF-kappaB activation in T cells. References_end</body> </html> </notes> <label text="MAP3K7"/> <bbox w="80.0" h="40.0" x="1470.0" y="2905.0"/> </glyph> <glyph class="macromolecule" id="s5152_sa893" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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:TRAF6 Identifiers_end Maps_Modules_begin: MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:15125833 MALT1 oligomers is critical for activation of the IKK complex17, 18, most likely by MALT1-dependent recruitment of the ubiquitin ligase TRAF6 (refs. 17,19) and subsequent lysine 63–mediated ubiquitination of IKK(also called NEMO)18. PMID:17948050 TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKgamma. http://link.springer.com/chapter/10.1007/978-1-4419-6676-6_7#page-2 References_end</body> </html> </notes> <label text="TRAF6"/> <bbox w="80.0" h="40.0" x="3640.0" y="2875.0"/> </glyph> <glyph class="macromolecule" id="s5153_sa908" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CRADD MODULE:TCR_SIGNALING CASCADE:TCR PMID:22323537 The “Death” Adaptor CRADD/RAIDD Targets BCL10 and Suppresses Agonist-Induced Cytokine Expression in T Lymphocytes Cradd-deficient spleen cells, CD4(+) T cells, and mice respond to T cell agonists with strikingly higher production of proinflammatory mediators, including IFN-γ, IL-2, TNF-α, and IL-17.</body> </html> </notes> <label text="CRADD"/> <bbox w="80.0" h="40.0" x="4080.0" y="3585.0"/> </glyph> <glyph class="complex" id="s5165_csa111" compartmentRef="c2_ca2"> <label text="s5165"/> <bbox w="100.0" h="120.0" x="4200.0" y="3535.0"/> <glyph class="macromolecule" id="s5167_sa897"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CRADD MODULE:TCR_SIGNALING CASCADE:TCR PMID:22323537 The “Death” Adaptor CRADD/RAIDD Targets BCL10 and Suppresses Agonist-Induced Cytokine Expression in T Lymphocytes Cradd-deficient spleen cells, CD4(+) T cells, and mice respond to T cell agonists with strikingly higher production of proinflammatory mediators, including IFN-γ, IL-2, TNF-α, and IL-17.</body> </html> </notes> <label text="CRADD"/> <bbox w="80.0" h="40.0" x="4210.0" y="3545.0"/> </glyph> <glyph class="macromolecule" id="s5166_sa907"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:BCL10 MODULE:TCR_SIGNALING PMID:18264101 Lymphocyte activation induces a smaller Bcl-10 isoform downstream of CD3 and CD28 Formation of the faster migrating Bcl-10 isoform depends on its recruitment by CARMA1 and on the formation of CARMA1 oligomers. activation of the NF-B pathway by antigen-presenting cells or by drugs that mimic the antigen receptor signal does not require MALT1-dependent cleavage of Bcl-10 but most likely depends on other MALT1 substrates. After activation with either anti-CD3 and anti-CD28 or PMA, cells expressing the R228G mutant had less adhesion to fibronectin than did cells expressing wild-type Bcl-10 (. In Jurkat T cells, adhesion to the 1 ligand fibronectin is mediated mainly by the integrin a4b1, with a minor contribution from a5b1) MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, In the CARMA1–Bcl-10–MALT1 signaling complex, Bcl-10 acts as an adaptor protein that binds, through its caspase-recruitment domain (CARD), to the CARD motif of CARMA1 (refs. 6,7,8,9,10,11,12); this interaction leads to the recruitment of MALT1 and/or the stabilization of the MALT1-CARMA1 interaction13, 14, 15. The formation of the CARMA1–Bcl-10–MALT1 complex is central to antigen receptor–mediated activation of the NF-B pathway and thereby controls the antigen receptor–induced expression and secretion of cytokines that are essential for lymphocyte proliferation PMID:11356195; PMID:17052756 CARMA1 induces BCL10 phosphorylation (data from non immune cells) Phosphorylation of Bcl10 at S138 Negatively Regulates T-Cell Receptor-Mediated NF-κB Activation. CaMKII phosphorylates Bcl10 on Ser138. Furthermore, a CaMKII inhibitor, KN93, and CaMKII siRNA substantially reduce Bcl10 phosphorylation induced by phorbol myristate acetate/ionomycin. S138A mutation prolongs Bcl10-induced NF-κB activation, suggesting that Bcl10 phosphorylation is involved in attenuation of NF-κB activation. Phosphorylation of Bcl10, especially at Ser138, has been linked to a signal-induced degradation of Bcl10. PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10. PMID:17462996 Bcl-10 links MALT1 to the active caspase complex in effector T cells.</body> </html> </notes> <label text="BCL10"/> <bbox w="80.0" h="40.0" x="4210.0" y="3585.0"/> <glyph class="state variable" id="_88bf71c8-67ac-41c8-b0b1-97574680c8e6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4205.0" y="3600.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s924_sa461" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:WIPF1 MODULE:TCR_SIGNALING 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.</body> </html> </notes> <label text="WIPF1"/> <bbox w="80.0" h="40.0" x="4777.5" y="4260.0"/> <glyph class="state variable" id="_6c4d6383-5115-4425-b7bb-bcba4cfaa823"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4772.5" y="4274.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s5168_sa912" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FLNA CASCADE:TCR MODULE:TCR_SIGNALING PMID:27242793 PIP5Kβ mediates the recruitment of filamin-A (FLN-A) and lipid rafts to the T:APC contact zone downstream of CD28. where filamin-A cooperates with Vav1 to integrate signaling pathways resulting in actin polymerization and lipid raft mobilizatio PMID:21277899 In searching for specific upstream activators linking CD28 to the IKKα/NF-κB cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-κB inducing kinase (NIK), in both Jurkat and human primary T cells. Following CD28 engagement by B7, in the absence of TCR, FLNa-associated NIK is activated and induces IKKα kinase activity. Both proline (P(208)YAP(211)P(212)) and tyrosine residues (Y(206)QPY(209)APP) within the C-terminal proline-rich motif of CD28 are involved in the recruitment of FLNa/NIK complexes to the membrane as well as in the activation of NIK and IKKα. PMID:16849481 TCR stimulation induced stable physical association of FLNa with PKCtheta. Furthermore, the TCR/CD28-induced membrane translocation of PKCtheta was inhibited in FLNa-depleted T cells.</body> </html> </notes> <label text="FLNA"/> <bbox w="80.0" h="40.0" x="2480.0" y="2420.0"/> </glyph> <glyph class="macromolecule" id="s5169_sa913" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:MAP3K14 PMID:21277899 In searching for specific upstream activators linking CD28 to the IKKα/NF-κB cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-κB inducing kinase (NIK), in both Jurkat and human primary T cells. Following CD28 engagement by B7, in the absence of TCR, FLNa-associated NIK is activated and induces IKKα kinase activity. Both proline (P(208)YAP(211)P(212)) and tyrosine residues (Y(206)QPY(209)APP) within the C-terminal proline-rich motif of CD28 are involved in the recruitment of FLNa/NIK complexes to the membrane as well as in the activation of NIK and IKKα. PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manne</body> </html> </notes> <label text="MAP3K14"/> <bbox w="80.0" h="40.0" x="3010.0" y="3605.0"/> <glyph class="state variable" id="_145e2700-9ea7-4a81-991b-cce1cb0e853e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3005.0" y="3620.0"/> </glyph> </glyph> <glyph class="complex" id="s5170_csa112" compartmentRef="c2_ca2"> <label text="s5170"/> <bbox w="100.0" h="120.0" x="3170.0" y="3465.0"/> <glyph class="macromolecule" id="s5171_sa914"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FLNA CASCADE:TCR MODULE:TCR_SIGNALING PMID:27242793 PIP5Kβ mediates the recruitment of filamin-A (FLN-A) and lipid rafts to the T:APC contact zone downstream of CD28. where filamin-A cooperates with Vav1 to integrate signaling pathways resulting in actin polymerization and lipid raft mobilizatio PMID:21277899 In searching for specific upstream activators linking CD28 to the IKKα/NF-κB cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-κB inducing kinase (NIK), in both Jurkat and human primary T cells. Following CD28 engagement by B7, in the absence of TCR, FLNa-associated NIK is activated and induces IKKα kinase activity. Both proline (P(208)YAP(211)P(212)) and tyrosine residues (Y(206)QPY(209)APP) within the C-terminal proline-rich motif of CD28 are involved in the recruitment of FLNa/NIK complexes to the membrane as well as in the activation of NIK and IKKα. PMID:16849481 TCR stimulation induced stable physical association of FLNa with PKCtheta. Furthermore, the TCR/CD28-induced membrane translocation of PKCtheta was inhibited in FLNa-depleted T cells.</body> </html> </notes> <label text="FLNA"/> <bbox w="80.0" h="40.0" x="3180.0" y="3515.0"/> </glyph> <glyph class="macromolecule" id="s5172_sa916"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:MAP3K14 PMID:21277899 In searching for specific upstream activators linking CD28 to the IKKα/NF-κB cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-κB inducing kinase (NIK), in both Jurkat and human primary T cells. Following CD28 engagement by B7, in the absence of TCR, FLNa-associated NIK is activated and induces IKKα kinase activity. Both proline (P(208)YAP(211)P(212)) and tyrosine residues (Y(206)QPY(209)APP) within the C-terminal proline-rich motif of CD28 are involved in the recruitment of FLNa/NIK complexes to the membrane as well as in the activation of NIK and IKKα. PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manne</body> </html> </notes> <label text="MAP3K14"/> <bbox w="80.0" h="40.0" x="3180.0" y="3475.0"/> <glyph class="state variable" id="_42885f1b-342f-4a0f-949a-4e474ff566df"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3172.5" y="3490.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule multimer" id="s5174_sa918" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 NFkB downstream of CD28 PMID: 16970925 The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. PMID:15536066 TCR/CD28 costimulation induces IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, and PKC is required for IkappaBalpha and IkappaBepsilon but not IkappaBbeta degradation. PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase. References_end</body> </html> </notes> <label text="IKKα*"/> <bbox w="86.0" h="46.0" x="3097.0" y="3772.0"/> <glyph class="unit of information" id="_f267cc34-7b62-4e4c-acb0-daa49d7870a3"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3130.0" y="3767.0"/> </glyph> <glyph class="state variable" id="_c3a836ba-e7c2-477d-98af-454b2b45e800"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3092.0" y="3790.0"/> </glyph> </glyph> <glyph class="complex" id="s5177_csa113" compartmentRef="c2_ca2"> <label text="s5177"/> <bbox w="100.0" h="120.0" x="4180.0" y="4365.0"/> <glyph class="macromolecule" id="s5175_sa920"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKB2 CASCADE:TCR MODULE:TCR_SIGNALING PMID: 16970925 The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manne</body> </html> </notes> <label text="NFKB2_p100*"/> <bbox w="80.0" h="40.0" x="4190.0" y="4375.0"/> </glyph> <glyph class="macromolecule" id="s5178_sa922"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="4190.0" y="4415.0"/> </glyph> </glyph> <glyph class="complex" id="s5179_csa114" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters</body> </html> </notes> <label text="s5179"/> <bbox w="100.0" h="120.0" x="4180.0" y="4565.0"/> <glyph class="macromolecule" id="s5176_sa921"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKB2 MODULE:TCR_SIGNALING CASCADE:TCR PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters</body> </html> </notes> <label text="NFKB2_p52*"/> <bbox w="80.0" h="40.0" x="4190.0" y="4575.0"/> <glyph class="unit of information" id="_2cace41d-a8c0-43ef-9c50-491ddf097264"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4205.0" y="4570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5180_sa923"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="4190.0" y="4625.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s5181_sa919" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:12133805 NFkB downstream of CD28 PMID: 16970925 The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. PMID:15536066 TCR/CD28 costimulation induces IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, and PKC is required for IkappaBalpha and IkappaBepsilon but not IkappaBbeta degradation. PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase. References_end</body> </html> </notes> <label text="IKKα*"/> <bbox w="86.0" h="46.0" x="3097.0" y="3872.0"/> <glyph class="unit of information" id="_5d14234d-ae51-46c0-a7d9-5cfc97e3cd9e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="3130.0" y="3867.0"/> </glyph> <glyph class="state variable" id="_98790a10-6094-4dbf-8b13-8c8e8ea6e898"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3089.5" y="3890.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5182_sa925" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CXCL8 MODULE:TCR_SIGNALING PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 downstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="CXCL8"/> <bbox w="70.0" h="25.0" x="1725.0" y="5842.5"/> </glyph> <glyph class="nucleic acid feature" id="s5183_sa926" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CXCL8 MODULE:TCR_SIGNALING PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 downstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="CXCL8"/> <bbox w="90.0" h="25.0" x="1715.0" y="5912.5"/> <glyph class="unit of information" id="_c588c7f7-64c8-4d72-8b49-e7a2b88ceab7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1750.0" y="5907.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5184_sa927" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2L1 PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:16227604 Expression of breakout gene Bcl-xL is dependent upon phosphatidylinositol 3-kinase. CD28 costimulation increases expression of the survival factor Bcl-xL (8), and this CD28-mediated activation is relatively resistant to the effects of CTLA-4 ligation (7) but not to those of PD-1 ligation so CTLA-4 and PD-1 blockage may have different susceptibilities to apoptosis. factors recruited to the PD-1 ITSM block CD28-mediated induction of Bcl-xL and PI3K. PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and downmodulation of BIM protein</body> </html> </notes> <label text="BCL2L1"/> <bbox w="70.0" h="25.0" x="3255.0" y="5632.5"/> </glyph> <glyph class="nucleic acid feature" id="s5185_sa928" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2L1 PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters</body> </html> </notes> <label text="BCL2L1"/> <bbox w="90.0" h="25.0" x="3245.0" y="5702.5"/> <glyph class="unit of information" id="_02e61c10-7022-4403-8699-1c41149f12ec"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3280.0" y="5697.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5186_sa929" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2L1 PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:16227604 Expression of breakout gene Bcl-xL is dependent upon phosphatidylinositol 3-kinase. CD28 costimulation increases expression of the survival factor Bcl-xL (8), and this CD28-mediated activation is relatively resistant to the effects of CTLA-4 ligation (7) but not to those of PD-1 ligation so CTLA-4 and PD-1 blockage may have different susceptibilities to apoptosis. factors recruited to the PD-1 ITSM block CD28-mediated induction of Bcl-xL and PI3K. PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and downmodulation of BIM protein</body> </html> </notes> <label text="BCL2L1"/> <bbox w="80.0" h="40.0" x="3250.0" y="5775.0"/> </glyph> <glyph class="macromolecule" id="s5188_sa931" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CXCL8 MODULE:TCR_SIGNALING PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 downstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="CXCL8"/> <bbox w="80.0" h="40.0" x="1720.0" y="5995.0"/> </glyph> <glyph class="macromolecule" id="s5189_sa932" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:BCL3 MODULE:TCR_SIGNALING PMID:14668329 Bcl-3 protein was induced after stimulation of tolerant but not activated T cells. Bcl-3 is interacting with p50-p50 homodimers and possibly cooperates with p50 to inhibit transcriptional activity of the IL-2 gene. p50-p50 homodimers could associate specifically with the nuclear IκB protein Bcl-3 in order to regulate their transcriptional activity.</body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="4040.0" y="5815.0"/> </glyph> <glyph class="complex" id="s5190_csa115" compartmentRef="c2_ca2"> <label text="s5190"/> <bbox w="110.0" h="150.0" x="4175.0" y="5620.0"/> <glyph class="macromolecule multimer" id="s5192_sa933"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65 PMID:15079071 when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:14668329 predominance of p50-p50 homodimers binding to the IL-2 promoter κB site in tolerant T cells CD4+ correlated with repression of NFκB-driven transcription. PMID: 8580069 PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="85.375" h="65.375" x="4182.3125" y="5677.3125"/> <glyph class="unit of information" id="_d1b9f53f-ab3e-466b-b8f4-f8f6adba64bd"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="4215.0" y="5672.3125"/> </glyph> <glyph class="unit of information" id="_069379c0-19c4-491b-a76b-4c337cdf6883"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4200.0" y="5672.3125"/> </glyph> </glyph> <glyph class="macromolecule" id="s5191_sa935"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:BCL3 MODULE:TCR_SIGNALING PMID:14668329 Bcl-3 protein was induced after stimulation of tolerant but not activated T cells. Bcl-3 is interacting with p50-p50 homodimers and possibly cooperates with p50 to inhibit transcriptional activity of the IL-2 gene. p50-p50 homodimers could associate specifically with the nuclear IκB protein Bcl-3 in order to regulate their transcriptional activity.</body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="4185.0" y="5630.0"/> </glyph> </glyph> <glyph class="phenotype" id="s5194_sa937" compartmentRef="c2_ca2"> <label text="induction_of_apoptosis"/> <bbox w="190.0" h="35.0" x="3865.0" y="5037.5"/> </glyph> <glyph class="macromolecule" id="s5196_sa939" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:CAMK2A HUGO:CAMK2B HUGO:CAMK2G HUGO:CAMK2D MODULE:TCR_SIGNALING PMID:11356195; PMID: 17052756; PMID:21199863 CARMA1 induces BCL10 phosphorylation via CaMKII PMID:16809782;PMID:17052756 In the immune synapse, CaMKII phosphorylates Carma1 on Ser109 and the phosphorylation increases the interaction between Carma1 and Bcl10. Carma1/Bcl10/Malt1 complex induces NF-κB activation (Sun et al., 2004). Accordingly based on the findings in the present study, CaMKII phosphorylates Bcl10 on Ser138 while IKKβ phosphorylates residues Ser134, 136, 138, 141 and 144 (Wegener et al., 2006). Phosphorylation of Bcl10 disrupts Bcl10/Malt1 association (Wegener et al., 2006), and attenuates NF-κB activation. PMID:15843557 Calcium/calmodulin-dependent protein kinase II (CaMKII),4 a multifunctional serine/threonine kinase, consists of four distinct isoforms (α, β, γ, and δ), and each comprises a family of alternatively spliced variants. A general feature of all CaMKII isoforms is their ability to decode the frequency of calcium oscillations by retaining calcium-independent kinase activity subsequent to the initial stimulation. The α and β isoforms are expressed abundantly in neurons, while the γ and δ isoforms are more widely expressed Active CaMKII-transduced T cells exhibit enhanced cytotoxic activity PMID:19349987 Ca2+ signaling requires myosin IIA activity</body> </html> </notes> <label text="CAMK2*"/> <bbox w="80.0" h="40.0" x="3950.0" y="3475.0"/> <glyph class="state variable" id="_19a4927e-3ee8-427f-b31e-0e701891fcef"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3942.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5198_sa941" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:BCL10 MODULE:TCR_SIGNALING PMID:18264101 Lymphocyte activation induces a smaller Bcl-10 isoform downstream of CD3 and CD28 Formation of the faster migrating Bcl-10 isoform depends on its recruitment by CARMA1 and on the formation of CARMA1 oligomers. activation of the NF-B pathway by antigen-presenting cells or by drugs that mimic the antigen receptor signal does not require MALT1-dependent cleavage of Bcl-10 but most likely depends on other MALT1 substrates. After activation with either anti-CD3 and anti-CD28 or PMA, cells expressing the R228G mutant had less adhesion to fibronectin than did cells expressing wild-type Bcl-10 (. In Jurkat T cells, adhesion to the 1 ligand fibronectin is mediated mainly by the integrin a4b1, with a minor contribution from a5b1) MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, In the CARMA1–Bcl-10–MALT1 signaling complex, Bcl-10 acts as an adaptor protein that binds, through its caspase-recruitment domain (CARD), to the CARD motif of CARMA1 (refs. 6,7,8,9,10,11,12); this interaction leads to the recruitment of MALT1 and/or the stabilization of the MALT1-CARMA1 interaction13, 14, 15. The formation of the CARMA1–Bcl-10–MALT1 complex is central to antigen receptor–mediated activation of the NF-B pathway and thereby controls the antigen receptor–induced expression and secretion of cytokines that are essential for lymphocyte proliferation PMID:11356195; PMID:17052756 CARMA1 induces BCL10 phosphorylation (data from non immune cells) Phosphorylation of Bcl10 at S138 Negatively Regulates T-Cell Receptor-Mediated NF-κB Activation. CaMKII phosphorylates Bcl10 on Ser138. Furthermore, a CaMKII inhibitor, KN93, and CaMKII siRNA substantially reduce Bcl10 phosphorylation induced by phorbol myristate acetate/ionomycin. S138A mutation prolongs Bcl10-induced NF-κB activation, suggesting that Bcl10 phosphorylation is involved in attenuation of NF-κB activation. Phosphorylation of Bcl10, especially at Ser138, has been linked to a signal-induced degradation of Bcl10. PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10. PMID:17462996 Bcl-10 links MALT1 to the active caspase complex in effector T cells.</body> </html> </notes> <label text="BCL10"/> <bbox w="80.0" h="40.0" x="3950.0" y="3755.0"/> <glyph class="state variable" id="_53e558ef-994f-4601-97cc-db19877c95ac"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3942.5" y="3770.0"/> </glyph> </glyph> <glyph class="complex" id="s5203_csa105" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:24560716 Following TCR stimulation, CARMA1 is phosphorylated by PKCθ, and this phosphorylation results in a conformational change that enable CARMA1 to associate with BCL10 [15], [16] and [17] and MALT1, a protein with paracaspase proteolitic activity required for NF-κB activation also involved in MALT lymphomas [18]. Correct assembly of the CBM complex is believed to be anessential step for triggering the subsequent events that lead to activation of NF-κB following antigen receptor stimulation. The exact mechanism by which the CBM complex activates NF-κB is still unknown. The CBM complex most likely serves as a molecular platform to recruit signaling components responsible for K63-linked polyubiquitination of NEMO, a regulatory subunit of the IKK complex that is responsible for activation of NF-κB [19] and [20]. Evidence for scaffolding filamentous assembly structures involving BCL10 and CARMA1 first came from cell microscopy observations, subsequently confirmed by structural studies [21] and [22]. Indeed, activation of the IKK complex is not only dependent on IKK phosphorylation but also on CARMA1-dependent recruitment and non-degradative ubiquitination of NEMO [19], [20] and [23]. The importance of the ubiquitination events for the CBM-dependent activation of NF-κB is furthermore underlined by the fact that enzymatic deubiquitinases such as A20 significantly inhibits activation of NF-κB mediated by the CBM complex</body> </html> </notes> <label text="s5148"/> <bbox w="130.0" h="190.0" x="4125.0" y="3050.0"/> <glyph class="macromolecule" id="s5204_sa887"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CARD11 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12356734 CARD11(CARMA1) mediates NF-kappaB activation by alphaCD3/alphaCD28 cross-linking. CARD11 functions upstream of the IKK complex. wild‐type CARD11 co‐precipitating with endogenous Bcl10 CARMA1 only expresses in lymphocytes PMID:20685844 CARMA1, a critical target of PKCθ phosphorylation, resides in lymphocytes in an inactive state. Extensive CARMA1 mutagenesis data suggest that this inactive state is maintained by intramolecular interactions that prevent the CARMA1 CARD from interacting with the CARD of BCL10 12 and 13. PKCθ phosphorylates human CARMA1 at three serine residues, S552, S645 and S637 (S564, S657, S649 in mice) PMID:11356195; PMID: 17052756; PMID:21199863 CARMA1 induces BCL10 phosphorylation via CaMKII PMID:16809782;PMID:17052756 In the immune synapse, CaMKII phosphorylates Carma1 on Ser109 and the phosphorylation increases the interaction between Carma1 and Bcl10. Carma1/Bcl10/Malt1 complex induces NF-κB activation (Sun et al., 2004). Accordingly based on the findings in the present study, CaMKII phosphorylates Bcl10 on Ser138 while IKKβ phosphorylates residues Ser134, 136, 138, 141 and 144 (Wegener et al., 2006). Phosphorylation of Bcl10 disrupts Bcl10/Malt1 association (Wegener et al., 2006), and attenuates NF-κB activation. PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKKα/β phosphorylation in the TCR signaling pathway. PKCθ, TAK1, and IKK assemble into a complex in a signal‐dependent but CARMA1‐independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKCθ–TAK1–IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKKα/β in a CARMA1‐independent manner, and, together with CARMA1‐dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF‐κB in antigen receptor signaling pathways CARMA1 is essential for the ubiquitination of NEMO NEMO, but not its ubiquitination, is required for IKKα/β phosphorylation</body> </html> </notes> <label text="CARD11"/> <bbox w="80.0" h="40.0" x="4145.0" y="3170.0"/> <glyph class="state variable" id="_d630a761-2db9-43ae-837a-d6c614218bd9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4137.5" y="3185.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5205_sa889"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:MALT1 MODULE:TCR_SIGNALING PMID:21873235 Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA- or c-Rel–containing NF-κB complexes. PMID:18264101 MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, PMID:17948050 TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKgamma.</body> </html> </notes> <label text="MALT1"/> <bbox w="80.0" h="40.0" x="4145.0" y="3060.0"/> <glyph class="state variable" id="_d510f522-687c-4e7d-892e-f6637bc974ee"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4140.0" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5206_sa888"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:BCL10 MODULE:TCR_SIGNALING PMID:18264101 Lymphocyte activation induces a smaller Bcl-10 isoform downstream of CD3 and CD28 Formation of the faster migrating Bcl-10 isoform depends on its recruitment by CARMA1 and on the formation of CARMA1 oligomers. activation of the NF-B pathway by antigen-presenting cells or by drugs that mimic the antigen receptor signal does not require MALT1-dependent cleavage of Bcl-10 but most likely depends on other MALT1 substrates. After activation with either anti-CD3 and anti-CD28 or PMA, cells expressing the R228G mutant had less adhesion to fibronectin than did cells expressing wild-type Bcl-10 (. In Jurkat T cells, adhesion to the 1 ligand fibronectin is mediated mainly by the integrin a4b1, with a minor contribution from a5b1) MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, In the CARMA1–Bcl-10–MALT1 signaling complex, Bcl-10 acts as an adaptor protein that binds, through its caspase-recruitment domain (CARD), to the CARD motif of CARMA1 (refs. 6,7,8,9,10,11,12); this interaction leads to the recruitment of MALT1 and/or the stabilization of the MALT1-CARMA1 interaction13, 14, 15. The formation of the CARMA1–Bcl-10–MALT1 complex is central to antigen receptor–mediated activation of the NF-B pathway and thereby controls the antigen receptor–induced expression and secretion of cytokines that are essential for lymphocyte proliferation PMID:11356195; PMID:17052756 CARMA1 induces BCL10 phosphorylation (data from non immune cells) Phosphorylation of Bcl10 at S138 Negatively Regulates T-Cell Receptor-Mediated NF-κB Activation. CaMKII phosphorylates Bcl10 on Ser138. Furthermore, a CaMKII inhibitor, KN93, and CaMKII siRNA substantially reduce Bcl10 phosphorylation induced by phorbol myristate acetate/ionomycin. S138A mutation prolongs Bcl10-induced NF-κB activation, suggesting that Bcl10 phosphorylation is involved in attenuation of NF-κB activation. Phosphorylation of Bcl10, especially at Ser138, has been linked to a signal-induced degradation of Bcl10. PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10. PMID:17462996 Bcl-10 links MALT1 to the active caspase complex in effector T cells.</body> </html> </notes> <label text="BCL10"/> <bbox w="80.0" h="40.0" x="4145.0" y="3110.0"/> <glyph class="state variable" id="_6efc44bc-af3e-462d-8f1b-ce0d474db4bb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4140.0" y="3125.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5212_sa951" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CFLAR CASCADE:TCR MODULE:TCR_SIGNALING PMID:12215447 The long form of FLIP c-FLIP(L) is an activator of caspase-8. FLIPL induces processing of caspase-8. (non immune cells) PMID:17462996 Following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="CFLAR"/> <bbox w="80.0" h="40.0" x="4120.0" y="2455.0"/> </glyph> <glyph class="macromolecule" id="s5213_sa955" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RALBP1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:17462996 Following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="RALBP1"/> <bbox w="80.0" h="40.0" x="3970.0" y="2715.0"/> </glyph> <glyph class="macromolecule" id="s5214_sa965" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:TRAF2 PMID:17462996 Following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. PMID:19392652 Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB.</body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="3780.0" y="2765.0"/> <glyph class="state variable" id="_20f2e0d4-3799-4717-8cab-37645231e47f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3775.0" y="2780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5215_sa958" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CASP8 MODULE:TCR MODULE:TCR_SIGNALING PMID:12215447 The long form of FLIP c-FLIP(L) is an activator of caspase-8. FLIPL induces processing of caspase-8. (non immune cells) PMID:17462996 Following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="cFLIP_L*"/> <bbox w="80.0" h="40.0" x="4040.0" y="2535.0"/> <glyph class="unit of information" id="_e85311dd-a6e6-4899-a680-b16bcf525400"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4055.0" y="2530.0"/> </glyph> </glyph> <glyph class="complex" id="s5216_csa118" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:17462996 , c-FLIPL co-precipitated with the active caspase complex in lipid rafts, the majority of which was processed to p43 FLIP despite the reverse ratio in the whole cell lysate</body> </html> </notes> <label text="s5216"/> <bbox w="100.0" h="120.0" x="3890.0" y="2535.0"/> <glyph class="macromolecule" id="s5217_sa959"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CASP8 MODULE:TCR MODULE:TCR_SIGNALING PMID:12215447 The long form of FLIP c-FLIP(L) is an activator of caspase-8. FLIPL induces processing of caspase-8. (non immune cells) PMID:17462996 Following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="cFLIP_L*"/> <bbox w="80.0" h="40.0" x="3900.0" y="2545.0"/> <glyph class="unit of information" id="_3b9b479b-fa0a-4c87-8d40-05d2620e947b"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3915.0" y="2540.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5220_sa962"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CASP8 MODULE:TCR MODULE:TCR_SIGNALING PMID:17462996 Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="caspase8*"/> <bbox w="80.0" h="40.0" x="3900.0" y="2595.0"/> <glyph class="unit of information" id="_9f3afa4c-85ed-40c6-8ee7-115f9f7f9148"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3915.0" y="2590.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5219_sa961" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CASP8 MODULE:TCR MODULE:TCR_SIGNALING PMID:17462996 Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="caspase8*"/> <bbox w="80.0" h="40.0" x="4080.0" y="2625.0"/> <glyph class="unit of information" id="_1ee7d86b-8444-47e8-9054-d23c9125ac7f"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4095.0" y="2620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5211_sa950" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CASP8 MODULE:TCR MODULE:TCR_SIGNALING PMID:17462996 Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR.</body> </html> </notes> <label text="CASP8"/> <bbox w="80.0" h="40.0" x="4200.0" y="2615.0"/> </glyph> <glyph class="macromolecule" id="s5221_sa963" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RALBP1 MODULE:TCR_SIGNALING PMID:26195820 In apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID immediately after the recruitment of RIP1 to the receptor complex, impairing IκB kinase (IKK) recruitment and NF-κB activation. In apoptosis-resistant cells, cFLIP restricts caspase-8 activity, resulting in limited RIP1 cleavage and generation of a KD-cleaved fragment capable of activating NF-κB but not apoptosis. (lymphoma cells) PMID:20154702 RIP1 creates a platform for the recruitment of the protein kinase TAK1 (which acts in concert with the regulatory proteins TAB2 and TAB3) and the IkB kinase complex IKKa–IKKb–NEMO</body> </html> </notes> <label text="RIP1*"/> <bbox w="80.0" h="40.0" x="3970.0" y="2855.0"/> <glyph class="unit of information" id="_963f96d6-5400-483b-8315-ee9d8dfe8656"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3985.0" y="2850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5222_sa964" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:SIVA1 PMID:19392652 Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB. Siva-1 Knockdown T Cells Demonstrate Decreased K48 and Increased K63 Ubiquitination of TRAF2</body> </html> </notes> <label text="SIVA1"/> <bbox w="80.0" h="40.0" x="3660.0" y="2725.0"/> </glyph> <glyph class="macromolecule" id="s5223_sa956" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:TRAF2 PMID:17462996 Following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. PMID:19392652 Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB.</body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="3780.0" y="2675.0"/> <glyph class="state variable" id="_71f1fe2d-8367-43e5-98ac-cf7de42adc5d"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="3770.0" y="2690.0"/> </glyph> </glyph> <glyph class="source and sink" id="s5224_sa966" compartmentRef="c2_ca2"> <label text="sa956_degraded"/> <bbox w="30.0" h="30.0" x="3805.0" y="2560.0"/> </glyph> <glyph class="complex" id="s5225_csa119" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:24560716 Following TCR stimulation, CARMA1 is phosphorylated by PKCθ, and this phosphorylation results in a conformational change that enable CARMA1 to associate with BCL10 [15], [16] and [17] and MALT1, a protein with paracaspase proteolitic activity required for NF-κB activation also involved in MALT lymphomas [18]. Correct assembly of the CBM complex is believed to be anessential step for triggering the subsequent events that lead to activation of NF-κB following antigen receptor stimulation. The exact mechanism by which the CBM complex activates NF-κB is still unknown. The CBM complex most likely serves as a molecular platform to recruit signaling components responsible for K63-linked polyubiquitination of NEMO, a regulatory subunit of the IKK complex that is responsible for activation of NF-κB [19] and [20]. Evidence for scaffolding filamentous assembly structures involving BCL10 and CARMA1 first came from cell microscopy observations, subsequently confirmed by structural studies [21] and [22]. Indeed, activation of the IKK complex is not only dependent on IKK phosphorylation but also on CARMA1-dependent recruitment and non-degradative ubiquitination of NEMO [19], [20] and [23]. The importance of the ubiquitination events for the CBM-dependent activation of NF-κB is furthermore underlined by the fact that enzymatic deubiquitinases such as A20 significantly inhibits activation of NF-κB mediated by the CBM complex</body> </html> </notes> <label text="s5148"/> <bbox w="130.0" h="190.0" x="3895.0" y="3050.0"/> <glyph class="macromolecule" id="s5226_sa967"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CARD11 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12356734 CARD11(CARMA1) mediates NF-kappaB activation by alphaCD3/alphaCD28 cross-linking. CARD11 functions upstream of the IKK complex. wild‐type CARD11 co‐precipitating with endogenous Bcl10 CARMA1 only expresses in lymphocytes PMID:20685844 CARMA1, a critical target of PKCθ phosphorylation, resides in lymphocytes in an inactive state. Extensive CARMA1 mutagenesis data suggest that this inactive state is maintained by intramolecular interactions that prevent the CARMA1 CARD from interacting with the CARD of BCL10 12 and 13. PKCθ phosphorylates human CARMA1 at three serine residues, S552, S645 and S637 (S564, S657, S649 in mice) PMID:11356195; PMID: 17052756; PMID:21199863 CARMA1 induces BCL10 phosphorylation via CaMKII PMID:16809782;PMID:17052756 In the immune synapse, CaMKII phosphorylates Carma1 on Ser109 and the phosphorylation increases the interaction between Carma1 and Bcl10. Carma1/Bcl10/Malt1 complex induces NF-κB activation (Sun et al., 2004). Accordingly based on the findings in the present study, CaMKII phosphorylates Bcl10 on Ser138 while IKKβ phosphorylates residues Ser134, 136, 138, 141 and 144 (Wegener et al., 2006). Phosphorylation of Bcl10 disrupts Bcl10/Malt1 association (Wegener et al., 2006), and attenuates NF-κB activation. PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKKα/β phosphorylation in the TCR signaling pathway. PKCθ, TAK1, and IKK assemble into a complex in a signal‐dependent but CARMA1‐independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKCθ–TAK1–IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKKα/β in a CARMA1‐independent manner, and, together with CARMA1‐dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF‐κB in antigen receptor signaling pathways CARMA1 is essential for the ubiquitination of NEMO NEMO, but not its ubiquitination, is required for IKKα/β phosphorylation</body> </html> </notes> <label text="CARD11"/> <bbox w="80.0" h="40.0" x="3915.0" y="3170.0"/> <glyph class="state variable" id="_510be2de-9092-4a9d-a227-5a023c033ee3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3907.5" y="3185.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5228_sa968"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:MALT1 MODULE:TCR_SIGNALING PMID:21873235 Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA- or c-Rel–containing NF-κB complexes. PMID:18264101 MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, PMID:17948050 TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKgamma.</body> </html> </notes> <label text="MALT1"/> <bbox w="80.0" h="40.0" x="3915.0" y="3060.0"/> <glyph class="state variable" id="_0ac5e7cb-f176-4d6e-a0b5-44ff25532f74"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="3905.0" y="3075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5227_sa969"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:BCL10 MODULE:TCR_SIGNALING PMID:18264101 Lymphocyte activation induces a smaller Bcl-10 isoform downstream of CD3 and CD28 Formation of the faster migrating Bcl-10 isoform depends on its recruitment by CARMA1 and on the formation of CARMA1 oligomers. activation of the NF-B pathway by antigen-presenting cells or by drugs that mimic the antigen receptor signal does not require MALT1-dependent cleavage of Bcl-10 but most likely depends on other MALT1 substrates. After activation with either anti-CD3 and anti-CD28 or PMA, cells expressing the R228G mutant had less adhesion to fibronectin than did cells expressing wild-type Bcl-10 (. In Jurkat T cells, adhesion to the 1 ligand fibronectin is mediated mainly by the integrin a4b1, with a minor contribution from a5b1) MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, In the CARMA1–Bcl-10–MALT1 signaling complex, Bcl-10 acts as an adaptor protein that binds, through its caspase-recruitment domain (CARD), to the CARD motif of CARMA1 (refs. 6,7,8,9,10,11,12); this interaction leads to the recruitment of MALT1 and/or the stabilization of the MALT1-CARMA1 interaction13, 14, 15. The formation of the CARMA1–Bcl-10–MALT1 complex is central to antigen receptor–mediated activation of the NF-B pathway and thereby controls the antigen receptor–induced expression and secretion of cytokines that are essential for lymphocyte proliferation PMID:11356195; PMID:17052756 CARMA1 induces BCL10 phosphorylation (data from non immune cells) Phosphorylation of Bcl10 at S138 Negatively Regulates T-Cell Receptor-Mediated NF-κB Activation. CaMKII phosphorylates Bcl10 on Ser138. Furthermore, a CaMKII inhibitor, KN93, and CaMKII siRNA substantially reduce Bcl10 phosphorylation induced by phorbol myristate acetate/ionomycin. S138A mutation prolongs Bcl10-induced NF-κB activation, suggesting that Bcl10 phosphorylation is involved in attenuation of NF-κB activation. Phosphorylation of Bcl10, especially at Ser138, has been linked to a signal-induced degradation of Bcl10. PMID:16818229 IKK2 (IKBKB) phoshorylates BCL10 downstream of TCR. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. PMID:21199863 The Ca2+-dependent Phosphatase Calcineurin Controls the Formation of the Carma1-Bcl10-Malt1 Complex during T Cell Receptor-induced NF-κB Activation. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10. PMID:17462996 Bcl-10 links MALT1 to the active caspase complex in effector T cells.</body> </html> </notes> <label text="BCL10"/> <bbox w="80.0" h="40.0" x="3915.0" y="3110.0"/> <glyph class="state variable" id="_7f3ca6b5-497b-4f46-9155-c1517e45a103"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3910.0" y="3125.0"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5230_sa975" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:FOXP3 PMID:18283119, PMID:18509048 T cell receptor signaling inhibits Foxp3 expression via PI3K, Akt, and mTOR. PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:16799562 Thymic generation of Treg cells requires TAK1 Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA PMID:22988108 Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa</body> </html> </notes> <label text="FOXP3"/> <bbox w="70.0" h="25.0" x="955.0" y="1297.5"/> </glyph> <glyph class="nucleic acid feature" id="s5231_sa976" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:FOXP3 PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells.</body> </html> </notes> <label text="FOXP3"/> <bbox w="90.0" h="25.0" x="955.0" y="1367.5"/> <glyph class="unit of information" id="_9e9a9d8f-189c-441b-a1c8-635525b558b3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="990.0" y="1362.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5232_sa977" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNF MODULE:TCR_SIGNALING PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="TNF"/> <bbox w="70.0" h="25.0" x="1875.0" y="6197.5"/> </glyph> <glyph class="nucleic acid feature" id="s5233_sa978" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNF MODULE:TCR_SIGNALING PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:20038811 , IFNG as well as TNF secretion was reduced when melanoma cell lines expressed HVEM (Figure (Figure6,6, C and D). This inhibition correlated significantly with percentages of T cells expressing BTLA (Figure (Figure6E).6E).</body> </html> </notes> <label text="TNF"/> <bbox w="90.0" h="25.0" x="1865.0" y="6282.5"/> <glyph class="unit of information" id="_f868f0b1-3419-47d9-be54-845ec634466a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1900.0" y="6277.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5234_sa980" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IFNG CASCADE:TCR MODULE:TCR_SIGNALING CASCADE:AR2A MODULE:TH1 PMID:20643337 We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. PMID:10523612 Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-gamma production by the cells through Th1 cell-specific positive transcriptional regulation of the IFN-gamma gene. PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. Two-way MLRs produced an increase in IFN-γ mRNA expression, an effect that was reduced with 10 nM ATL313.</body> </html> </notes> <label text="IFNG"/> <bbox w="70.0" h="25.0" x="2035.0" y="6197.5"/> </glyph> <glyph class="nucleic acid feature" id="s5235_sa981" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IFNG CASCADE:TCR MODULE:TCR_SIGNALING CASCADE:AR2A MODULE:TH1 PMID:10523612 Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-gamma production by the cells through Th1 cell-specific positive transcriptional regulation of the IFN-gamma gene.</body> </html> </notes> <label text="IFNG"/> <bbox w="90.0" h="25.0" x="2025.0" y="6282.5"/> <glyph class="unit of information" id="_0d4ce1bd-7017-4807-9125-2b32b5d0797b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2060.0" y="6277.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5237_sa983" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TEC CASCADE:TCR MODULE:TCR_SIGNALING PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated. PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. Tec family kinases directly activate PLCγ1 and regulate Ca2+ responses in immune cells AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release.</body> </html> </notes> <label text="TEC"/> <bbox w="80.0" h="40.0" x="2860.0" y="1740.0"/> <glyph class="state variable" id="_ec5ecd67-361f-4f7a-88ce-1c77eb05c351"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2855.0" y="1755.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5238_sa984" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:STK39 MODULE:TCR_SIGNALING PMID:14988727 SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta. SPAK-specific RNAi or a dominant-negative SPAK mutant inhibited PKCtheta- and TCR/CD28-induced AP-1, but not NF-kappaB, activation.</body> </html> </notes> <label text="STK39"/> <bbox w="80.0" h="40.0" x="1800.0" y="4835.0"/> <glyph class="state variable" id="_cf75c7c6-268e-4de2-b257-4fee24123827"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1795.0" y="4850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5239_sa985" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:STK39 MODULE:TCR_SIGNALING PMID:14988727 SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta. SPAK-specific RNAi or a dominant-negative SPAK mutant inhibited PKCtheta- and TCR/CD28-induced AP-1, but not NF-kappaB, activation.</body> </html> </notes> <label text="STK39"/> <bbox w="80.0" h="40.0" x="1800.0" y="4915.0"/> <glyph class="state variable" id="_6553525e-db78-48ee-b685-b870df0bf58a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1792.5" y="4930.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5240_sa986" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS HUGO:HIF1A PMID: 26513405 in T lymphocytes HIF‐1α protein expression can be robustly induced also by T cell receptor (TCR) stimulation, followed by activation of PI3 kinase/mTOR pathway 28. Alternatively, the pro‐inflammatory cytokine IL‐6 drives HIF‐1α expression by activation of STAT3 transcription factor 29. PMID:16110315 REW Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors PMID:22988108 Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa</body> </html> </notes> <label text="HIF1A"/> <bbox w="80.0" h="40.0" x="810.0" y="1320.0"/> </glyph> <glyph class="macromolecule" id="s5258_sa827" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: CASCADE:TCR MODULE:TCR_SIGNALING Maps_Modules_end References_begin: PMID:8383323 The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters when T cells were stimulated with anti-CD3 antibody, RelA, c-Rel, and p50 were preferentially recruited to the IL-2 promoter PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. References_end</body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="3530.0" y="3950.0"/> </glyph> <glyph class="macromolecule" id="s5259_sa1003" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNF MODULE:TCR_SIGNALING PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:20038811 , IFNG as well as TNF secretion was reduced when melanoma cell lines expressed HVEM (Figure (Figure6,6, C and D). This inhibition correlated significantly with percentages of T cells expressing BTLA (Figure (Figure6E).6E).</body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="1870.0" y="6370.0"/> </glyph> <glyph class="source and sink" id="s5270_sa945" compartmentRef="c2_ca2"> <label text="csa111_degraded"/> <bbox w="30.0" h="30.0" x="4155.0" y="3750.0"/> </glyph> <glyph class="macromolecule" id="s5274_sa482"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMH CELL:TCD8 MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human</body> </html> </notes> <label text="GZMH"/> <bbox w="80.0" h="40.0" x="3480.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5275_sa481"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 HUGO:GZMM MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human</body> </html> </notes> <label text="GZMM"/> <bbox w="80.0" h="40.0" x="3760.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5276_sa480"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GNLY MODULE:TCR_SIGNALING PMID: 19254247 Granulysin is a cytolytic and proinflammatory molecule first identified by a screen for genes expressed 'late' (3-5 days) after activation of human peripheral blood mononuclear cells. Granulysin is present in cytolytic granules of cytotoxic T lymphocytes and natural killer cells. Granulysin is made in a 15-kDa form that is cleaved into a 9-kDa form at both the amino and the carboxy termini. The 15-kDa form is constitutively secreted, and its function remains poorly understood. The 9-kDa form is released by receptor-mediated granule exocytosis. Nine kiloDalton granulysin is broadly cytolytic against tumors and microbes, including gram-positive and gram-negative bacteria, fungi/yeast and parasites. It kills the causative agents of both tuberculosis and malaria. Granulysin is also a chemoattractant for T lymphocytes, monocytes and other inflammatory cells and activates the expression of a number of cytokines, including regulated upon activation T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1 alpha, interleukin (IL)-10, IL-1, IL-6 and interferon (IFN)-alpha. granulysin expression in tumor infiltrates is associated with good outcomes. Pages et al. found low granulysin expression in effector memory T cells in tumor infiltrates to correlate early metastasis and poor survival rates, while high levels of granulysin correlated with good outcomes in colorectal carcinoma Recombinant 9 kDa granulysin attracts T cells, monocytic and NK-cell tumor lines but not Epstein-Barr virus-transformed B-cell lines. Granulysin shows maximal chemotactic activity for CD4+ and CD8+ T cells and monocytes at 10 nM.</body> </html> </notes> <label text="GNLY"/> <bbox w="80.0" h="40.0" x="4170.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5277_sa478"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMA CELL:TCD8 MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human PMID:8432729 Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor.</body> </html> </notes> <label text="GZMA"/> <bbox w="80.0" h="40.0" x="3890.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5278_sa476"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMB MODULE:TCR_SIGNALING CELL:TCD8 PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human PMID:8432729 Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor.</body> </html> </notes> <label text="GZMB"/> <bbox w="70.0" h="40.0" x="3995.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5279_sa479"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMK CELL:TCD8 MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human</body> </html> </notes> <label text="GZMK"/> <bbox w="80.0" h="40.0" x="3640.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5280_sa477"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRF1 MODULE:TCR_SIGNALING PMID: 19380804 Activated CD8+ T cells rapidly up-regulate perforin. Following Ag-specific activation, newly synthesized perforin rapidly appears at the immunological synapse, both in association with and independent of cytotoxic granules, where it functions to promote cytotoxicity. PMID:7520535 Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways.</body> </html> </notes> <label text="PRF1"/> <bbox w="80.0" h="40.0" x="4300.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5285_sa613" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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 ------ HUGO:ICAM1 MODULE:SMAC 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</body> </html> </notes> <label text="ICAM1"/> <bbox w="80.0" h="40.0" x="4430.0" y="440.0"/> </glyph> <glyph class="simple chemical" id="s5291_sa691" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:CD226 CASCADE:TCR PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. 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:15214048 AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release.</body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="2847.5" y="3277.5"/> </glyph> <glyph class="macromolecule" id="s5057_sa738" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PAK1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:14764585 TCR-induced phosphorylation of Pak1 on its autophosphorylation sites (serines 144, 199, and 204) Incubation of Vav1+/+ DP thymocytes with Tat-PID, resulted in an inhibition of TCR-induced Pak1 phosphorylation and, by inference, its activation (Fig. 2B). In contrast, treatment of cells with Tat-PID had no effect on TCR-induced ERK activation (Fig. 2B). We conclude that in DP thymocytes Pak1 does not transduce TCR signals to the ERK pathway.</body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="80.0" h="40.0" x="4180.0" y="5175.0"/> </glyph> <glyph class="macromolecule" id="s5057_sa739" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PAK1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:14764585 TCR-induced phosphorylation of Pak1 on its autophosphorylation sites (serines 144, 199, and 204) Incubation of Vav1+/+ DP thymocytes with Tat-PID, resulted in an inhibition of TCR-induced Pak1 phosphorylation and, by inference, its activation (Fig. 2B). In contrast, treatment of cells with Tat-PID had no effect on TCR-induced ERK activation (Fig. 2B). We conclude that in DP thymocytes Pak1 does not transduce TCR signals to the ERK pathway.</body> </html> </notes> <label text="PAK1"/> <clone/> <bbox w="80.0" h="40.0" x="4180.0" y="5285.0"/> </glyph> <glyph class="macromolecule" id="s5085_sa798" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LCK CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508;PMID:21127503 Lck (lymphocyte-specific tyrosine-protein kinase) is a membrane-tethered kinase that phosphorylates tyrosine residues in the ITAMs in the TCR–CD3 complex. Doubly phosphorylated ITAMs are the docking sites for ZAP70 and other TCR signaling-associated proteins. Lck is often associated with the CD4 or CD8 co-receptors, which might potentiate its activity by bringing it into the proximity of the CD3 chains PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function</body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="3100.0" y="1165.0"/> <glyph class="state variable" id="_0b107fd1-9995-422e-895e-77405d61308e"> <state value="P" variable="Y505"/> <bbox w="35.0" h="10.0" x="3082.5" y="1165.4865"/> </glyph> <glyph class="state variable" id="_caab6e96-a270-4b1b-942d-f973ba45d886"> <state value="" variable="Y394"/> <bbox w="30.0" h="10.0" x="3165.0" y="1199.638"/> </glyph> </glyph> <glyph class="macromolecule" id="s5306_sa1008" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FYN CASCADE:TCR MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells PMID:10648627 Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="2940.0" y="1065.0"/> <glyph class="state variable" id="_5b208c93-b7c9-4a17-974e-7b0ba3adfa62"> <state value="P" variable="Y417"/> <bbox w="35.0" h="10.0" x="3002.5" y="1098.2294"/> </glyph> <glyph class="state variable" id="_05afc32b-3026-4654-85e1-39738f6d2bab"> <state value="" variable="Y528"/> <bbox w="30.0" h="10.0" x="2928.446" y="1060.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5054_sa731" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GSK3B HUGO:GSK3A CELL:TCD4 CELL:TCD8 CASCADE:TCR MODULE:CHEKPOINTS MODULE:TCR_SIGNALING PMID:19836308 CD28 stimulation inhibits GSK3 by increasing inhibitory serine phosphorylation mediated by the phosphatidylinositol 3-kinase (PI3K) pathway, but independently of the guanine nucleotide exchange factor Vav-1 [25]. By inhibiting GSK3, CD28 relieves inhibition of nuclear factor of activated T cells (NFAT), thus providing a mechanism by which cells can monitor receptor occupancy to maintain T-cell responses Maintenance of GSK3 inhibition is critical for CD4+ and CD8+ T-cell survival after activation GSK3 inhibition increased the production of anti-inflammatory IL-10 by memory CD4+ T cells T-cell migration across endothelial cell barriers separating blood from tissue is critical for accessing targets and failure to clear pathogens can result from blocked migration, for example, due to a lack of necessary recognition molecules. T-cell motility is promoted by the chemokine CXCL12, which inhibits GSK3-mediated phosphorylation of CRMP2 mitogenic stimulation of T lymphocytes causes rapid activation of protein synthesis, in part due to increased expression of many translational components such as the initiation factor eIF2B. eIF2B is phosphorylated by GSK3, which inhibits nucleotide exchange, and this inhibition is released by TCR activation-induced inhibition of GSK3 PMID:19836308 GSK3 inactivates NFATc by phosphorylation-dependent stimulation of NFATc nuclear export PMID:26885856 TCR and CD28 phosphorylate and inactivate GSK-3 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID:23732914 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β</body> </html> </notes> <label text="GSK3*"/> <bbox w="80.0" h="40.0" x="4460.0" y="3325.0"/> <glyph class="state variable" id="_378c3b41-d5e7-4313-8be7-17a344024b0a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4452.5" y="3340.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5195_sa938" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:CAMK2A HUGO:CAMK2B HUGO:CAMK2G HUGO:CAMK2D MODULE:TCR_SIGNALING PMID:11356195; PMID: 17052756; PMID:21199863 CARMA1 induces BCL10 phosphorylation via CaMKII PMID:16809782;PMID:17052756 In the immune synapse, CaMKII phosphorylates Carma1 on Ser109 and the phosphorylation increases the interaction between Carma1 and Bcl10. Carma1/Bcl10/Malt1 complex induces NF-κB activation (Sun et al., 2004). Accordingly based on the findings in the present study, CaMKII phosphorylates Bcl10 on Ser138 while IKKβ phosphorylates residues Ser134, 136, 138, 141 and 144 (Wegener et al., 2006). Phosphorylation of Bcl10 disrupts Bcl10/Malt1 association (Wegener et al., 2006), and attenuates NF-κB activation. PMID:15843557 Calcium/calmodulin-dependent protein kinase II (CaMKII),4 a multifunctional serine/threonine kinase, consists of four distinct isoforms (α, β, γ, and δ), and each comprises a family of alternatively spliced variants. A general feature of all CaMKII isoforms is their ability to decode the frequency of calcium oscillations by retaining calcium-independent kinase activity subsequent to the initial stimulation. The α and β isoforms are expressed abundantly in neurons, while the γ and δ isoforms are more widely expressed Active CaMKII-transduced T cells exhibit enhanced cytotoxic activity PMID:19349987 Ca2+ signaling requires myosin IIA activity</body> </html> </notes> <label text="CAMK2*"/> <bbox w="80.0" h="40.0" x="3950.0" y="3365.0"/> <glyph class="state variable" id="_b9e7b75e-b906-4a22-b197-cd050a176997"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3945.0" y="3380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5309_sa1009" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD6 CASCADE:TCR MODULE:SMAC PMID:25137453; PMID:24584089 CD6, which is expressed on the surface of T cells, is also phosphorylated by Zap70 regardless of the presence of Lat. CD6 nucleates the assembly of a signalosome that also involves SLP-76 and probably accounts for the many TCR-induced tyrosine-phosphorylated species that remain in the absence of Lat CD6–SLP-76 association requires Zap70 SLP-76 associates with CD6 in a Lat-independent manner. PMID:19960310 CD6 is presented in immunological synaps CD6 has been shown to co-localize with the TCR/CD3 complex in central-SMAC</body> </html> </notes> <label text="CD6"/> <bbox w="80.0" h="50.0" x="3700.0" y="1455.0"/> <glyph class="state variable" id="_6f0e9b3e-5ffa-49b4-b64a-93c07f589163"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3692.5" y="1475.0"/> </glyph> <glyph class="unit of information" id="_1ae4bf56-202f-4838-9b0e-047ad3ee5652"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3717.5" y="1450.0"/> </glyph> </glyph> <glyph class="complex" id="s5311_csa120" compartmentRef="c2_ca2"> <label text="LAT_signalosome"/> <bbox w="215.0" h="195.0" x="3342.5" y="1712.5"/> <glyph class="macromolecule" id="s5313_sa1011"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:GRAP2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. GRAP2 (GADS, GRPL) PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:10209041 GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76.</body> </html> </notes> <label text="GRAP2"/> <bbox w="80.0" h="40.0" x="3460.0" y="1780.0"/> </glyph> <glyph class="macromolecule" id="s5312_sa1012"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:GRB2 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="3457.5" y="1837.5"/> </glyph> <glyph class="macromolecule" id="s5314_sa1013"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING HUGO:LAT PMID:23620508 LAT (linker for activation of T cells) is a scaffold protein that assembles key effectors of T cell activation, such as SLP-76, PLCγ1, Grb2 and others. After its phosphorylation by ZAP70 and Lck, LAT recruits many other signaling proteins to form protein microclusters that are distinct from TCR microclusters PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:25137453; PMID:16102570 LAT as a signaling hub in TCR signaling Subsequent biochemical studies helped define the binding partners of phosphorylated LAT molecules and showed that in T cells most of the signalling activity of LAT is funnelled through the four COOH‐terminal tyrosine residues found at positions 136, 175, 195, and 235 of the mouse LAT sequence (Figure 1 ; Figure 2) (Lin 2001; Paz 2001; Zhang 2000 ; Zhu 2003). After TCR‐induced phosphorylation, these four tyrosines manifest some specialization in the SH2‐domain‐containing proteins they recruit. For instance, mutation of tyrosine (Y) 136 primarily eliminates binding of phospholipase C‐γ1 (PLC‐γ1), whereas the simultaneous mutation of Y175 and Y195, or of Y175, Y195, and Y235 results in loss of binding of the Gads and Grb2/Grap adaptors, respectively Gads interacts constitutively with the adaptor SLP‐76, thereby recruiting it to LAT, together with its constellation of associated molecules (Vav, Nck, Itk, adhesion and degranulation promoting adaptor protein (ADAP)). SLP‐76 contributes to PLC‐γ1 activation by stabilizing the LAT‐PLC‐γ1 association and by bringing the Tec family PTK Itk in the vicinity of its PLC‐γ1‐substrate In addition to PLC‐γ1, another major effector molecule functioning downstream of LAT is the Ras GTPase, whose activation is defective in both Lat‐ and Slp‐76‐deficient T cells. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. In Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR.</body> </html> </notes> <label text="LAT"/> <bbox w="80.0" h="40.0" x="3362.5" y="1722.5"/> <glyph class="state variable" id="_0664793b-b4ec-4e08-aed7-3e8d4658ce03"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3355.0" y="1737.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5319_sa1018"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PLCG1 MODULE:TCR_SIGNALING CASCADE:CD226 CASCADE:TCR PMID:1712101; PMID:25456276 Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. The exception is T-cell receptor activation, which is linked to PLCG1, not PLCG2. PLCγ enzymes are mainly activated through tyrosine phosphorylation by receptor and non-receptor kinases. As in all other PLC families, the main signaling output is generation of the second messengers inositol 1,4,5- trisphosphate (IP3, or InsP3) and diacylglycerol (DAG), from phosphatidylinositol 4,5- bisphosphate (PIP2, or PtdIns(4,5)P2). The released IP3 binds to IP3 receptors on the endoplasmic reticulum resulting in Ca2+ release into the cytoplasm. D PMID:10811803; PMID:9846483 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. LAT Is Required for TCR-Mediated Activation of PLCγ1 and the Ras Pathways. PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. Tec family kinases directly activate PLCγ1 and regulate Ca2+ responses in immune cells AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release. PMID:14764585; PMID:11994416 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="3360.0" y="1780.0"/> <glyph class="state variable" id="_907529ab-d91a-4a96-97cf-558b6ea804b2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3355.0" y="1795.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5333_sa1034"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GRAP MODULE:TCR_SIGNALING CASCADE:TCR PMID:8995379; PMID:9489702 The Grb2‐like adaptor Grap is specifically expressed in lymphocytes. GRAP itreacts with LAT. T cell activation effects an increase in Grap association with p36/38, Shc, Sos, and dynamin.</body> </html> </notes> <label text="GRAP"/> <bbox w="80.0" h="40.0" x="3457.5" y="1727.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5316_sa1015" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC MODULE:TCR_SIGNALING HUGO:FYB1 PMID:20164171 ADAP (FYB1) can be recruited to the Carma1-Bcl10-Malt1 (CBM) complex upon CD3/CD28 stimulation, a key complex that regulates NF-κB activation via the classical pathway NF-kappaB activation following engagement of the antigen-specific T cell receptor involves protein kinase C-theta-dependent assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, which coordinates downstream activation of IkappaB kinase (IKK). We previously identified a novel role for the adhesion- and degranulation-promoting adapter protein (ADAP) in regulating the assembly of the CBM complex via an interaction of ADAP with CARMA1. In this study, we identify a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C-theta. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKgamma. Thus, distinct sites within ADAP control two key activation responses that are required for NF-kappaB activation in T cells.</body> </html> </notes> <label text="FYB1"/> <bbox w="80.0" h="40.0" x="1750.0" y="3010.0"/> </glyph> <glyph class="macromolecule" id="s5318_sa1017" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:SKAP1 PMID:18760924 ADAP binds to SKAP1 in a pathway linked to the activation of integrin adhesion SKAP-55, SKAP-55-related and ADAP adaptors modulate integrin-mediated immune-cell adhesion</body> </html> </notes> <label text="SKAP1"/> <bbox w="80.0" h="40.0" x="4520.0" y="1175.0"/> </glyph> <glyph class="complex" id="s5320_csa121" compartmentRef="c2_ca2"> <label text="LAT_signalosome"/> <bbox w="215.0" h="195.0" x="3342.5" y="2042.5"/> <glyph class="macromolecule" id="s5324_sa1014"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PLCG1 MODULE:TCR_SIGNALING CASCADE:CD226 CASCADE:TCR PMID:1712101; PMID:25456276 Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. The exception is T-cell receptor activation, which is linked to PLCG1, not PLCG2. PLCγ enzymes are mainly activated through tyrosine phosphorylation by receptor and non-receptor kinases. As in all other PLC families, the main signaling output is generation of the second messengers inositol 1,4,5- trisphosphate (IP3, or InsP3) and diacylglycerol (DAG), from phosphatidylinositol 4,5- bisphosphate (PIP2, or PtdIns(4,5)P2). The released IP3 binds to IP3 receptors on the endoplasmic reticulum resulting in Ca2+ release into the cytoplasm. D PMID:10811803; PMID:9846483 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. LAT Is Required for TCR-Mediated Activation of PLCγ1 and the Ras Pathways. PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. Tec family kinases directly activate PLCγ1 and regulate Ca2+ responses in immune cells AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release. PMID:14764585; PMID:11994416 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="3367.5" y="2117.5"/> <glyph class="state variable" id="_faf81dcf-1aa4-444e-a72a-d6fa0cd3c713"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3360.0" y="2132.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5321_sa1019"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:GRAP2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. GRAP2 (GADS, GRPL) PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:10209041 GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76.</body> </html> </notes> <label text="GRAP2"/> <bbox w="80.0" h="40.0" x="3467.5" y="2117.5"/> </glyph> <glyph class="macromolecule" id="s5322_sa1020"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:GRB2 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="3467.5" y="2167.5"/> </glyph> <glyph class="macromolecule" id="s5323_sa1021"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING HUGO:LAT PMID:23620508 LAT (linker for activation of T cells) is a scaffold protein that assembles key effectors of T cell activation, such as SLP-76, PLCγ1, Grb2 and others. After its phosphorylation by ZAP70 and Lck, LAT recruits many other signaling proteins to form protein microclusters that are distinct from TCR microclusters PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:25137453; PMID:16102570 LAT as a signaling hub in TCR signaling Subsequent biochemical studies helped define the binding partners of phosphorylated LAT molecules and showed that in T cells most of the signalling activity of LAT is funnelled through the four COOH‐terminal tyrosine residues found at positions 136, 175, 195, and 235 of the mouse LAT sequence (Figure 1 ; Figure 2) (Lin 2001; Paz 2001; Zhang 2000 ; Zhu 2003). After TCR‐induced phosphorylation, these four tyrosines manifest some specialization in the SH2‐domain‐containing proteins they recruit. For instance, mutation of tyrosine (Y) 136 primarily eliminates binding of phospholipase C‐γ1 (PLC‐γ1), whereas the simultaneous mutation of Y175 and Y195, or of Y175, Y195, and Y235 results in loss of binding of the Gads and Grb2/Grap adaptors, respectively Gads interacts constitutively with the adaptor SLP‐76, thereby recruiting it to LAT, together with its constellation of associated molecules (Vav, Nck, Itk, adhesion and degranulation promoting adaptor protein (ADAP)). SLP‐76 contributes to PLC‐γ1 activation by stabilizing the LAT‐PLC‐γ1 association and by bringing the Tec family PTK Itk in the vicinity of its PLC‐γ1‐substrate In addition to PLC‐γ1, another major effector molecule functioning downstream of LAT is the Ras GTPase, whose activation is defective in both Lat‐ and Slp‐76‐deficient T cells. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. In Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR.</body> </html> </notes> <label text="LAT"/> <bbox w="80.0" h="40.0" x="3367.5" y="2057.5"/> <glyph class="state variable" id="_f7b87125-3395-4271-b781-a09b36fad6a2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3360.0" y="2072.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5331_sa1032"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GRAP MODULE:TCR_SIGNALING CASCADE:TCR PMID:8995379; PMID:9489702 The Grb2‐like adaptor Grap is specifically expressed in lymphocytes. GRAP itreacts with LAT. T cell activation effects an increase in Grap association with p36/38, Shc, Sos, and dynamin.</body> </html> </notes> <label text="GRAP"/> <bbox w="80.0" h="40.0" x="3467.5" y="2057.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5325_sa1024" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD101 PMID:9647226 V7 (CD101) ligation inhibits TCR/CD3-induced IL-2 production by blocking Ca2+ flux and nuclear factor of activated T cell nuclear translocation, probably via inhibitioon of of PLCG1 tyrosine phosphorylation.</body> </html> </notes> <label text="CD101"/> <clone/> <bbox w="80.0" h="50.0" x="1440.0" y="765.0"/> <glyph class="unit of information" id="_024f570d-dc90-4d6a-9719-afc6b54cc40e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1457.5" y="760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5325_sa1385" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD101 PMID:9647226 V7 (CD101) ligation inhibits TCR/CD3-induced IL-2 production by blocking Ca2+ flux and nuclear factor of activated T cell nuclear translocation, probably via inhibitioon of of PLCG1 tyrosine phosphorylation.</body> </html> </notes> <label text="CD101"/> <clone/> <bbox w="80.0" h="50.0" x="1440.0" y="665.0"/> <glyph class="unit of information" id="_f89c0607-7873-4d40-b948-1dc736d8e8eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1457.5" y="660.0"/> </glyph> </glyph> <glyph class="complex" id="s5328_csa122" compartmentRef="c9_ca9"> <label text="s5328"/> <bbox w="100.0" h="120.0" x="4310.0" y="1190.0"/> <glyph class="macromolecule" id="s5329_sa1030"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC MODULE:TCR_SIGNALING HUGO:FYB1 PMID:20164171 ADAP (FYB1) can be recruited to the Carma1-Bcl10-Malt1 (CBM) complex upon CD3/CD28 stimulation, a key complex that regulates NF-κB activation via the classical pathway NF-kappaB activation following engagement of the antigen-specific T cell receptor involves protein kinase C-theta-dependent assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, which coordinates downstream activation of IkappaB kinase (IKK). We previously identified a novel role for the adhesion- and degranulation-promoting adapter protein (ADAP) in regulating the assembly of the CBM complex via an interaction of ADAP with CARMA1. In this study, we identify a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C-theta. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKgamma. Thus, distinct sites within ADAP control two key activation responses that are required for NF-kappaB activation in T cells.</body> </html> </notes> <label text="FYB1"/> <bbox w="80.0" h="40.0" x="4320.0" y="1250.0"/> </glyph> <glyph class="macromolecule" id="s5330_sa1031"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:SKAP1 PMID:18760924 ADAP binds to SKAP1 in a pathway linked to the activation of integrin adhesion SKAP-55, SKAP-55-related and ADAP adaptors modulate integrin-mediated immune-cell adhesion</body> </html> </notes> <label text="SKAP1"/> <bbox w="80.0" h="40.0" x="4320.0" y="1200.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5334_sa1036" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RASGRP1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10807788; PMID:24027568; PMID:14764585 RasGRP, a Ras activator that contains calcium-binding EF hands and a DAG-binding domain, is expressed in T cells. A PLC-gamma1 inhibitor diminished activation of Ras following TCR stimulation. Membranes from TCR-stimulated Jurkat T cells exhibited increased RasGRP and increased Ras-guanyl nucleotide association activity that was inhibited by antibodies directed against RasGRP. Overexpression of RasGRP in T cells enhanced TCR-Ras-Erk signaling and augmented interleukin-2 secretion in response to calcium ionophore plus DAG analogues phorbol ester myristate or bryostatin-1. Thus, RasGRP links TCR and PLC-gamma1 to Ras-Erk signaling, a pathway amenable to pharmacologic manipulation. Biochemical Synergy between SOS1 and RasGRP1 in Ras activation both the phosphorylation of ERK and the activation of Ras were reduced by treatment with U73122 (PLCG inhibitor) to a level similar to that observed in Vav1–/– cells In contrast to the effects of U73122, treatment of wild-type DP thymocytes with BAPTA, which blocks the intracellular calcium flux by chelating Ca2+, had no effect on TCR-induced ERK phosphorylation PMID:15184873 The action of Vav and Rac1 proteins on RasGRP1 is specifically dependent on PLCG activity The effect of the Vav/Rac pathway on RasGRP1 is independent of the kinase activity of PI3-K Vav and Rac1 proteins promote constitutive tyrosine phosphorylation and increased membrane localization of PLC- in Jurkat cells The interaction between Vav and RasGRP1 results in enhanced activation of Ras- and Rac-dependent biological responses</body> </html> </notes> <label text="RASGRP1"/> <bbox w="80.0" h="40.0" x="3300.0" y="2305.0"/> </glyph> <glyph class="complex" id="s5335_csa123" compartmentRef="c2_ca2"> <label text="s5335"/> <bbox w="100.0" h="120.0" x="3090.0" y="2440.0"/> <glyph class="macromolecule" id="s5336_sa1035"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RASGRP1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:10807788; PMID:24027568; PMID:14764585 RasGRP, a Ras activator that contains calcium-binding EF hands and a DAG-binding domain, is expressed in T cells. A PLC-gamma1 inhibitor diminished activation of Ras following TCR stimulation. Membranes from TCR-stimulated Jurkat T cells exhibited increased RasGRP and increased Ras-guanyl nucleotide association activity that was inhibited by antibodies directed against RasGRP. Overexpression of RasGRP in T cells enhanced TCR-Ras-Erk signaling and augmented interleukin-2 secretion in response to calcium ionophore plus DAG analogues phorbol ester myristate or bryostatin-1. Thus, RasGRP links TCR and PLC-gamma1 to Ras-Erk signaling, a pathway amenable to pharmacologic manipulation. Biochemical Synergy between SOS1 and RasGRP1 in Ras activation both the phosphorylation of ERK and the activation of Ras were reduced by treatment with U73122 (PLCG inhibitor) to a level similar to that observed in Vav1–/– cells In contrast to the effects of U73122, treatment of wild-type DP thymocytes with BAPTA, which blocks the intracellular calcium flux by chelating Ca2+, had no effect on TCR-induced ERK phosphorylation PMID:15184873 The action of Vav and Rac1 proteins on RasGRP1 is specifically dependent on PLCG activity The effect of the Vav/Rac pathway on RasGRP1 is independent of the kinase activity of PI3-K Vav and Rac1 proteins promote constitutive tyrosine phosphorylation and increased membrane localization of PLC- in Jurkat cells The interaction between Vav and RasGRP1 results in enhanced activation of Ras- and Rac-dependent biological responses</body> </html> </notes> <label text="RASGRP1"/> <bbox w="80.0" h="40.0" x="3100.0" y="2490.0"/> </glyph> <glyph class="simple chemical" id="s5337_sa1037"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING PMID:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 PMID:25456276 Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. The exception is T-cell receptor activation, which is linked to PLCG1, not PLCG2. PLCγ enzymes are mainly activated through tyrosine phosphorylation by receptor and non-receptor kinases. As in all other PLC families, the main signaling output is generation of the second messengers inositol 1,4,5- trisphosphate (IP3, or InsP3) and diacylglycerol (DAG), from phosphatidylinositol 4,5- bisphosphate (PIP2, or PtdIns(4,5)P2). The released IP3 binds to IP3 receptors on the endoplasmic reticulum resulting in Ca2+ release into the cytoplasm. D</body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="3105.0" y="2457.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5338_sa1040" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GAB2 CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement Gab2 Is Associated with LAT in a Tyrosine Phosphorylation-dependent Manner PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. Competitive function of Gab2 with SLP-76 for Gads/Grb2 binding.</body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="3190.0" y="1560.0"/> <glyph class="state variable" id="_5802b286-4ab4-4d2b-81d2-f8b9605fdffe"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3185.0" y="1575.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5340_sa1038" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GAB2 CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement Gab2 Is Associated with LAT in a Tyrosine Phosphorylation-dependent Manner PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. Competitive function of Gab2 with SLP-76 for Gads/Grb2 binding.</body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="3190.0" y="1680.0"/> <glyph class="state variable" id="_09456693-2baf-4dc7-a512-d286804acff1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3182.5" y="1695.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5342_sa1042" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:PD1 HUGO:PTPN11 MODULE:INHIBITING_CHECKPOINTS PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement CD247 chain has been reported to be a substrate of SHP-2 in T cells (12), we examined the phosphorylation levels of CD267 in these lines after TCR engagement by immunoprecipitation with anti-CD247 mAb,followed by blotting with anti-PY mAb. As shown in Fig. 3 D, the phosphorylation levels of theCD247 chain were attenuated by Gab2(WT) expression but not by Gab2(Y614F). Therefore, the inhibitory function of Gab2 is mediated, at least in part, through SHP-2-dependent dephosphorylation of the CD247 chain. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="1200.0" y="1280.0"/> </glyph> <glyph class="complex" id="s5343_csa124" compartmentRef="c2_ca2"> <label text="s5343"/> <bbox w="120.0" h="130.0" x="1510.0" y="1265.0"/> <glyph class="macromolecule" id="s5345_sa1043"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GAB2 CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement Gab2 Is Associated with LAT in a Tyrosine Phosphorylation-dependent Manner PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. Competitive function of Gab2 with SLP-76 for Gads/Grb2 binding.</body> </html> </notes> <label text="GAB2"/> <bbox w="80.0" h="40.0" x="1530.0" y="1275.0"/> <glyph class="state variable" id="_dc67e709-c67f-4ab5-82f3-01b5805b6c22"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1522.5" y="1290.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5346_sa1044"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:PD1 HUGO:PTPN11 MODULE:INHIBITING_CHECKPOINTS PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement CD247 chain has been reported to be a substrate of SHP-2 in T cells (12), we examined the phosphorylation levels of CD267 in these lines after TCR engagement by immunoprecipitation with anti-CD247 mAb,followed by blotting with anti-PY mAb. As shown in Fig. 3 D, the phosphorylation levels of theCD247 chain were attenuated by Gab2(WT) expression but not by Gab2(Y614F). Therefore, the inhibitory function of Gab2 is mediated, at least in part, through SHP-2-dependent dephosphorylation of the CD247 chain. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="1530.0" y="1325.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5347_sa1045" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LCP2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:23620508 LCP2(SLP76) SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa, also known as LCP2), an adaptor that mediates interactions between a host of proteins, including LAT and the actin-regulatory proteins Nck and Vav1. SLP-76 is activated through phosphorylation by Lck and ZAP70 as well as through TCR-independent pathways PMID:12640133 the induced Gab2 potentially competes with SLP-76 for Gads binding, and this may play a role in the efficient negative regulation of TCR signaling through Gab2. PMID:24584089 CD6, which is expressed on the surface of T cells, is also phosphorylated by Zap70 regardless of the presence of Lat. CD6 nucleates the assembly of a signalosome that also involves SLP-76 and probably accounts for the many TCR-induced tyrosine-phosphorylated species that remain in the absence of Lat CD6–SLP-76 association requires Zap70 SLP-76 associates with CD6 in a Lat-independent manner. PMID:21536650 Lat-bound SLP-76 also interacts with Nck and with Vav1 to promote reorganization of the actin cytoskeleton PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation</body> </html> </notes> <label text="LCP2"/> <bbox w="80.0" h="40.0" x="2480.0" y="2040.0"/> <glyph class="state variable" id="_63775cec-0ac3-4938-8c05-2d175fa96a52"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2472.5" y="2055.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5348_sa1010" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD6 CASCADE:TCR MODULE:SMAC PMID:25137453; PMID:24584089 CD6, which is expressed on the surface of T cells, is also phosphorylated by Zap70 regardless of the presence of Lat. CD6 nucleates the assembly of a signalosome that also involves SLP-76 and probably accounts for the many TCR-induced tyrosine-phosphorylated species that remain in the absence of Lat CD6–SLP-76 association requires Zap70 SLP-76 associates with CD6 in a Lat-independent manner. PMID:19960310 CD6 is presented in immunological synaps CD6 has been shown to co-localize with the TCR/CD3 complex in central-SMAC</body> </html> </notes> <label text="CD6"/> <bbox w="80.0" h="50.0" x="3700.0" y="1355.0"/> <glyph class="state variable" id="_996d2638-c679-4d23-9254-715ce0c8ad25"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3695.0" y="1375.0"/> </glyph> <glyph class="unit of information" id="_bb636bbb-d44a-4f35-9bb9-a35b902ddb99"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3717.5" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5349_sa1046" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:SH2D2A PMID:27896837 CD6 and Linker of Activated T cells are potential interaction partners for T cell Specific Adaptor protein TSAd co-immunoprecipitates with CD6 and LAT in Jurkat cells PMID:10975797 T Cell-Specific Adapter Protein Inhibits T Cell Activation by Modulating Lck Activity Overexpression of TSAd in Jurkat T cells interfered with TCR-mediated signaling by down-modulating anti-CD3/PMA-induced IL-2 promoter activity and anti-CD3 induced Ca2+ mobilization. The TCR-induced tyrosine phosphorylation of phospholipase C-gamma1, SH2-domain-containing leukocyte-specific phosphoprotein of 76kDa, and linker for activation of T cells was also reduced. Furthermore, TSAd inhibited Zap-70 recruitment to the CD3zeta-chains in a dose-dependent manner. Consistent with this, Lck kinase activity was reduced 3- to 4-fold in COS-7 cells transfected with both TSAd and Lck, indicating a regulatory effect of TSAd on Lck. In conclusion, our data strongly suggest an inhibitory role for TSAd in proximal T cell activation.</body> </html> </notes> <label text="SH2D2A"/> <bbox w="80.0" h="40.0" x="1200.0" y="1420.0"/> </glyph> <glyph class="macromolecule" id="s5351_sa1048" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VAV2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:15886116; PMID:14623913 Vav2 and Vav3 have been shown to undergo TCR-induced phosphorylation All Three Vav Proteins Are Tyrosine Phosphorylated and Recruited by Antigen Receptors in Primary T and B Lymphocytes. PMID:10934226 The Rho Family Guanine Nucleotide Exchange Factor Vav-2 Regulates the Development of Cell-Mediated Cytotoxicity Vav-2 Becomes Tyrosine Phosphorylated after TCR Cross-Linking. Vav-2 Does Not Activate NFAT–AP-1–mediated Gene Transcription after TCR Cross-Linking. Vav-2 does not regulate the IL-2 promoter after TCR cross-linking. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation (robably via RAS) Vav2 Functions Upstream of Cn to Inhibit TCR-induced NF-AT Activation</body> </html> </notes> <label text="VAV2"/> <bbox w="80.0" h="40.0" x="2182.5" y="2172.5"/> <glyph class="state variable" id="_0b86996a-3635-43d3-80ff-dde0c43bef66"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2177.5" y="2187.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5352_sa1049" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VAV3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:15886116; PMID:14623913 Vav2 and Vav3 have been shown to undergo TCR-induced phosphorylation All Three Vav Proteins Are Tyrosine Phosphorylated and Recruited by Antigen Receptors in Primary T and B Lymphocytes. Vav3 Functionally Compensates for the Loss of Vav1 in T Cell Proliferative Responses. Ca2+ fluxes were totally disrupted in Vav1/2/3ko T cells Vav family is indispensable for Ca2+ signaling downstream of both the TCR and BCR. PMID:14757747 Vav1, Vav3 undergoes rapid tyrosine phosphorylation after T cell receptor (TCR) cross-linkage and interacts with the adaptor molecules SLP76 and 3BP2 in a SH2-dependent manner. Vav3 function is specifically required for coupling TCR stimulation to serum response element-mediated gene transcription.</body> </html> </notes> <label text="VAV3"/> <bbox w="80.0" h="40.0" x="2330.0" y="2170.0"/> <glyph class="state variable" id="_cffbe9d9-dea2-493c-a6a1-836b0720ec29"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2325.0" y="2185.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5353_sa1050" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VAV2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:15886116; PMID:14623913 Vav2 and Vav3 have been shown to undergo TCR-induced phosphorylation All Three Vav Proteins Are Tyrosine Phosphorylated and Recruited by Antigen Receptors in Primary T and B Lymphocytes. PMID:10934226 The Rho Family Guanine Nucleotide Exchange Factor Vav-2 Regulates the Development of Cell-Mediated Cytotoxicity Vav-2 Becomes Tyrosine Phosphorylated after TCR Cross-Linking. Vav-2 Does Not Activate NFAT–AP-1–mediated Gene Transcription after TCR Cross-Linking. Vav-2 does not regulate the IL-2 promoter after TCR cross-linking. PMID:11262396 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. either Vav1 or Vav2 further increased ERK2 activation following TCR stimulation (robably via RAS) Vav2 Functions Upstream of Cn to Inhibit TCR-induced NF-AT Activation</body> </html> </notes> <label text="VAV2"/> <bbox w="80.0" h="40.0" x="2180.0" y="2360.0"/> <glyph class="state variable" id="_11f5011a-48a1-4074-a064-b9418ef0b6e6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2172.5" y="2375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5354_sa1051" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VAV3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:15886116; PMID:14623913 Vav2 and Vav3 have been shown to undergo TCR-induced phosphorylation All Three Vav Proteins Are Tyrosine Phosphorylated and Recruited by Antigen Receptors in Primary T and B Lymphocytes. Vav3 Functionally Compensates for the Loss of Vav1 in T Cell Proliferative Responses. Ca2+ fluxes were totally disrupted in Vav1/2/3ko T cells Vav family is indispensable for Ca2+ signaling downstream of both the TCR and BCR. PMID:14757747 Vav1, Vav3 undergoes rapid tyrosine phosphorylation after T cell receptor (TCR) cross-linkage and interacts with the adaptor molecules SLP76 and 3BP2 in a SH2-dependent manner. Vav3 function is specifically required for coupling TCR stimulation to serum response element-mediated gene transcription.</body> </html> </notes> <label text="VAV3"/> <bbox w="80.0" h="40.0" x="2330.0" y="2360.0"/> <glyph class="state variable" id="_f57b3d0f-fa53-4ecd-89e5-da146713203b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2322.5" y="2375.0"/> </glyph> </glyph> <glyph class="complex" id="s5358_csa125" compartmentRef="c2_ca2"> <label text="s5358"/> <bbox w="100.0" h="120.0" x="2840.0" y="2060.0"/> <glyph class="simple chemical" id="s5362_sa1055"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:11777960 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="2855.0" y="2077.5"/> </glyph> <glyph class="macromolecule" id="s5357_sa1057"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TEC CASCADE:TCR MODULE:TCR_SIGNALING PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated. PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. Tec family kinases directly activate PLCγ1 and regulate Ca2+ responses in immune cells AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release.</body> </html> </notes> <label text="TEC"/> <bbox w="80.0" h="40.0" x="2850.0" y="2110.0"/> <glyph class="state variable" id="_94886214-6b82-4d1e-a610-43d291cd8f94"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2842.5" y="2125.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5359_csa126" compartmentRef="c2_ca2"> <label text="s5359"/> <bbox w="100.0" h="120.0" x="2840.0" y="1840.0"/> <glyph class="simple chemical" id="s5361_sa1054"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:11777960 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="2855.0" y="1857.5"/> </glyph> <glyph class="macromolecule" id="s5360_sa1056"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TEC CASCADE:TCR MODULE:TCR_SIGNALING PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated. PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. Tec family kinases directly activate PLCγ1 and regulate Ca2+ responses in immune cells AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release.</body> </html> </notes> <label text="TEC"/> <bbox w="80.0" h="40.0" x="2850.0" y="1890.0"/> <glyph class="state variable" id="_ed1f83d2-ee68-4810-a0fe-f4b689003a3a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2845.0" y="1905.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s5364_csa127" compartmentRef="c2_ca2"> <label text="s5364"/> <bbox w="100.0" h="120.0" x="3020.0" y="1840.0"/> <glyph class="macromolecule" id="s5027_sa750"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITK CASCADE:TCR MODULE:TCR_SIGNALING PMID:25137453 Once bound to phosphorylated Lat molecules via GRAP2, SLP-76 is phosphorylated by Zap70 and recruits the Tec-family tyrosine kinase Itk. In turn, Itk phosphorylates PLC-γ1 and enhances its enzymatic activity PMID:12186560 Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. PMID:15661896 Kinase-Independent Functions for Itk in TCR-Induced Regulation of Vav and the Actin Cytoskeleton Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated.</body> </html> </notes> <label text="ITK"/> <bbox w="80.0" h="40.0" x="3030.0" y="1890.0"/> <glyph class="state variable" id="_9f78ef23-2d32-41e0-87b0-af05aded78c0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3025.0" y="1905.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s5363_sa1058"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:11777960 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="3035.0" y="1857.5"/> </glyph> </glyph> <glyph class="complex" id="s5365_csa128" compartmentRef="c2_ca2"> <label text="s5365"/> <bbox w="100.0" h="120.0" x="3020.0" y="2060.0"/> <glyph class="macromolecule" id="s5061_sa682"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITK CASCADE:TCR MODULE:TCR_SIGNALING PMID:25137453 Once bound to phosphorylated Lat molecules via GRAP2, SLP-76 is phosphorylated by Zap70 and recruits the Tec-family tyrosine kinase Itk. In turn, Itk phosphorylates PLC-γ1 and enhances its enzymatic activity PMID:12186560 Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. PMID:15661896 Kinase-Independent Functions for Itk in TCR-Induced Regulation of Vav and the Actin Cytoskeleton Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated.</body> </html> </notes> <label text="ITK"/> <bbox w="80.0" h="40.0" x="3027.5" y="2117.5"/> <glyph class="state variable" id="_5ee92486-3d9d-43b6-986b-fa89d29ae36f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3020.0" y="2132.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s5367_sa1059"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:11777960 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="3035.0" y="2067.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5368_sa1060" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ITK CASCADE:TCR MODULE:TCR_SIGNALING PMID:25137453 Once bound to phosphorylated Lat molecules via GRAP2, SLP-76 is phosphorylated by Zap70 and recruits the Tec-family tyrosine kinase Itk. In turn, Itk phosphorylates PLC-γ1 and enhances its enzymatic activity PMID:12186560 Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. PMID:15661896 Kinase-Independent Functions for Itk in TCR-Induced Regulation of Vav and the Actin Cytoskeleton Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated.</body> </html> </notes> <label text="ITK"/> <bbox w="80.0" h="40.0" x="3060.0" y="1740.0"/> <glyph class="state variable" id="_71e20b93-cbd9-40dc-b9cc-c08bc8ff8c5f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3055.0" y="1755.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5369_sa1061" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TXK MODULE:TH1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated. In T cells, mutation of Itk or combined mutation of Itk and Rlk/TXK leads to parallel defects in response to anti-CD3 stimulation, with impaired proliferation and cytokine production . PMID:10523612 Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-gamma production by the cells through Th1 cell-specific positive transcriptional regulation of the IFN-gamma gene. we cotransfected pIFN-γ(-538)-luciferase and pME18S-Txk into Jurkat cells. We found that Txk transfection induced several-fold more luciferase activity in the cells than the mock (pIFN-γ[-538]-luciferase and pME18S)-transfected cells (Fig. 2 e). As control cytokine-promoter plasmids, we used pIL-2(-568)-luciferase and pIL-4(-265)-CAT. We found that Txk transfection did not affect activities of pIL-2 promoter-luciferase– and pIL-4 promoter-CAT–transfected Jurkat cells, regardless of the presence or absence of mitogenic stimulation. The results revealed that Txk acts specifically on IFN-γ promoter/enhancer (-538) and upregulates IFN-γ gene transcription. IL-2 treatment of the CD4+ T cells did not affect Txk expression levels. IL-4 markedly reduced Txk expression of the CD4+ T cells (Fig. 5). In contrast, IL-12 treatment for 4 h was sufficient to enhance Txk expression of the CD4+ T cells (Fig. 5). This further supports an intimate association between Th1 cells and Txk expression. IL-12 may be involved in the polarization toward Th1 cells of T cells via Txk but is not affected by the outcome of IFN-γ production via Txk.</body> </html> </notes> <label text="TXK"/> <bbox w="80.0" h="40.0" x="2640.0" y="1740.0"/> <glyph class="state variable" id="_7253a850-6eb0-4673-8214-269cbad886ed"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2635.0" y="1755.0"/> </glyph> </glyph> <glyph class="complex" id="s5372_csa129" compartmentRef="c2_ca2"> <label text="s5372"/> <bbox w="100.0" h="120.0" x="2640.0" y="1840.0"/> <glyph class="macromolecule" id="s5375_sa1062"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TXK MODULE:TH1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated. In T cells, mutation of Itk or combined mutation of Itk and Rlk/TXK leads to parallel defects in response to anti-CD3 stimulation, with impaired proliferation and cytokine production . PMID:10523612 Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-gamma production by the cells through Th1 cell-specific positive transcriptional regulation of the IFN-gamma gene. we cotransfected pIFN-γ(-538)-luciferase and pME18S-Txk into Jurkat cells. We found that Txk transfection induced several-fold more luciferase activity in the cells than the mock (pIFN-γ[-538]-luciferase and pME18S)-transfected cells (Fig. 2 e). As control cytokine-promoter plasmids, we used pIL-2(-568)-luciferase and pIL-4(-265)-CAT. We found that Txk transfection did not affect activities of pIL-2 promoter-luciferase– and pIL-4 promoter-CAT–transfected Jurkat cells, regardless of the presence or absence of mitogenic stimulation. The results revealed that Txk acts specifically on IFN-γ promoter/enhancer (-538) and upregulates IFN-γ gene transcription. IL-2 treatment of the CD4+ T cells did not affect Txk expression levels. IL-4 markedly reduced Txk expression of the CD4+ T cells (Fig. 5). In contrast, IL-12 treatment for 4 h was sufficient to enhance Txk expression of the CD4+ T cells (Fig. 5). This further supports an intimate association between Th1 cells and Txk expression. IL-12 may be involved in the polarization toward Th1 cells of T cells via Txk but is not affected by the outcome of IFN-γ production via Txk.</body> </html> </notes> <label text="TXK"/> <bbox w="80.0" h="40.0" x="2650.0" y="1890.0"/> <glyph class="state variable" id="_c11820cb-359e-4dbb-b7df-76cb36967297"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2645.0" y="1905.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s5374_sa1064"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:11777960 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="2655.0" y="1857.5"/> </glyph> </glyph> <glyph class="complex" id="s5373_csa130" compartmentRef="c2_ca2"> <label text="s5373"/> <bbox w="100.0" h="120.0" x="2640.0" y="2060.0"/> <glyph class="macromolecule" id="s5371_sa1063"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TXK MODULE:TH1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:11406363 The activation of Tec kinases occurs in two steps. Step 1: the Tec kinase PH domain can engage the products of PI3K to localize to the membrane. Alternatively, protein–protein interactions, such as with the FERM domain of FAK or heterotrimeric G-protein subunits, may assist in this step of activation. Step 2: once at the membrane, Tec kinases are phosphorylated on a tyrosine in their activation loop by SFKs. Subsequently, the SH3 domain is autophosphorylated. In T cells, mutation of Itk or combined mutation of Itk and Rlk/TXK leads to parallel defects in response to anti-CD3 stimulation, with impaired proliferation and cytokine production . PMID:10523612 Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-gamma production by the cells through Th1 cell-specific positive transcriptional regulation of the IFN-gamma gene. we cotransfected pIFN-γ(-538)-luciferase and pME18S-Txk into Jurkat cells. We found that Txk transfection induced several-fold more luciferase activity in the cells than the mock (pIFN-γ[-538]-luciferase and pME18S)-transfected cells (Fig. 2 e). As control cytokine-promoter plasmids, we used pIL-2(-568)-luciferase and pIL-4(-265)-CAT. We found that Txk transfection did not affect activities of pIL-2 promoter-luciferase– and pIL-4 promoter-CAT–transfected Jurkat cells, regardless of the presence or absence of mitogenic stimulation. The results revealed that Txk acts specifically on IFN-γ promoter/enhancer (-538) and upregulates IFN-γ gene transcription. IL-2 treatment of the CD4+ T cells did not affect Txk expression levels. IL-4 markedly reduced Txk expression of the CD4+ T cells (Fig. 5). In contrast, IL-12 treatment for 4 h was sufficient to enhance Txk expression of the CD4+ T cells (Fig. 5). This further supports an intimate association between Th1 cells and Txk expression. IL-12 may be involved in the polarization toward Th1 cells of T cells via Txk but is not affected by the outcome of IFN-γ production via Txk.</body> </html> </notes> <label text="TXK"/> <bbox w="80.0" h="40.0" x="2650.0" y="2110.0"/> <glyph class="state variable" id="_08e992d7-5d85-4adf-bccb-b570777e948d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2642.5" y="2125.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s5376_sa1065"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING 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:11777960 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="2655.0" y="2067.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5381_sa1069" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:NCK1 PMID:24670066 Using specific shRNA we down-regulated the expression of Nck1 or Nck2 to approximately 10% each in Jurkat T cells. We found that down-regulation of Nck1 impaired TCR-induced phosphorylation of the kinases Erk and MEK, activation of the AP-1 and NFAT transcription factors and subsequently, IL-2 and CD69 expression. In sharp contrast, down-regulation of Nck2 hardly impacts these activation read-outs. Thus, in contrast to Nck2, Nck1 is a positive regulator for TCR-induced stimulation of the Erk pathway. Mutation of the third SH3 domain of Nck1 showed that this domain was required for this activity. Further, TCR-induced NFAT activity was reduced in both Nck1 and Nck2 knock-down cells, showing that both isoforms are involved in NFAT activation. Lastly, we show that neither Nck isoform is upstream of p38 phosphorylation or Ca2+influx. In conclusion, Nck1 and Nck2 have non-redundant roles in human T cell activation in contrast to murine T cells.</body> </html> </notes> <label text="NCK1"/> <bbox w="80.0" h="40.0" x="4040.0" y="5160.0"/> </glyph> <glyph class="macromolecule" id="s5385_sa1073" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:NCK2 PMID:24670066 Using specific shRNA we down-regulated the expression of Nck1 or Nck2 to approximately 10% each in Jurkat T cells. We found that down-regulation of Nck1 impaired TCR-induced phosphorylation of the kinases Erk and MEK, activation of the AP-1 and NFAT transcription factors and subsequently, IL-2 and CD69 expression. In sharp contrast, down-regulation of Nck2 hardly impacts these activation read-outs. Thus, in contrast to Nck2, Nck1 is a positive regulator for TCR-induced stimulation of the Erk pathway. Mutation of the third SH3 domain of Nck1 showed that this domain was required for this activity. Further, TCR-induced NFAT activity was reduced in both Nck1 and Nck2 knock-down cells, showing that both isoforms are involved in NFAT activation. Lastly, we show that neither Nck isoform is upstream of p38 phosphorylation or Ca2+influx. In conclusion, Nck1 and Nck2 have non-redundant roles in human T cell activation in contrast to murine T cells.</body> </html> </notes> <label text="NCK2"/> <bbox w="80.0" h="40.0" x="4300.0" y="5165.0"/> </glyph> <glyph class="complex" id="s5388_csa131" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Vav proteins and the regulation of the cytoskeleton In view of the well-established role for Rho-family GTPases in controlling the actin cytoskeleton [51], it has been proposed that by virtue of being Rho-family GEFs, Vav proteins might transduce TCR signals leading to the reorganisation of the cytoskeleton [52]. When a T cell interacts with an antigen-presenting cell (APC), several events occur that require cytoskeletal rearrangements. TCR triggering by peptide–MHC complexes on the APC results in the activation of the integrin lymphocyte function-associated antigen-1 (LFA-1) which then binds to ICAM-1 on the APC leading to the formation of a stable T cell–APC conjugate [53]. This activation of LFA-1 is caused in part by clustering of the integrin leading to high avidity binding of its ligand; cytoskeletal changes are required for this clustering. When a conjugate forms, an ordered array of proteins termed an immunological synapse (IS) is assembled at the interface, characterised by a central accumulation of TCR molecules surrounded by a ring of LFA-1 [54]. Again, this movement of proteins requires actin rearrangements. Finally, the T cell becomes polarised, as exemplified by movement of the microtubule organising centre (MTOC) to face the APC [55]. In support of the proposal that Vav1 can regulate the cytoskeleton, several of the above processes have been found to be Vav1-dependent. Vav1 transduces TCR inside-out signals, leading to the activation of LFA-1 such that, in the absence of Vav1, T cells and thymocytes are inefficient at forming antigen-specific conjugates with APCs [56,57•]. Furthermore, this defect is probably due to a failure to cluster LFA-1, possibly caused by a failure to rearrange the actin cytoskeleton, although there is no direct evidence for this. Antigen-induced clustering of the TCR and of lipid rafts at the centre of the synapse is also defective in Vav1-deficient T cells [58,59]. However, another study found no defect in TCR clustering in Vav1-deficient T cells [57•]. The difference in these results remains unclear, but probably relates to technical differences in the assays used. Finally, antigen-induced polarisation of the MTOC was defective in Vav1-deficient DP thymocytes [57•]. In contrast to the requirement for Vav1 for inside-out activation of LFA-1, TCR clustering and cell polarisation, the characteristic cell shape changes that occur following conjugate formation are unaffected by Vav1 deficiency, demonstrating that Vav1 transduces signals selectively to some but not all cytoskeletal rearrangements [57•]. Although Vav1 transduces TCR signals to several cell biological processes known to require rearrangement of the cytoskeleton, the precise pathways by which it does so are not known. Just because Vav1 is a Rho-family GEF, it does not follow that Vav1 necessarily contributes to these pathways by controlling remodelling of the actin cytoskeleton. For example, the inside-out activation of LFA-1 has been shown to require a calcium-dependent protease [60], and thus the defective LFA-1 activation in Vav1-deficient T cells might be secondary to the defect in calcium flux. Nonetheless, several recent studies have suggested mechanisms by which Vav1 might control the cytoskeleton. WASP When activated, Wiskott-Aldrich syndrome protein (WASP) binds to and activates the actin nucleation complex Arp2/3. Antigen stimulation of T cells leads to the recruitment of WASP to the IS through binding to the adapters Nck and SLP-76, where it is then activated by Cdc42-GTP [61•]. Vav1 is also recruited to SLP-76 adaptor following TCR stimulation, and so is co-localised with WASP. In Vav1-deficient T cells, the recruitment of WASP to the immunological synapse is unaffected, but its activation is greatly reduced, as is the accumulation of active Cdc42-GTP [61•]. Taken together, this suggests that Vav1 might transduce TCR signals via Cdc42 and WASP to Arp2/3 and, hence, actin polymerisation. ERM Ezrin/Radixin/Moesin (ERM) proteins form crosslinks between the cortical actin cytoskeleton and the plasma membrane and thereby contribute to cell rigidity. TCR stimulation leads to the dephosphorylation and hence inactivation of ERM proteins, resulting in less rigidity [62]. This may be important in enabling the T cell to deform while forming a conjugate with an APC. In Vav1-deficient T cells, or in T cells expressing dominant negative Rac1, TCR-induced dephosphorylation of ERM is greatly reduced, suggesting the existence of a Vav1/Rac1 pathway which transduces TCR signals to the inactivation of ERM proteins [63•].</body> </html> </notes> <label text="s5388"/> <bbox w="100.0" h="120.0" x="4452.5" y="4260.0"/> <glyph class="macromolecule" id="s5386_sa1074"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DNM2 MODULE:TCR_SIGNALING PMID:15696170 Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse Dyn2 interacted directly with the Rho family guanine nucleotide exchange factor Vav1, and this interaction was required for T cell activation.</body> </html> </notes> <label text="DNM2"/> <bbox w="80.0" h="40.0" x="4462.5" y="4320.0"/> </glyph> <glyph class="macromolecule" id="s5387_sa1075"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:VAV1 MODULE:TCR_SIGNALING PMID:10714681 PKCθ is regulated by Vav1, a guanine nucleotide exchange factor for Rac and Cdc42 that plays an important role in T cell development and activation46. Thus, a dominant negative PKCθ mutant blocked a number of growth signals, which are normally induced by overexpression of Vav1, namely, activation of JNK, the IL-2 gene promoter and NFAT or AP-1 reporter genes. Conversely, a dominant negative Vav1 mutant did not significantly inhibit the same signaling events induced by a constitutively active PKCθ mutant46, tentatively placing PKCθ downstream of Vav1 in these growth signaling pathways. Vav promoted PKCθ translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCθ to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production. PMID:25539813 Vav1 is the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions. PMID:12186560 Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. PMID:11754814 CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. PMID:10849438; PMID:10077632 ;PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function Tyrosine-phosphorylated Vav1 as a Point of Integration for T-cell Receptor- and CD28-mediated Activation of JNK, p38, and Interleukin-2 Transcription Vav1 is phosphorylated probably by Lck. The Rho-family GTP exchange factor Vav is a critical transducer of T cell receptor signals to the calcium, ERK, and NF-κB pathways PMID:10898494 Vav-induced NFAT activation involves a MEK/ERK pathway 3 Vav functions upstream of Ras in the NFAT activation pathway Ras function is required for Vav-induced ERK activation Vav up-regulates the expression of CD69 via a Ras-dependent, but Rac-independent, PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. Vav1 Transduces TCR Signals to Ras and ERK via PLC and DAG Defective TCR-induced DAG Production in Vav1-deficient Cells Defective phosphorylation of PKCθ and PKD in Vav1–/– thymocytes. Vav1 Is Required for TCR-induced Translocation of Ras-GRP1 in Vav1–/– cells, whereasGrb2 was constitutively associated with Sos1 and Sos2, there was very little or no inducible association with LAT. Taken together these results show that in Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:11994416 Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways PMID:10646608 Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b Cbl-b negatively regulates Vav1 tyrosine phosphorylation. Probably downstream of PI3K) PMID:11526404 inhibition of PI3K leads to a reduction in TCR-induced Vav phosphorylation PMID:12616499 Vav1 transduces TCR signals required for LFA-1 function and cell polarization at the immunological synapse. Vav1 is required for TCR-induced activation of LFA-1 Vav1 is required for TCR-induced polarization of the MTOC PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="VAV1"/> <bbox w="80.0" h="40.0" x="4462.5" y="4270.0"/> <glyph class="state variable" id="_ce0c0389-0a40-4a76-bb68-9493722ed0f5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4455.0" y="4285.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5389_sa1076" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DNM2 MODULE:TCR_SIGNALING PMID:15696170 Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse Dyn2 interacted directly with the Rho family guanine nucleotide exchange factor Vav1, and this interaction was required for T cell activation.</body> </html> </notes> <label text="DNM2"/> <bbox w="80.0" h="40.0" x="1860.0" y="2370.0"/> </glyph> <glyph class="macromolecule" id="s5391_sa1078" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45A MODULE:TCR_SIGNALING PMID:16799472; PMID:15735649 GADD45 inhibited p38 activated by ZAP70 (that is, through phosphorylation of Tyr323) but not by MKK6 (that is, through phosphorylation of Thr180 and Tyr182).</body> </html> </notes> <label text="GADD45A "/> <bbox w="80.0" h="40.0" x="1740.0" y="3975.0"/> </glyph> <glyph class="macromolecule" id="s5392_sa1079" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45B MODULE:TH1 CASCADE:TCR CASCADE:IL12 CASCADE:IL18 CASCADE:IL4 MODULE:TCR_SIGNALING PMID:24104473; PMID:14691480 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG</body> </html> </notes> <label text="GADD45B"/> <bbox w="80.0" h="40.0" x="1590.0" y="3275.0"/> </glyph> <glyph class="macromolecule" id="s5393_sa1095" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45G MODULE:TH1 CASCADE:TCR CASCADE:IL2 CASCADE:IL12 CASCADE:IL18 MODULE:TCR_SIGNALING PMID:24104473 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 GADD45G was highly expressed in TH1 versus TH2 cells p38 kinase activity was induced when TH1 cells were activated by α-CD3 antibody. However, it was not induced in GADD45γ−/− TH1 effector cells GADD45γ protein therefore mediates TCR-stimulated p38 MAP kinase activation in TH1 effector cells. JNK activity was induced in wild-type TH1 effector cells upon α-CD3 antibody treatment, it was not induced in GADD45γ−/− TH1 effector cells (Figure 4B). Therefore, GADD45γ is required for both p38 and JNK MAP kinase activation through TCR stimulation in TH1 effector cells. The reduction in IFN-γ secretion was the result of reduced expression of IFN-γ mRNA by GADD45γ−/− CD4+ T cells (probably via p38)</body> </html> </notes> <label text="GADD45G"/> <bbox w="80.0" h="40.0" x="1870.0" y="3285.0"/> </glyph> <glyph class="macromolecule" id="s5395_sa1083" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K3 MODULE:TCR_SIGNALING MODULE:TH1 CASCADE:TCR PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 mice deficient in MKK3, a direct upstream activator of the p38 kinase pathway, have impaired type I cytokine immune responses (Lu et al., 1999) PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK3 and MKK6 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3 Baseline phosphorylation of MKK4 did not increase with anti-CD3 stimulation</body> </html> </notes> <label text="MAP2K3"/> <bbox w="80.0" h="40.0" x="1610.0" y="3505.0"/> <glyph class="state variable" id="_8c985df8-25c4-4349-9c8d-623653889d0f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1605.0" y="3519.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s5396_sa1084" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K6 MODULE:TCR_SIGNALING CASCADE:TCR PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK3 and MKK6 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3 Baseline phosphorylation of MKK4 did not increase with anti-CD3 stimulation</body> </html> </notes> <label text="MAP2K6"/> <bbox w="80.0" h="40.0" x="1780.0" y="3505.0"/> <glyph class="state variable" id="_f426681a-d990-4a82-8108-2a2ee2a60aba"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1775.0" y="3520.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5397_sa1085" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: CASCADE:TCR CASCADE:IL18 CASCADE:IL12 MODULE:TCR_SIGNALING MOGULE:TH1 Maps_Modules_end References_begin: PMID:10395678 TCR and CD28 Are Coupled Via ZAP-70 to the Activation of the Vav/Rac-1-/PAK-1/p38 MAPK Signaling Pathway PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:16799472 GADD45 inhibited p38 activated by ZAP70 (that is, through phosphorylation of Tyr323) but not by MKK6 (that is, through phosphorylation of Thr180 and Tyr182). PMID:24104473 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 p38 and JNK pathways are very important for the responses of TH1 effector cells (Lu et al., 1999; Rincon et al., 1998; Yang et al., 1998). The p38 kinase can be activated efficiently in TH1 effector cells but not in TH2 effector cells; blocking the pathway inhibits and agonists of the pathway potentiate TH1 responses PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent References_end</body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="1910.0" y="4080.0"/> <glyph class="state variable" id="_1fecb35e-2dcb-459a-ac46-18613f0e0894"> <state value="P" variable="Tyr180"/> <bbox w="45.0" h="10.0" x="1964.8706" y="4075.0"/> </glyph> <glyph class="state variable" id="_a0b4c650-439d-409d-bba2-a5dcfb7bfd0f"> <state value="P" variable="Tyr323"/> <bbox w="45.0" h="10.0" x="1888.0948" y="4075.0"/> </glyph> <glyph class="state variable" id="_f62ccd40-4e3d-4744-98ef-a9c4ec349d6d"> <state value="P" variable="TYR182"/> <bbox w="45.0" h="10.0" x="1963.8782" y="4115.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5398_sa1086" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: CASCADE:TCR CASCADE:IL18 CASCADE:IL12 MODULE:TCR_SIGNALING MOGULE:TH1 Maps_Modules_end References_begin: PMID:10395678 TCR and CD28 Are Coupled Via ZAP-70 to the Activation of the Vav/Rac-1-/PAK-1/p38 MAPK Signaling Pathway PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:16799472 GADD45 inhibited p38 activated by ZAP70 (that is, through phosphorylation of Tyr323) but not by MKK6 (that is, through phosphorylation of Thr180 and Tyr182). PMID:24104473 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 p38 and JNK pathways are very important for the responses of TH1 effector cells (Lu et al., 1999; Rincon et al., 1998; Yang et al., 1998). The p38 kinase can be activated efficiently in TH1 effector cells but not in TH2 effector cells; blocking the pathway inhibits and agonists of the pathway potentiate TH1 responses PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent References_end</body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="1570.0" y="4105.0"/> <glyph class="state variable" id="_50787443-e074-4664-92de-827bf49f7cdc"> <state value="P" variable="Tyr180"/> <bbox w="45.0" h="10.0" x="1624.8706" y="4100.0"/> </glyph> <glyph class="state variable" id="_846a38b2-1f9b-4b6c-826d-c22ea7219873"> <state value="" variable="Tyr323"/> <bbox w="40.0" h="10.0" x="1550.5948" y="4100.0"/> </glyph> <glyph class="state variable" id="_fb3310d2-06e6-4de4-99a8-ba0c9d5d90b4"> <state value="P" variable="TYR182"/> <bbox w="45.0" h="10.0" x="1623.8782" y="4140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5399_sa1087" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K3 MODULE:TCR_SIGNALING MODULE:TH1 CASCADE:TCR PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11371360 mice deficient in MKK3, a direct upstream activator of the p38 kinase pathway, have impaired type I cytokine immune responses (Lu et al., 1999) PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK3 and MKK6 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3 Baseline phosphorylation of MKK4 did not increase with anti-CD3 stimulation</body> </html> </notes> <label text="MAP2K3"/> <bbox w="80.0" h="40.0" x="1610.0" y="3605.0"/> <glyph class="state variable" id="_f317f932-c396-4497-b270-e5bc1e5e0e6c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1602.5" y="3619.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s5400_sa1088" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP2K6 MODULE:TCR_SIGNALING CASCADE:TCR PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:15735649 In the classical MAPK enzymatic cascade, p38 dual phosphorylation is mediated by the MAPKKs MKK3, MKK4 and MKK6, which themselves are activated by MAPKK kinase−mediated phosphorylation Spontaneous phosphorylation of MKK3 and MKK6 was low in CD4+ T cells and increased equivalently in a dose-dependent way after stimulation with anti-CD3 Baseline phosphorylation of MKK4 did not increase with anti-CD3 stimulation</body> </html> </notes> <label text="MAP2K6"/> <bbox w="80.0" h="40.0" x="1780.0" y="3605.0"/> <glyph class="state variable" id="_fc533f72-7eb9-4ecb-9b43-62c5f4874308"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1772.5" y="3620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s863_sa447" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CFL1 CASCADE:TCR MODULE:TCR_SIGNALING 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. PMID:11093160 Following co-stimulation through accessory receptors (e.g. CD2 or CD28) - however, not following TCR/CD3 stimulation alone - cofilin undergoes dephosphorylation. The subcellular localization as well as the actin-binding activity of cofilin are regulated by the phosphorylation state of serine-3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM-kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation.</body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="5210.0" y="5935.0"/> <glyph class="state variable" id="_47e9e131-06cf-439f-9cf5-779ee5d9a35c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5202.5" y="5950.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s857_sa448" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CFL1 CASCADE:TCR MODULE:TCR_SIGNALING 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. PMID:11093160 Following co-stimulation through accessory receptors (e.g. CD2 or CD28) - however, not following TCR/CD3 stimulation alone - cofilin undergoes dephosphorylation. The subcellular localization as well as the actin-binding activity of cofilin are regulated by the phosphorylation state of serine-3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM-kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation.</body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="5210.0" y="6055.0"/> <glyph class="state variable" id="_d38a87db-2dfe-42a3-8677-7d6ad2228196"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5205.0" y="6070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5401_sa1092" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DTX1 MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text=" DTX1"/> <bbox w="80.0" h="40.0" x="3130.0" y="5535.0"/> </glyph> <glyph class="nucleic acid feature" id="s5402_sa1093" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DTX1 MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text="DTX1"/> <bbox w="70.0" h="25.0" x="3135.0" y="5372.5"/> </glyph> <glyph class="nucleic acid feature" id="s5403_sa1094" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DTX1 MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text="DTX1"/> <bbox w="90.0" h="25.0" x="3125.0" y="5442.5"/> <glyph class="unit of information" id="_77221894-7de4-4787-b8b8-536261acd007"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3160.0" y="5437.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5404_sa1096" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45B MODULE:TH1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. PMID:11371360 GADD45B was also highly expressed in TH1 versus TH2 cells the expression of this gene is both upregulated by TCR signaling and IL-12 but repressed by IL-4. PMID:11175814 GADD45 beta, which activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4), was induced by IL-18 and augmented by IL-12. GADD45 beta expression in naïve CD4+ T cells activated p38 MAPK and selectively increased cytokine-induced, but not TCR-induced, IFN-gamma production. Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both selectively inhibit cytokine-induced, but not TCR-induced, IFN-gamma production. Thus, the synergy between IL-12 and IL-18 may involve GADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production. PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG</body> </html> </notes> <label text="GADD45B"/> <bbox w="70.0" h="25.0" x="2915.0" y="5452.5"/> </glyph> <glyph class="nucleic acid feature" id="s5405_sa1097" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45B MODULE:TCR_SIGNALING CASCADE:TCR PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation.</body> </html> </notes> <label text="GADD45B"/> <bbox w="90.0" h="25.0" x="2905.0" y="5372.5"/> <glyph class="unit of information" id="_ef72e75e-69c5-4613-808a-709ab3a462ca"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2940.0" y="5367.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5406_sa1098" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ERG2 MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text="ERG2"/> <bbox w="80.0" h="40.0" x="2870.0" y="5635.0"/> </glyph> <glyph class="nucleic acid feature" id="s5407_sa1099" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CBLB MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text="CBLB"/> <bbox w="70.0" h="25.0" x="3025.0" y="5752.5"/> </glyph> <glyph class="nucleic acid feature" id="s5408_sa1100" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CBLB MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text="CBLB"/> <bbox w="90.0" h="25.0" x="3015.0" y="5812.5"/> <glyph class="unit of information" id="_5bcc8b08-dc72-4d1d-867a-609bdd902869"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3050.0" y="5807.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5409_sa1102" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CBLB MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 PMID: 12415267 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. PMID:10646608 Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b Cbl-b negatively regulates Vav1 tyrosine phosphorylation. PMID:11526404 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. The p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) was identified as a substrate for Cbl-b. We have shown that Cbl-b negatively regulated p85 recruitment of p85 to CD28 and T cell antigen receptor through its E3 ubiquitin ligase activity. The enhanced activation of Cbl-b-/- T cells was suppressed by the inhibition of PI3K.</body> </html> </notes> <label text="CBLB"/> <bbox w="80.0" h="40.0" x="3020.0" y="5895.0"/> </glyph> <glyph class="complex" id="s5410_csa132" compartmentRef="c2_ca2"> <label text="s5410"/> <bbox w="100.0" h="120.0" x="2870.0" y="5715.0"/> <glyph class="macromolecule" id="s5412_sa1103"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ERG2 MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text="ERG2"/> <bbox w="80.0" h="40.0" x="2880.0" y="5765.0"/> </glyph> <glyph class="macromolecule" id="s5411_sa1104"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DTX1 MODULE:TCR_SIGNALING PMID:19592273 Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1</body> </html> </notes> <label text=" DTX1"/> <bbox w="80.0" h="40.0" x="2880.0" y="5725.0"/> </glyph> </glyph> <glyph class="phenotype" id="s5413_sa1105" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Cblb, Itch, Dgka, Rnf128, Egr2, Egr3, and Gadd45b are anergy-associated molecules</body> </html> </notes> <label text="T-cell_anergy"/> <bbox w="240.0" h="75.0" x="2630.0" y="5922.5"/> </glyph> <glyph class="nucleic acid feature" id="s5415_sa1107" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45G CASCADE:IL2 CASCADE:IL12 CASCADE:IL18 MODULE:TCR_SIGNALING MODULE:TH1 PMID:11371360 GADD45G was highly expressed in TH1 versus TH2 cells p38 kinase activity was induced when TH1 cells were activated by α-CD3 antibody. However, it was not induced in GADD45γ−/− TH1 effector cells GADD45γ protein therefore mediates TCR-stimulated p38 MAP kinase activation in TH1 effector cells. JNK activity was induced in wild-type TH1 effector cells upon α-CD3 antibody treatment, it was not induced in GADD45γ−/− TH1 effector cells (Figure 4B). Therefore, GADD45γ is required for both p38 and JNK MAP kinase activation through TCR stimulation in TH1 effector cells. The reduction in IFN-γ secretion was the result of reduced expression of IFN-γ mRNA by GADD45γ−/− CD4+ T cells</body> </html> </notes> <label text="GADD45G"/> <bbox w="90.0" h="25.0" x="2775.0" y="5372.5"/> <glyph class="unit of information" id="_4074b64f-cf4e-41db-a294-c44250192b28"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2810.0" y="5367.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5420_sa1112" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:DUSP14 PMID:24403530 DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.</body> </html> </notes> <label text="DUSP14"/> <bbox w="80.0" h="40.0" x="1110.0" y="3015.0"/> </glyph> <glyph class="nucleic acid feature" id="s5424_sa1115" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL10 MODULE:TCR_SIGNALING CASCADE:TCR PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent PMID:26013006 IL-27 stimulation of Tregs induced expression of Lag3 qPCR analysis confirmed that IL-27 upregulated Tbx21, Lag3, Ccl3, Ccl4, and Il10 expression</body> </html> </notes> <label text="IL10"/> <bbox w="70.0" h="25.0" x="2035.0" y="5842.5"/> </glyph> <glyph class="nucleic acid feature" id="s5425_sa1116" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL10 CASCADE:TCR MODULE:TCR_SIGNALING PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent</body> </html> </notes> <label text="IL10"/> <bbox w="90.0" h="25.0" x="2025.0" y="5912.5"/> <glyph class="unit of information" id="_d13d6816-ef2a-4080-a71b-bed62084423e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2060.0" y="5907.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5426_sa1117" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL10 MODULE:TCR_SIGNALING CASCADE:TCR PMID:16200688; PMID:15282297 Phosphorylation of p38 after TCR stimulation was enhanced in anergic CD4+ T cells over that in naive CD4+ T cells, which showed limited phosphorylation. In contrast, the phosphorylation of ERK and JNK in anergic CD4+ T cells was severely reduced, consistent with the previous report of T cells that were anergized in vitro T-cell proliferation is inhibited by p38 MAPK activity in anergic CD4+ T cells. The production of IL-2 is inhibited by p38 activity in anergic CD4+ T cells, while IL-10 production is p38 dependent PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ PMID:12818165 By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. It inhibits IL-2, IL-4, IL-10, and IFN-γ secretion from B7-1 costimulated T cells.</body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="2030.0" y="5995.0"/> </glyph> <glyph class="macromolecule" id="s5429_sa1120" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TAB1 HUGO:TAB2 HUGO:TAB3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:16200688; PMID:15282297 TAB1 activates p38 in T-cells PMID:24403530 DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown.</body> </html> </notes> <label text="TAB*"/> <bbox w="80.0" h="40.0" x="1320.0" y="2905.0"/> <glyph class="state variable" id="_b28873a0-1345-45fd-a07f-57d58c7fae2e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1315.0" y="2920.0"/> </glyph> </glyph> <glyph class="complex" id="s5430_csa134" compartmentRef="c2_ca2"> <label text="s5430"/> <bbox w="100.0" h="120.0" x="1380.0" y="3055.0"/> <glyph class="macromolecule" id="s5431_sa1121"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TAB1 HUGO:TAB2 HUGO:TAB3 CASCADE:TCR MODULE:TCR_SIGNALING PMID:16200688; PMID:15282297 TAB1 activates p38 in T-cells PMID:24403530 DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown.</body> </html> </notes> <label text="TAB*"/> <bbox w="80.0" h="40.0" x="1390.0" y="3105.0"/> <glyph class="state variable" id="_b59ead45-121d-43bb-8c7e-f446a12f3888"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1382.5" y="3120.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5432_sa1122"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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:MAP3K7 Identifiers_end Maps_Modules_begin: CASCADE:TCR MODULE:TCR_SIGNALING CELL:TREG Maps_Modules_end References_begin: PMID: 15125833 The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. PMID:24403530 the activation of MKK4 and IKK is inhibited by DUSP14; thus, DUSP14 may function upstream of both MKK4 and IKK upon T cell activation The phosphorylation levels of the TAB1–TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IKK, but not ERK, activation of DUSP14-deficient T cells was attenuated by TAB1 shRNA knockdown PMID:17363905 PKC-θ regulates TGF-β–activated kinase 1 (TAK1), a member of the MAPKK kinase family, leading to activation of IKK and NF-κB in a CARMA1-independent manner in the TCR pathway TAK1 activation was significantly inhibited with the pretreatment of the PKC inhibitor in both Jurkat and JPM50.6 cells (Figure 6A, lower panels). Together, these results suggest that PKC functions upstream of TAK1 and TAK1 regulates IKKα/β phosphorylation in the TCR signaling pathway. PKCθ, TAK1, and IKK assemble into a complex in a signal‐dependent but CARMA1‐independent manner, whereas BCL10 and MALT1 require CARMA1 to associate with the PKCθ–TAK1–IKK complex. Together, our results suggest a model in which TAK1 functions downstream of PKC and phosphorylates IKKα/β in a CARMA1‐independent manner, and, together with CARMA1‐dependent ubiquitination of NEMO, leads to activation of the IKK complex and NF‐κB in antigen receptor signaling pathways PMID:22941947 TAK1 can also activate MKK4/7 and MKK3/6, resulting in the activation of JNK and p38, respectively. PMID:16799562 Thymic generation of Treg cells requires TAK1 Foxp3 and Cd25 mRNA was also much lower in TAK1-deficient CD4 SP thymocytes, indicating that the reduced Foxp3 and CD25 were a result of decreased expression of their mRNA IL-7-mediated T cell survival depends on TAK1 TAK1 is required for TCR-mediated cellular responses and NF-B and Jnk activation in mature thymocytes. TCR-induced Jnk but not NF-B in effector T cells requires TAK1 TAK1 is essential for IL-2-, IL-7- and IL-15-mediated p38 activation in effector T cells. PMID:17363905 TAK1 is essential for JNK and NF-κB activation during TCR signaling in primary T cells PMID:20164171 a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C-theta. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKgamma. Thus, distinct sites within ADAP control two key activation responses that are required for NF-kappaB activation in T cells. References_end</body> </html> </notes> <label text="MAP3K7"/> <bbox w="80.0" h="40.0" x="1390.0" y="3065.0"/> </glyph> </glyph> <glyph class="complex" id="s5433_csa46" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR PMID:18287025 JNK induces assosiation of Paxilin with MTOC resulted in polarization of the MTOC and cytolytic granules, and finally exocytosis of cytolytic proteins in NK. PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2 PMID:24655141; PMID:17006514 REW PMID:12616499 Vav1 is required for TCR-induced polarization of the MTOC</body> </html> </notes> <label text="MTOC"/> <bbox w="200.0" h="293.125" x="4510.0" y="5538.4375"/> <glyph class="macromolecule" id="s850_sa514"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PXN CASCADE:TCR MODULE:TCR_SIGNALING PMID:22043013 Paxillin associates with the microtubule cytoskeleton and the immunological synapse of CTL through its leucine-aspartic acid domains and contributes to microtubule organizing center reorientation. LFA-1 or CD3 engagement alone was insufficient for paxillin recruitment because there was no paxillin accumulation at the site of CTL contact with anti-LFA-1- or anti-CD3-coated beads. In contrast, paxillin accumulation was detected when beads coated with both anti-CD3 and anti-LFA-1 were bound to CTL, suggesting that signals from both the TCR and LFA-1 are required for paxillin accumulation. Paxillin was shown to be phosphorylated downstream of ERK, paxillin was demonstrated to be a direct target of ERK phosphorylation PMID:29021139 Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors</body> </html> </notes> <label text="PXN"/> <bbox w="80.0" h="40.0" x="4542.5" y="5756.5625"/> <glyph class="state variable" id="_e1d57c8e-02a1-45e3-811b-79a787f39cdb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4537.5" y="5771.5625"/> </glyph> </glyph> <glyph class="macromolecule" id="s5434_sa515"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBB HUGO:TUBB1 HUGO:TUBB2A HUGO:TUBB2B HUGO:TUBB2C HUGO:TUBB3 HUGO:TUBB4 HUGO:TUBB4Q HUGO:TUBB6 MODULE:TCR_SIGNALING PMID:18287025</body> </html> </notes> <label text="Tubulin-β*"/> <bbox w="80.0" h="40.0" x="4610.0" y="5710.0"/> </glyph> <glyph class="macromolecule" id="s5435_sa516"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBA1A HGNC:20766 ENTREZ:7846 UNIPROT:Q71U36 GENECARDS:TUBA1A REACTOME:191692 KEGG:7846 ATLASONC:GC_TUBA1A WIKI:TUBA1A SwissProt:Q71U36 HUGO:TUBA1B HGNC:18809 ENTREZ:10376 UNIPROT:P68363 GENECARDS:TUBA1B REACTOME:191693 KEGG:10376 ATLASONC:GC_TUBA1B WIKI:TUBA1B SwissProt:P68363 HUGO:TUBA1C HGNC:20768 ENTREZ:84790 UNIPROT:Q9BQE3 GENECARDS:TUBA1C REACTOME:65667 KEGG:84790 ATLASONC:GC_TUBA1C WIKI:TUBA1C SwissProt:Q9BQE3 tubulin, alpha 3c HUGO:TUBA3C HGNC:12408 ENTREZ:7278 UNIPROT:Q13748 GENECARDS:TUBA3C REACTOME:154750 KEGG:7278 WIKI:TUBA3C SwissProt: Q13748 HUGO:TUBA3D HGNC:24071 ENTREZ:113457 UNIPROT:Q13748 GENECARDS:TUBA3D REACTOME:154750 KEGG:113457 WIKI:TUBA3D tubulin, alpha 3e HUGO:TUBA3E HGNC:20765 ENTREZ:112714 UNIPROT:Q6PEY2 GENECARDS:TUBA3E WIKI:TUBA3E SwissProt:Q6PEY2 HUGO:TUBA4A HGNC:12407 ENTREZ:7277 UNIPROT:P68366 GENECARDS:TUBA4A REACTOME:191690 KEGG:7277 ATLASONC:GC_TUBA4A WIKI:TUBA4A SwissProt: P68366 HUGO:TUBA8 HGNC:12410 ENTREZ:51807 UNIPROT:Q9NY65 GENECARDS:TUBA8 KEGG:51807 WIKI:TUBA8 SwissProt:Q9NY65 MODULE:TCR_SIGNALING PMID:18287025</body> </html> </notes> <label text="Tubulin-α*"/> <bbox w="80.0" h="40.0" x="4526.25" y="5711.5625"/> </glyph> <glyph class="macromolecule" id="s5436_sa517"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP6 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP6"/> <bbox w="80.0" h="40.0" x="4620.0" y="5631.5625"/> </glyph> <glyph class="macromolecule" id="s5437_sa518"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP4 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP4"/> <bbox w="80.0" h="40.0" x="4530.0" y="5631.5625"/> </glyph> <glyph class="macromolecule" id="s5438_sa519"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP3 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP3"/> <bbox w="80.0" h="40.0" x="4530.0" y="5591.5625"/> </glyph> <glyph class="macromolecule" id="s5439_sa520"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP2 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP2"/> <bbox w="80.0" h="40.0" x="4530.0" y="5551.5625"/> </glyph> <glyph class="macromolecule" id="s5440_sa521"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBG1 HUGO:TUBG2 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="Tubulin-γ*"/> <bbox w="80.0" h="40.0" x="4620.0" y="5551.5625"/> </glyph> <glyph class="macromolecule" id="s5441_sa522"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TUBGCP5 MODULE:TCR_SIGNALING PMID:18802074 TCR-induced MTOC reorientation is regulated by Fyn, Zap, Lat, SLP-76, and Erk1/2</body> </html> </notes> <label text="TUBGCP5"/> <bbox w="80.0" h="40.0" x="4620.0" y="5591.5625"/> </glyph> </glyph> <glyph class="macromolecule" id="s5443_sa1126" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CBLC PMID:12415267; PMID:9671496 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. c-Cbl was highly expressed in thymocytes, whereas Cbl-b was preferentially expressed in mature T cells. In the TCR signaling pathway, c-Cbl inhibits ZAP-70 activation in thymocytes</body> </html> </notes> <label text="CBLC"/> <bbox w="80.0" h="40.0" x="3450.0" y="1590.0"/> </glyph> <glyph class="macromolecule" id="s5444_sa1127" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CBL PMID:11353765 Among all potential pathways leading to TCR·CD3 down-regulation, ubiquitin (Ub) conjugation to the TCR·CD3 subunits, and particularly to the TCRζ chain, has been shown in activated T cells Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.</body> </html> </notes> <label text="CBL"/> <bbox w="80.0" h="40.0" x="3000.0" y="1590.0"/> </glyph> <glyph class="source and sink" id="s5450_sa1132" compartmentRef="c8_ca8"> <label text="csa135_degraded"/> <bbox w="30.0" h="30.0" x="2815.0" y="1355.0"/> </glyph> <glyph class="complex" id="s5451_csa135" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:23886063 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta</body> </html> </notes> <label text="s4356"/> <bbox w="118.75" h="210.0" x="2940.625" y="1267.0"/> <glyph class="macromolecule" id="s5452_sa1128"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRA HUGO:TRB CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)].</body> </html> </notes> <label text="alpha_/beta_TCR*"/> <bbox w="80.0" h="50.0" x="2959.375" y="1272.0"/> <glyph class="unit of information" id="_43067d4d-8627-4dc6-86dd-8ae4db52fac0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2976.875" y="1267.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5453_sa1129"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD3E HUGO:CD3G HUGO:CD3D CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is localized in the central part of immunological synapse.</body> </html> </notes> <label text="CD3*"/> <bbox w="80.0" h="50.0" x="2959.375" y="1352.0"/> <glyph class="state variable" id="_c5e33cc4-9391-46ef-b805-4a9b9ab72c35"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2951.875" y="1372.0"/> </glyph> <glyph class="unit of information" id="_e7030045-64e4-4580-9331-73017ad82d64"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2976.875" y="1347.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5455_sa1130"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD247 CASCADE:TCR MODULE:SMAC PMID:9738502 TCR–CD3 complex is lolalized in the central part of immunological synapse. PMID:21059766 The TCR of αβ T cells is composed of the ligand-binding subunits TCRα and TCRβ, which form the disulfide-linked TCRαβ heterodimer, non-covalently bound to the signal transducing CD3 subunits [CD3γ, CD3δ, CD3ε and CD3ζ (CD247)]. PMID:11353765 Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.</body> </html> </notes> <label text="CD247"/> <bbox w="80.0" h="50.0" x="2960.375" y="1312.0"/> <glyph class="state variable" id="_ff2f0505-d062-4392-a0ca-b1d1fe409dfc"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="3030.375" y="1333.4689"/> </glyph> <glyph class="state variable" id="_9bdef48d-b2bb-42b5-99cc-a66ba06df82e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2952.875" y="1332.0"/> </glyph> <glyph class="unit of information" id="_eaa96d4b-5e35-4639-9d3b-44ea15a5aff1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2977.875" y="1307.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5454_sa1131"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ZAP70 CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508 ZAP70 (ζ-chain-associated protein of 70 kDa) is a tyrosine-protein kinase from the Syk family that docks at phosphorylated ITAMs of the TCR. Docking, subsequent phosphorylation by Lck and trans-autophosphorylation all increase kinase activity. ZAP70 phosphorylates a number of signaling proteins, including LAT and SLP-76 PMID:7600293; PMID:8642247 ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta TCR ligation promotes a large increase in the tyrosine phosphorylation of ZAP-70 by Lck PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:12415267 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. c-Cbl was highly expressed in thymocytes, whereas Cbl-b was preferentially expressed in mature T cells. In the TCR signaling pathway, c-Cbl inhibits ZAP-70 activation in thymocytes PMID:17371980 AR2A agonist ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="2960.0" y="1412.0"/> <glyph class="state variable" id="_fcecb6cd-021a-4398-9971-3c6686323527"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2955.0" y="1427.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5456_sa1133" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIK3R1 HUGO:PIK3R2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells Ligation of the T cell receptor for antigen (TCR) and/or costimulatory receptor CD28 results in rapid activation of phosphoinositide-3 kinase (PI-3 kinase). The primary mechanism for class IA PI-3 kinase activation by tyrosine kinase-coupled receptors is recruitment of the p85/p110 heterodimer to phosphorylated tyrosine kinase receptors via interaction of p85 Src homology 2 (SH2) domain(s) with phosphotyrosine moieties on the receptors PMID:11526404 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. The p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) was identified as a substrate for Cbl-b. We have shown that Cbl-b negatively regulated p85 recruitment of p85 to CD28 and T cell antigen receptor through its E3 ubiquitin ligase activity. The enhanced activation of Cbl-b-/- T cells was suppressed by the inhibition of PI3K. PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="PI3KR(p85)*"/> <bbox w="80.0" h="40.0" x="5420.0" y="1650.0"/> <glyph class="state variable" id="_619e4857-50c6-4878-8b30-c6d2f32282c4"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="5410.0" y="1664.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s5457_sa1134" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:NFKB2 CASCADE:TCR MODULE:TCR_SIGNALING PMID: 16970925 The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. PMID:15079071 In T cells the alternative NFkB pathway acts via RELA/p52 dimer not via RELB/p52 sownstream CD28 CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manne</body> </html> </notes> <label text="NFKB2_p100*"/> <bbox w="80.0" h="40.0" x="4050.0" y="4175.0"/> </glyph> <glyph class="nucleic acid feature" id="s5458_sa1135" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING HUGO:NFKB2 PMID:15536066 The p100 gene promoter is itself a target of NF-κB (23), so it was possible that the increase in p100 level and the generation of p52 in response to TCR/CD28 signaling is an indirect effect of PKCθ-mediated NF-κB activation. We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner</body> </html> </notes> <label text="NFKB2_p100*"/> <bbox w="90.0" h="25.0" x="4045.0" y="4252.5"/> <glyph class="unit of information" id="_19dd43fd-e8d7-4402-843b-977162115ce3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4080.0" y="4247.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5459_sa1136" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING HUGO:NFKB2 PMID:15536066 The p100 gene promoter is itself a target of NF-κB (23), so it was possible that the increase in p100 level and the generation of p52 in response to TCR/CD28 signaling is an indirect effect of PKCθ-mediated NF-κB activation. We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner</body> </html> </notes> <label text="NFKB2_p100*"/> <bbox w="70.0" h="25.0" x="4055.0" y="4322.5"/> </glyph> <glyph class="macromolecule" id="s5460_sa1137" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:BAD MODULE:TCR_SIGNALING PMID:11342610 Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD.</body> </html> </notes> <label text="BAD"/> <bbox w="80.0" h="40.0" x="3620.0" y="5650.0"/> <glyph class="state variable" id="_0b2942cd-b369-4b7f-818b-88de72842356"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3615.0" y="5665.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5467_sa743" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: HUGO:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MODULE:TCELL MODULE:TCR_SIGNALING CADCADE:TCR Maps_Modules_end References_begin: PMID:11148124 JNK/AP1 signaling is activated in T-cells downstream of TCR signaling PMID:15214048; PMID:10807788; PMID:24027568 AP-1 activation by Tec is largely dependent on PLCγ1 function. Moreover, ionomycin did not enhance Tec-induced AP-1 activation (Fig. 4C), also suggesting that Tec contributes to AP-1 activation upstream of Ca2+ release. probably via RAS/ERK pathway PMID: 11262396 We examined whether Vav2 overexpression results in stimulation of c-fos SRE transcriptional activity. We transfected Jurkat-TAg cells with Myc-tagged Vav1 or Vav2 along with a luciferase reporter driven by SRE-binding sequences. Similarly both Vav1 and Vav2 induced a marked increase of either the basal or TCR-stimulated activities of SRE reporter plasmid References_end PMID:12818166 the expression of JunB, a component of the AP-1 family induced after T cell activation, was reduced by 49% after B7S1 costimulation. On the other hand, there was little change in c-Jun expression (11% reduction) with B7S1-Ig treatment. JunB has been previously shown to bind to the IL-2 promoter (Boise et al., 1993 and JunB overexpression resulted in greater IL-2 production (our unpublished data). Since JunB is induced after T cell activation (Jain et al., 1995, the mechanism of which is unknown, B7S1 costimulation may result in inefficient JunB induction.</body> </html> </notes> <label text="AP1*"/> <bbox w="280.0" h="160.0" x="1590.0" y="5175.0"/> <glyph class="state variable" id="_ca18f10c-36a5-4239-b691-72340e5dde44"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1582.5" y="5250.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5468_sa756" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRAT1 CASCADE:TCR MODULE:SMAC PMID:20828560 In T cells, a dimer of the TCR interacting molecule (TRIM) is also part of the receptor complex (Fig. 1a). However, it is not known what percentage of TCRs contain TRIM. TRIM-deficient mice produce a functional, surface-expressed TCR, demonstrating that TRIM is dispensable for a functional TCR in vivo PMID: 9687533 TRAT1 (TRIM)after T cell activation, TRIM becomes rapidly phosphorylated on tyrosine residues and then associates with the 85-kD regulatory subunit of PI3-kinase via an YxxM motif. Thus, TRIM represents a TCR-associated transmembrane adaptor protein which is likely involved in targeting of intracellular signaling proteins to the plasma membrane after triggering of the TCR. TRIM becomes tyrosine phosphorylated by lck and fyn but not by ZAP70. In addition, concomitant expression of lck and ZAP70 does not induce higher levels of TRIM tyrosine phosphorylation than expression of lck alone. Also, coexpression of TRIM and Syk in COS cells did not result in tyrosine phosphorylation of TRIM (not shown). These data indicate that TRIM could represent a protein that is preferentially phosphorylated by tyrosine kinases of the src family. To further substantiate this assumption, TCR-mediated tyrosine phosphorylation of TRIM was analyzed in wild-type Jurkat cells and in a Jurkat variant lacking expression of both ZAP70 and Syk tyrosine kinases (P116 cells [12]). As shown in Fig. Fig.1010 C, TRIM becomes strongly tyrosine phosphorylated in P116 cells after engagement of the TCR or upon Pervanadate stimulation. In addition, preincubation of P116 cells with the recently described inhibitor for src-kinases, PP1 (15), completely abrogates TCR-mediated tyrosine phosphorylation of TRIM. Thus, tyrosine phosphorylation of TRIM can occur independently of expression of members of the Syk family PTKs and can be prevented by an inhibitor with a proposed specificity for src-kinases.</body> </html> </notes> <label text="TRAT1"/> <bbox w="80.0" h="40.0" x="3580.0" y="1165.0"/> <glyph class="state variable" id="_e4a34165-d8db-4dc6-82ee-976af759204d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3572.5" y="1180.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5469_sa1144" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:INPP5D CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS 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:12421919 SHIP is tyrosine phosphorylated in response to CD28 and CD3 ligation in CEM and MOLT-4 cells (The human leukemic T cell lines Jurkat, CEM, MOLT-4, and HUT78) Differential expression of lipid phosphatases correlates with PKB phosphorylation levels availability of SHIP may determine the activity of the PI3K-dependent signaling cascades was confirmed by the expression of constitutively active membrane-localized SHIP construct which was sufficient to reduce both PKB-PH domain membrane localization and phosphorylation.</body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="1200.0" y="1360.0"/> </glyph> <glyph class="macromolecule" id="s5471_sa1146" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:19276087 DPYSL2 (CRMP2) CXCL12 Induces CRMP2 Polarization at the T Lymphocyte Uropod CXCL12 Modulates CRMP2 Binding to the Cytoskeleton CRMP2 was distributed in the cytoskeletal compartment of T lymphocytes and that CXCL12 had the ability to alter this distribution, enhancing CRMP2 association with cytoskeletal elements. CXCL12 decreases phosphorylation of the glycogen synthase kinase-3β-targeted residues CRMP2-Thr-509/514; and 3) tyrosine Tyr-479 is a new phosphorylation CRMP2 residue and a target for the Src-family kinase Yes. Moreover, phospho-Tyr-479 increased under CXCL12 signaling while phospho-Thr-509/514 decreased.</body> </html> </notes> <label text="DPYSL2"/> <bbox w="80.0" h="40.0" x="4392.5" y="4030.0"/> <glyph class="state variable" id="_978c4cef-ea08-4a6a-ac33-7d4cec2891c7"> <state value="" variable="Tyr479"/> <bbox w="40.0" h="10.0" x="4449.586" y="4065.0"/> </glyph> <glyph class="state variable" id="_bc984a63-f5c9-416f-81d7-d4ad48d0df6e"> <state value="" variable="Thr509/514"/> <bbox w="60.0" h="10.0" x="4362.5" y="4028.0996"/> </glyph> </glyph> <glyph class="macromolecule" id="s5472_sa1148" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:19276087 DPYSL2 (CRMP2) CXCL12 Induces CRMP2 Polarization at the T Lymphocyte Uropod CXCL12 Modulates CRMP2 Binding to the Cytoskeleton CRMP2 was distributed in the cytoskeletal compartment of T lymphocytes and that CXCL12 had the ability to alter this distribution, enhancing CRMP2 association with cytoskeletal elements. CXCL12 decreases phosphorylation of the glycogen synthase kinase-3β-targeted residues CRMP2-Thr-509/514; and 3) tyrosine Tyr-479 is a new phosphorylation CRMP2 residue and a target for the Src-family kinase Yes. Moreover, phospho-Tyr-479 increased under CXCL12 signaling while phospho-Thr-509/514 decreased.</body> </html> </notes> <label text="DPYSL2"/> <bbox w="80.0" h="40.0" x="4392.5" y="4110.0"/> <glyph class="state variable" id="_3edf4098-e990-4a03-a406-d19d96dad671"> <state value="P" variable="Tyr479"/> <bbox w="45.0" h="10.0" x="4447.086" y="4145.0"/> </glyph> <glyph class="state variable" id="_15dde289-51df-451b-beb9-2faf10977500"> <state value="" variable="Thr509/514"/> <bbox w="60.0" h="10.0" x="4362.5" y="4108.0996"/> </glyph> </glyph> <glyph class="macromolecule" id="s5473_sa1147" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:19276087 DPYSL2 (CRMP2) CXCL12 Induces CRMP2 Polarization at the T Lymphocyte Uropod CXCL12 Modulates CRMP2 Binding to the Cytoskeleton CRMP2 was distributed in the cytoskeletal compartment of T lymphocytes and that CXCL12 had the ability to alter this distribution, enhancing CRMP2 association with cytoskeletal elements. CXCL12 decreases phosphorylation of the glycogen synthase kinase-3β-targeted residues CRMP2-Thr-509/514; and 3) tyrosine Tyr-479 is a new phosphorylation CRMP2 residue and a target for the Src-family kinase Yes. Moreover, phospho-Tyr-479 increased under CXCL12 signaling while phospho-Thr-509/514 decreased.</body> </html> </notes> <label text="DPYSL2"/> <bbox w="80.0" h="40.0" x="4392.5" y="3940.0"/> <glyph class="state variable" id="_91bf0697-9a92-4c15-aff3-5771e7428e5a"> <state value="" variable="Tyr479"/> <bbox w="40.0" h="10.0" x="4449.586" y="3975.0"/> </glyph> <glyph class="state variable" id="_e661cbb2-a036-4091-89f6-8d19fe283ef9"> <state value="P" variable="Thr509/514"/> <bbox w="65.0" h="10.0" x="4360.0" y="3938.0996"/> </glyph> </glyph> <glyph class="macromolecule" id="s5474_sa1149" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CXCL12 decreases phosphorylation of the glycogen synthase kinase-3β-targeted residues CRMP2-Thr-509/514; and 3) tyrosine Tyr-479 is a new phosphorylation CRMP2 residue and a target for the Src-family kinase Yes. Moreover, phospho-Tyr-479 increased under CXCL12 signaling while phospho-Thr-509/514 decreased.</body> </html> </notes> <label text="YES1"/> <bbox w="80.0" h="40.0" x="4512.5" y="4060.0"/> </glyph> <glyph class="nucleic acid feature" id="s5476_sa1150" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PDCD1 CASCADE:TCR PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID:27806234 Transcription of PD-1 in T cells requires nuclear translocation of NFAT and binding of NFATc1 (NFAT2) to the PDCD1 promoter.15 FOXO1, Notch, and IRF9 also promote PD-1 transcription, whereas T-bet functions as a transcriptional repressor.</body> </html> </notes> <label text="PDCD1"/> <bbox w="70.0" h="25.0" x="1855.0" y="987.5"/> </glyph> <glyph class="nucleic acid feature" id="s5477_sa1151" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PDCD1 CASCADE:TCR PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.</body> </html> </notes> <label text="PDCD1"/> <bbox w="90.0" h="25.0" x="1845.0" y="887.5"/> <glyph class="unit of information" id="_835f3bfe-db4d-4878-b25e-a5dadf2ef4f5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1880.0" y="882.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5478_sa1152" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR HUGO:TBX21 MODULE:INHIBITING_CHECKPOINTS PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID:26013006 IL-27 stimulation of Tregs induced expression of Lag3 qPCR analysis confirmed that IL-27 upregulated Tbx21, Lag3, Ccl3, Ccl4, and Il10 expression</body> </html> </notes> <label text="TBX21"/> <bbox w="70.0" h="25.0" x="707.0" y="1107.5"/> </glyph> <glyph class="nucleic acid feature" id="s5479_sa1153" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS HUGO:TBX21 PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.</body> </html> </notes> <label text="TBX21"/> <bbox w="90.0" h="25.0" x="695.0" y="1187.5"/> <glyph class="unit of information" id="_4556043e-3cea-417b-b905-cf061ea5ff9d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="730.0" y="1182.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5480_sa467" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMH CELL:TCD8 MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human</body> </html> </notes> <label text="GZMH"/> <bbox w="80.0" h="40.0" x="3370.0" y="6457.5"/> </glyph> <glyph class="macromolecule" id="s5481_sa466" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 HUGO:GZMM MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human</body> </html> </notes> <label text="GZMM"/> <bbox w="80.0" h="40.0" x="3510.0" y="6427.5"/> </glyph> <glyph class="macromolecule" id="s5482_sa470" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMB MODULE:TCR_SIGNALING CELL:TCD8 PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human PMID:8432729 Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor.</body> </html> </notes> <label text="GZMB"/> <bbox w="80.0" h="40.0" x="3750.0" y="6337.5"/> </glyph> <glyph class="macromolecule" id="s5483_sa468" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMK CELL:TCD8 MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human</body> </html> </notes> <label text="GZMK"/> <bbox w="80.0" h="40.0" x="3460.0" y="6507.5"/> </glyph> <glyph class="macromolecule" id="s5484_sa465" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRF1 MODULE:TCR_SIGNALING PMID: 19380804 Activated CD8+ T cells rapidly up-regulate perforin. Following Ag-specific activation, newly synthesized perforin rapidly appears at the immunological synapse, both in association with and independent of cytotoxic granules, where it functions to promote cytotoxicity. PMID:7520535 Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways.</body> </html> </notes> <label text="PRF1"/> <bbox w="80.0" h="40.0" x="3870.0" y="6340.0"/> </glyph> <glyph class="macromolecule" id="s5485_sa472" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GZMA CELL:TCD8 MODULE:TCR_SIGNALING PMID:14499263 Five granzymes are expressed in human T 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. The most extensively studied granzymes are A and B, for which the reader is referred to several recent reviews regarding their discovery, function, and mechanisms of action, Additional granzyme genes have also been described, but little is known about their functions, hence their designation as ‘orphans’. The orphan granzymes include H, K and M in the human PMID:8432729 Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor.</body> </html> </notes> <label text="GZMA"/> <bbox w="80.0" h="40.0" x="3620.0" y="6430.0"/> </glyph> <glyph class="macromolecule" id="s5486_sa469" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GNLY MODULE:TCR_SIGNALING PMID: 19254247 Granulysin is a cytolytic and proinflammatory molecule first identified by a screen for genes expressed 'late' (3-5 days) after activation of human peripheral blood mononuclear cells. Granulysin is present in cytolytic granules of cytotoxic T lymphocytes and natural killer cells. Granulysin is made in a 15-kDa form that is cleaved into a 9-kDa form at both the amino and the carboxy termini. The 15-kDa form is constitutively secreted, and its function remains poorly understood. The 9-kDa form is released by receptor-mediated granule exocytosis. Nine kiloDalton granulysin is broadly cytolytic against tumors and microbes, including gram-positive and gram-negative bacteria, fungi/yeast and parasites. It kills the causative agents of both tuberculosis and malaria. Granulysin is also a chemoattractant for T lymphocytes, monocytes and other inflammatory cells and activates the expression of a number of cytokines, including regulated upon activation T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1 alpha, interleukin (IL)-10, IL-1, IL-6 and interferon (IFN)-alpha. granulysin expression in tumor infiltrates is associated with good outcomes. Pages et al. found low granulysin expression in effector memory T cells in tumor infiltrates to correlate early metastasis and poor survival rates, while high levels of granulysin correlated with good outcomes in colorectal carcinoma Recombinant 9 kDa granulysin attracts T cells, monocytic and NK-cell tumor lines but not Epstein-Barr virus-transformed B-cell lines. Granulysin shows maximal chemotactic activity for CD4+ and CD8+ T cells and monocytes at 10 nM.</body> </html> </notes> <label text="GNLY"/> <bbox w="80.0" h="40.0" x="3900.0" y="6480.0"/> </glyph> <glyph class="complex" id="s5498_csa102" compartmentRef="c8_ca8"> <label text="s5042"/> <bbox w="100.0" h="120.0" x="3720.0" y="995.0"/> <glyph class="macromolecule" id="s5499_sa879"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 MODULE:SMAC MODULE:TCR_SIGNALING HUGO:PRKCQ CASCADE:TCR PMID:23433459 PKCtheta in tregs. PMID:23886063; PMID:9738502 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta PMID:17544292 ; PMID:23433459 Protein kinase C theta (PKCtheta): a key player in T cell life and death. Mutation of the PKCθ gene leads to impaired receptor-induced stimulation of the transcription factors AP-1, NF-κB and NFAT, which results in defective T cell activation, and to aberrant expression of apoptosis-related proteins, resulting in poor T cell survival. Furthermore, PKCθ-deficient mice display defects in the differentiation of T helper subsets, particularly in Th2 and Th17-mediated inflammatory responses. The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation PMID: 10746729 The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:15536066 Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. PMID:10652356 The C2-like domain contains a tyrosine residue (Tyr-90), which is phosphorylated by the T cell tyrosine kinase Lck PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner PKCθ was required for the survival of both activated CD4 and CD8+ T cells</body> </html> </notes> <label text="PRKCQ"/> <bbox w="80.0" h="40.0" x="3730.0" y="1005.0"/> <glyph class="state variable" id="_1bf28666-6a1c-4657-9e48-67aa1e2872a7"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3725.0" y="1020.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s5500_sa880"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IFNAB 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="3735.0" y="1062.5"/> </glyph> </glyph> <glyph class="complex" id="s5501_csa104" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL15 CASCADE:IL21 CASCADE:CSF2 CASCADE:IFNG MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION</body> </html> </notes> <label text="s1115"/> <bbox w="100.0" h="120.0" x="3800.0" y="1135.0"/> <glyph class="macromolecule" id="s5502_sa884"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PDK1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:19122654 ;PMID:15802604 TCR-CD28–mediated NF-κB activation requires PDK1 PDK1 and PKC-θ also localized together at the immunological synapse following stimulation of primary CD4+ T cells recruitment of PDK1 and PKC-θ can occur independently; that is, treatment with anti-CD3 alone led to PKC-θ recruitment, whereas treatment with anti-CD28 alone led to PDK1 recruitment The protein kinase PDK1 is considered essential for PKCθ activation as PDK1-deficient Jurkat and primary CD4 T cells show a defect in PKCθ phosphorylation and NF-κB activation. PDK1 bound to PKC-θ in primary T cells (Supplementary Fig. 9) and Jurkat T cells16 (Fig. 4c). Moreover, PDK1 can induce weak PKC-θ phosphorylation in vitro, which is associated with the relatively weak binding between these proteins in in vitro conditions.</body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="3810.0" y="1145.0"/> </glyph> <glyph class="simple chemical" id="s5503_sa885"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:NK PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:9438848 PI3K product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav proteins 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="3815.0" y="1202.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5504_sa190" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CTLA4 CELL:CD4 CELL:TREG MODULE:SMAC CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS 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:22116087 CTLA4 has been reported to recruit phosphatases — such as protein phosphatase 2A (PP2A)72,73 and SYP (also known as PTPN11)74 — and to decrease the phosphorylation of several key proteins in the TCR signalling cascade, including CD3ζ and linker for activation of T cells (LAT). PMID:16227604 similarly constructed CD3/CD28/PD-1 aAPCs inhibited T-cell expansion and IL-2 production as well as CD3/CD28/CTLA-4-coated beads. CTLA-4 and PD-1 ablate the effect of costimulation on glucose uptake in T lymphocytes. PD-1 signaling blocks CD28-mediated activation of PI3K and Akt. CTLA-4 ligation blocks Akt but not PI3K activation. PD-1 suppression of PI3K/Akt is dependent upon factors binding to the ITSM motif in its cytoplasmic tail. CTLA-4-mediated suppression of Akt phosphorylation is inhibited by the PP2A inhibitor okadaic acid.</body> </html> </notes> <label text="CTLA4"/> <bbox w="80.0" h="50.0" x="2740.0" y="710.0"/> <glyph class="unit of information" id="_62d7e000-55d0-4a8d-a985-f01e3a586547"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2757.5" y="705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5505_sa605" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LCK CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508;PMID:21127503 Lck (lymphocyte-specific tyrosine-protein kinase) is a membrane-tethered kinase that phosphorylates tyrosine residues in the ITAMs in the TCR–CD3 complex. Doubly phosphorylated ITAMs are the docking sites for ZAP70 and other TCR signaling-associated proteins. Lck is often associated with the CD4 or CD8 co-receptors, which might potentiate its activity by bringing it into the proximity of the CD3 chains PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:9438848 Tyr174 of Vav is thought to be the site of phosphorylation by Lck that regulates Vav function</body> </html> </notes> <label text="LCK"/> <bbox w="80.0" h="40.0" x="3100.0" y="985.0"/> <glyph class="state variable" id="_bd018374-809e-4df7-ab3e-26febcf9281f"> <state value="" variable="Y505"/> <bbox w="30.0" h="10.0" x="3085.0" y="985.4865"/> </glyph> <glyph class="state variable" id="_5a7b39f3-722b-42ed-9c8f-5d81b442d492"> <state value="" variable="Y394"/> <bbox w="30.0" h="10.0" x="3165.0" y="1019.638"/> </glyph> </glyph> <glyph class="macromolecule" id="s5506_sa686" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ZAP70 CASCADE:TCR MODULE:SMAC CASCADE:AR2A PMID:23620508 ZAP70 (ζ-chain-associated protein of 70 kDa) is a tyrosine-protein kinase from the Syk family that docks at phosphorylated ITAMs of the TCR. Docking, subsequent phosphorylation by Lck and trans-autophosphorylation all increase kinase activity. ZAP70 phosphorylates a number of signaling proteins, including LAT and SLP-76 PMID:7600293; PMID:8642247 ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta TCR ligation promotes a large increase in the tyrosine phosphorylation of ZAP-70 by Lck PMID:15735648 T cell Src family kinases (lck and fyn) and Zap70 activate p38 by phosphorylating Tyr323 downstream of TCR. Lck is required for activation of Zap70, which in turn phosphorylates and activates p38. PMID:12415267 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. c-Cbl was highly expressed in thymocytes, whereas Cbl-b was preferentially expressed in mature T cells. In the TCR signaling pathway, c-Cbl inhibits ZAP-70 activation in thymocytes PMID:17371980 AR2A agonist ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="ZAP70"/> <bbox w="80.0" h="40.0" x="3130.0" y="1230.0"/> <glyph class="state variable" id="_6f9eaa8c-b72e-4c53-aa35-0d88fd5bb706"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3125.0" y="1245.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4415_sa1355" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:STAT1 PMID:21263073 Among the three components of type I IFN-induced ISGF3 (STAT1, STAT2, and cytosolic IRF9), IRF9 contains the DNA-binding motif for ISRE. The chromatin precipitated by anti–IRF-9 was enriched in the PD-1 promoter of IFN-α–treated, but not nontreated, T cells, suggesting that the ISGF3 complex bound directly to the PD-1 promoter in activated primary T cells PMID:12796776 expression of BTLA mRNA is partially dependent on STAT1</body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="1210.0" y="1105.0"/> <glyph class="state variable" id="_946ddb5a-9771-4ba4-96f5-5bc2795d97da"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1205.0" y="1120.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5555_sa473"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LAMP1 HUGO:LAMP2 MODULE:TCR_SIGNALING PMID:15603439; PMID: 19380804; PMID:14580882 LAMP1 (CD107a) and LAMP2 surface presentation is a marker of T cell degranulation the exposure of CD107a and b, present in the membrane of cytotoxic granules, onto the cell surface as a result of degranulation. Acquisition of cell surface CD107a and b is associated with loss of intracellular perforin and is inhibited by colchicine, indicating that exposure of CD107a and b to the cell surface is dependent on degranulation.</body> </html> </notes> <label text="LAMP*"/> <bbox w="80.0" h="40.0" x="4450.0" y="6815.0"/> </glyph> <glyph class="macromolecule" id="s5556_sa471" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LAMP1 HUGO:LAMP2 MODULE:TCR_SIGNALING PMID:15603439; PMID: 19380804; PMID:14580882 LAMP1 (CD107a) and LAMP2 surface presentation is a marker of T cell degranulation the exposure of CD107a and b, present in the membrane of cytotoxic granules, onto the cell surface as a result of degranulation. Acquisition of cell surface CD107a and b is associated with loss of intracellular perforin and is inhibited by colchicine, indicating that exposure of CD107a and b to the cell surface is dependent on degranulation.</body> </html> </notes> <label text="LAMP*"/> <bbox w="80.0" h="40.0" x="3990.0" y="6410.0"/> </glyph> <glyph class="macromolecule" id="s5575_sa1170" compartmentRef="c15_ca15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:M6PR MODULE:TCR_SIGNALING PMID:20634814 Granzymes and other soluble proteins, including lysosomal hydrolases, are sorted from the trans-Golgi network by the mannose-6-phosphate receptor (M6PR) and transported to early endosomes before they are sorted to late endosomes. M6PR is then recycled to the trans-Golgi network. PMID:11081635 Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. PMID:8432729 Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor.</body> </html> </notes> <label text="M6PR"/> <bbox w="80.0" h="50.0" x="3460.0" y="6325.0"/> <glyph class="unit of information" id="_a23f17b2-45fa-4c8b-9f0c-7b261013dbb9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3477.5" y="6320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5576_sa1171" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VAMP1 HUGO:VAMP2 HUGO:VAMP3 HUGO:VAMP4 HUGO:VAMP5 HUGO:VAMP6 HUGO:VAMP7 HUGO:VAMP8 MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="VAMP*"/> <bbox w="80.0" h="40.0" x="4230.0" y="5895.0"/> </glyph> <glyph class="macromolecule" id="s5577_sa1172" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:RAB27A PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="RAB27A"/> <bbox w="80.0" h="40.0" x="4350.0" y="5785.0"/> </glyph> <glyph class="macromolecule" id="s5578_sa1173" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:SYTL1 HUGO:SYTL2 MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="SLP1/2*"/> <bbox w="80.0" h="40.0" x="4350.0" y="5845.0"/> </glyph> <glyph class="macromolecule" id="s5579_sa1174" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:UNC13D MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="UNC13D"/> <bbox w="80.0" h="40.0" x="4350.0" y="5955.0"/> </glyph> <glyph class="macromolecule" id="s5582_sa1177" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:SNAP23 PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="SNAP23"/> <bbox w="80.0" h="40.0" x="4350.0" y="5895.0"/> </glyph> <glyph class="complex" id="s5583_csa138" compartmentRef="c2_ca2"> <label text="s5583"/> <bbox w="100.0" h="120.0" x="4110.0" y="5905.0"/> <glyph class="macromolecule" id="s5580_sa1175"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:STXBP2 MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="STXBP2"/> <bbox w="80.0" h="40.0" x="4120.0" y="5915.0"/> </glyph> <glyph class="macromolecule" id="s5581_sa1176"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:STX11 PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="STX11"/> <bbox w="80.0" h="40.0" x="4120.0" y="5955.0"/> </glyph> </glyph> <glyph class="complex" id="s5584_csa139" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="s5584"/> <bbox w="200.0" h="215.0" x="4330.0" y="6062.5"/> <glyph class="macromolecule" id="s5589_sa1178"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:SNAP23 PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="SNAP23"/> <bbox w="80.0" h="40.0" x="4440.0" y="6167.5"/> </glyph> <glyph class="macromolecule" id="s5586_sa1179"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:SYTL1 HUGO:SYTL2 MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="SLP1/2*"/> <bbox w="80.0" h="40.0" x="4440.0" y="6117.5"/> </glyph> <glyph class="macromolecule" id="s5587_sa1180"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:RAB27A PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="RAB27A"/> <bbox w="80.0" h="40.0" x="4440.0" y="6077.5"/> </glyph> <glyph class="macromolecule" id="s5588_sa1181"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:VAMP1 HUGO:VAMP2 HUGO:VAMP3 HUGO:VAMP4 HUGO:VAMP5 HUGO:VAMP6 HUGO:VAMP7 HUGO:VAMP8 MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="VAMP*"/> <bbox w="80.0" h="40.0" x="4340.0" y="6167.5"/> </glyph> <glyph class="macromolecule" id="s5590_sa1182"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:UNC13D MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="UNC13D"/> <bbox w="80.0" h="40.0" x="4340.0" y="6227.5"/> </glyph> <glyph class="macromolecule" id="s5591_sa1183"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:STXBP2 MODULE:TCR_SIGNALING PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="STXBP2"/> <bbox w="80.0" h="40.0" x="4340.0" y="6077.5"/> </glyph> <glyph class="macromolecule" id="s5592_sa1184"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:STX11 PMID:20634814 Following antigen recognition and proximal signalling events, cytotoxic granules are polarized towards the cytotoxic T lymphocyte (CTL)–target cell contact site where the immunological synapse forms. Actin filaments are cleared away from the site of secretion (not shown). Mature cytotoxic granules dock at the plasma membrane through the interaction of RAB27a with synaptotagmin-like protein 1 (SLP1) or SLP2. In addition, cytotoxic granules interact with a docking complex of MUNC18-2 and syntaxin 11 in the closed conformation. Docked vesicles are then primed by MUNC13-4, which probably triggers the switch of syntaxin 11 from a closed to an open conformation. A SNARE (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex then forms between a vesicle membrane SNARE, possibly vesicle-associated membrane protein 7 (VAMP7) and/or VAMP8, on one side and the target membrane SNAREs syntaxin 11 and SNAP23 (synaptosomal-associated protein of 23 kDa), on the other side. Completion of the fusion reaction occurs when MUNC18-2 clasps across the zippering four-helix SNARE complex bundle.</body> </html> </notes> <label text="STX11"/> <bbox w="80.0" h="40.0" x="4340.0" y="6117.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5595_sa1187" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IQGAP1 CASCADE:TCR MODULE:TCR_SIGNALING PMID:22573807 The cytoskeletal adaptor protein IQGAP1 regulates TCR-mediated signaling and filamentous actin dynamics. IQGAP1 deﬁciency increases cytokine (IL2, IFNG) gene expression and signaling IQGAP1-suppresssed Jurkat T cells showed increased F-actin after TCR ligation, so IQGAP1 negatively regulates F-actin accumulation at the IS.</body> </html> </notes> <label text="IQGAP1"/> <bbox w="80.0" h="40.0" x="4770.0" y="6250.0"/> </glyph> <glyph class="macromolecule" id="s5596_sa1188" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FMNL1 MODULE:TCR_SIGNALING PMID:17306570 Diaphanous-1 (DIA1) and Formin-like-1 (FMNL1), did not affect TCR-stimulated F-actin-rich structures, but instead displayed unique patterns of centrosome colocalization and controlled TCR-mediated centrosome polarization. Depletion of FMNL1 or DIA1 in cytotoxic lymphocytes abrogated cell-mediated killing.</body> </html> </notes> <label text="FMNL1 "/> <bbox w="80.0" h="40.0" x="4720.0" y="6080.0"/> </glyph> <glyph class="macromolecule" id="s5597_sa1189" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:DIAPH1 MODULE:TCR_SIGNALING PMID:17306570 Diaphanous-1 (DIA1) and Formin-like-1 (FMNL1), did not affect TCR-stimulated F-actin-rich structures, but instead displayed unique patterns of centrosome colocalization and controlled TCR-mediated centrosome polarization. Depletion of FMNL1 or DIA1 in cytotoxic lymphocytes abrogated cell-mediated killing.</body> </html> </notes> <label text="DIAPH1"/> <bbox w="80.0" h="40.0" x="4670.0" y="6380.0"/> </glyph> <glyph class="phenotype" id="s871_sa456" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:24655141; PMID:17006514 REW PMID:18802074 MTOC reorientation has been shown to be regulated by molecules also involved in reorganization of the actin cytoskeleton, including formins FMNL1 and DIA1 (4) and ρ GTP-ases RAC1 (4), Cdc42 (3), and its effector IQGAP1 (6). PMID:20634814 MTOC polarization also requires proteins such as CDC42 (cell-division cycle 42)69 and its effectors IQGAP1 (IQ motif-containing GTPase-activating protein 1)62,70 and CIP4 (CDC42-interacting protein 4), as well as the function of the formins formin-like 1 and diaphanous 1, which link microtubules and the peripheral actin networks at the cytotoxic synapse71,72.</body> </html> </notes> <label text="Centrosome polarization"/> <bbox w="210.0" h="37.5" x="4525.0" y="6601.25"/> </glyph> <glyph class="macromolecule" id="s5598_sa440" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PXN CASCADE:TCR MODULE:TCR_SIGNALING PMID:22043013 Paxillin associates with the microtubule cytoskeleton and the immunological synapse of CTL through its leucine-aspartic acid domains and contributes to microtubule organizing center reorientation. LFA-1 or CD3 engagement alone was insufficient for paxillin recruitment because there was no paxillin accumulation at the site of CTL contact with anti-LFA-1- or anti-CD3-coated beads. In contrast, paxillin accumulation was detected when beads coated with both anti-CD3 and anti-LFA-1 were bound to CTL, suggesting that signals from both the TCR and LFA-1 are required for paxillin accumulation. Paxillin was shown to be phosphorylated downstream of ERK, paxillin was demonstrated to be a direct target of ERK phosphorylation PMID:29021139 Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors</body> </html> </notes> <label text="PXN"/> <bbox w="80.0" h="40.0" x="4780.0" y="5355.0"/> <glyph class="state variable" id="_791aa8bf-431e-46ba-8e10-02a42f2fdacc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4772.5" y="5370.0"/> </glyph> </glyph> <glyph class="complex" id="s5602_csa140" compartmentRef="c2_ca2"> <label text="s5602"/> <bbox w="100.0" h="120.0" x="4790.0" y="5610.0"/> <glyph class="macromolecule" id="s5603_sa1185"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CDC42 PMID:7761442 Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Overexpression of dominant negative forms of Cdc42 prevents centrosome polarization, but actin polymerization is unaffected PMID:22821962 Cytokine Secretion by CD4+ T Cells at the Immunological Synapse Requires Cdc42-Dependent Local Actin Remodeling but Not Microtubule Organizing Center Polarity</body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="4800.0" y="5620.0"/> </glyph> <glyph class="simple chemical" id="s5604_sa1194"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="4805.0" y="5667.5"/> </glyph> </glyph> <glyph class="complex" id="s5605_csa141" compartmentRef="c2_ca2"> <label text="s5605"/> <bbox w="100.0" h="120.0" x="5180.0" y="5605.0"/> <glyph class="macromolecule" id="s5593_sa1191"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CDC42 PMID:7761442 Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Overexpression of dominant negative forms of Cdc42 prevents centrosome polarization, but actin polymerization is unaffected PMID:22821962 Cytokine Secretion by CD4+ T Cells at the Immunological Synapse Requires Cdc42-Dependent Local Actin Remodeling but Not Microtubule Organizing Center Polarity</body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="5190.0" y="5615.0"/> </glyph> <glyph class="simple chemical" id="s5606_sa1195"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <bbox w="62.5" h="26.25" x="5198.75" y="5661.875"/> </glyph> </glyph> <glyph class="macromolecule" id="s5607_sa1196" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING PMID:19349987 Both ROCK and MLCK phosphorylate and activate MLC and both ML7 and Y27632 inhibited phosphorylation of MLC during T cell stimulation with soluble TCR antibody PMID:27785353 RhoA-ROCK pathway is activated downstream of chemokine receptors such as CXCL12 in T cells PMID:11698448 A Role for a RhoA/ROCK/LIM-Kinase Pathway in the Regulation of Cytotoxic Lymphocytes ROCK inhibition in a a human CD8+ cytotoxic T cell line showed a similar dose-dependent inhibition of cell-mediated killing of anti-CD3-coated P815 (data not shown) Probably via LiMK. PMID:10652353 Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop (in vitro assay)</body> </html> </notes> <label text="ROCK1"/> <bbox w="80.0" h="40.0" x="5060.0" y="3955.0"/> </glyph> <glyph class="complex" id="s5611_csa142" compartmentRef="c2_ca2"> <label text="s5611"/> <bbox w="100.0" h="120.0" x="4697.5" y="3640.0"/> <glyph class="macromolecule" id="s5609_sa1198"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:PTPN12 PMID:14707117 mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation.</body> </html> </notes> <label text="PTPN12"/> <bbox w="80.0" h="40.0" x="4707.5" y="3660.0"/> </glyph> <glyph class="macromolecule" id="s5610_sa1199"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:PSTPIP1 PMID:14707117 both WASp and PTP-PEST coimmunoprecipitated with PSTPIP1. PTP-PEST was also detected in WASp immunoprecipitates from stimulated T cells (Fig. 4 B), but recombinant WASp and PST-PEST did not associate in an in vitro binding assay, suggesting that their interaction is indirect and possibly mediated via PSTPIP1.</body> </html> </notes> <label text="PSTPIP1"/> <bbox w="80.0" h="40.0" x="4707.5" y="3700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5612_sa1200" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PPP1CA HUGO:PPP1CB HUGO:PPP1CC MODULE:TCR_SIGNALING PMID:11093160 Following co-stimulation through accessory receptors (e.g. CD2 or CD28) - however, not following TCR/CD3 stimulation alone - cofilin undergoes dephosphorylation. The subcellular localization as well as the actin-binding activity of cofilin are regulated by the phosphorylation state of serine-3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM-kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation.</body> </html> </notes> <label text="PP1*"/> <bbox w="80.0" h="40.0" x="5130.0" y="5995.0"/> </glyph> <glyph class="macromolecule" id="s5614_sa1203" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:LIMK1 PMID:11698448 A Role for a RhoA/ROCK/LIM-Kinase Pathway in the Regulation of Cytotoxic Lymphocytes ROCK inhibition in a a human CD8+ cytotoxic T cell line showed a similar dose-dependent inhibition of cell-mediated killing of anti-CD3-coated P815 (data not shown) Probably via LiMK. PMID: 11784854 Stromal cell-derived factor 1alpha activates LIM kinase 1 and induces cofilin phosphorylation for T-cell chemotaxis. PMID:10652353 Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop (in vitro assay)</body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="5080.0" y="4975.0"/> <glyph class="state variable" id="_fa008219-1775-4cd7-995a-17a8b76e339a"> <state value="" variable="Thr508"/> <bbox w="40.0" h="10.0" x="5061.91" y="4970.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5615_sa1202" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:LIMK1 PMID:11698448 A Role for a RhoA/ROCK/LIM-Kinase Pathway in the Regulation of Cytotoxic Lymphocytes ROCK inhibition in a a human CD8+ cytotoxic T cell line showed a similar dose-dependent inhibition of cell-mediated killing of anti-CD3-coated P815 (data not shown) Probably via LiMK. PMID: 11784854 Stromal cell-derived factor 1alpha activates LIM kinase 1 and induces cofilin phosphorylation for T-cell chemotaxis. PMID:10652353 Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop (in vitro assay)</body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="5080.0" y="5065.0"/> <glyph class="state variable" id="_dc71c467-1213-488e-843a-bc191a294dd7"> <state value="P" variable="Thr508"/> <bbox w="45.0" h="10.0" x="5059.41" y="5060.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5617_sa1201" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PPP2CA HUGO:PPP2CB MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING MODULE:SMAC PMID:11093160 Following co-stimulation through accessory receptors (e.g. CD2 or CD28) - however, not following TCR/CD3 stimulation alone - cofilin undergoes dephosphorylation. The subcellular localization as well as the actin-binding activity of cofilin are regulated by the phosphorylation state of serine-3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM-kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation.</body> </html> </notes> <label text="PP2A*"/> <clone/> <bbox w="80.0" h="40.0" x="5290.0" y="5995.0"/> </glyph> <glyph class="macromolecule" id="s5617_sa1205" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PPP2CA HUGO:PPP2CB MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING MODULE:SMAC PMID:11093160 Following co-stimulation through accessory receptors (e.g. CD2 or CD28) - however, not following TCR/CD3 stimulation alone - cofilin undergoes dephosphorylation. The subcellular localization as well as the actin-binding activity of cofilin are regulated by the phosphorylation state of serine-3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM-kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation.</body> </html> </notes> <label text="PP2A*"/> <clone/> <bbox w="80.0" h="40.0" x="1190.0" y="1490.0"/> </glyph> <glyph class="macromolecule" id="s5618_sa1207" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:PD1 HUGO:PTPN6 MODULE:INHIBITING_CHECKPOINTS PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN6"/> <bbox w="80.0" h="40.0" x="1200.0" y="1220.0"/> </glyph> <glyph class="complex" id="s5619_csa143" compartmentRef="c8_ca8"> <label text="s5619"/> <bbox w="100.0" h="120.0" x="2730.0" y="865.0"/> <glyph class="macromolecule" id="s5620_sa191"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CTLA4 CELL:CD4 CELL:TREG MODULE:SMAC CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS 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:22116087 CTLA4 has been reported to recruit phosphatases — such as protein phosphatase 2A (PP2A)72,73 and SYP (also known as PTPN11)74 — and to decrease the phosphorylation of several key proteins in the TCR signalling cascade, including CD3ζ and linker for activation of T cells (LAT). PMID:16227604 similarly constructed CD3/CD28/PD-1 aAPCs inhibited T-cell expansion and IL-2 production as well as CD3/CD28/CTLA-4-coated beads. CTLA-4 and PD-1 ablate the effect of costimulation on glucose uptake in T lymphocytes. PD-1 signaling blocks CD28-mediated activation of PI3K and Akt. CTLA-4 ligation blocks Akt but not PI3K activation. PD-1 suppression of PI3K/Akt is dependent upon factors binding to the ITSM motif in its cytoplasmic tail. CTLA-4-mediated suppression of Akt phosphorylation is inhibited by the PP2A inhibitor okadaic acid.</body> </html> </notes> <label text="CTLA4"/> <bbox w="80.0" h="50.0" x="2740.0" y="870.0"/> <glyph class="unit of information" id="_bc312c3f-ed7e-4d20-9a55-d2f81b4b62b9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2757.5" y="865.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5621_sa1208"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PPP2CA HUGO:PPP2CB MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING MODULE:SMAC PMID:11093160 Following co-stimulation through accessory receptors (e.g. CD2 or CD28) - however, not following TCR/CD3 stimulation alone - cofilin undergoes dephosphorylation. The subcellular localization as well as the actin-binding activity of cofilin are regulated by the phosphorylation state of serine-3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM-kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation.</body> </html> </notes> <label text="PP2A*"/> <bbox w="80.0" h="40.0" x="2740.0" y="925.0"/> </glyph> </glyph> <glyph class="complex" id="s5622_csa144" compartmentRef="c2_ca2"> <label text="s5622"/> <bbox w="110.0" h="180.0" x="1765.0" y="1060.0"/> <glyph class="macromolecule" id="s5623_sa187"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:PDCD1 CASCADE:PD1 CASCADE:TCR PMID:27806234 REW PMID:22437870 PMID:26885856 GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM SHP-2 is recruited to the PD-1 cytoplasmic tail in absence of receptor ligation ITSM of PD-1 does not recruit SH2D1A PMID:23732914 PD-1 Increases PTEN Phosphatase Activity While Decreasing PTEN Protein Stability by Inhibiting Casein Kinase 2 PMID:28893624 Frequencies of PD-1+ TIGIT+ CD226− CD8+ T cells are increased in AML patients and correlate with poor clinical prognosis. PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="PDCD1"/> <bbox w="80.0" h="50.0" x="1775.0" y="1075.0"/> <glyph class="unit of information" id="_3051bc61-3832-4252-b8f5-575042896ec8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1792.5" y="1070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5624_sa1209"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:PD1 HUGO:PTPN11 MODULE:INHIBITING_CHECKPOINTS PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement CD247 chain has been reported to be a substrate of SHP-2 in T cells (12), we examined the phosphorylation levels of CD267 in these lines after TCR engagement by immunoprecipitation with anti-CD247 mAb,followed by blotting with anti-PY mAb. As shown in Fig. 3 D, the phosphorylation levels of theCD247 chain were attenuated by Gab2(WT) expression but not by Gab2(Y614F). Therefore, the inhibitory function of Gab2 is mediated, at least in part, through SHP-2-dependent dephosphorylation of the CD247 chain. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="1775.0" y="1170.0"/> </glyph> <glyph class="macromolecule" id="s5625_sa1210"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:PD1 HUGO:PTPN6 MODULE:INHIBITING_CHECKPOINTS PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN6"/> <bbox w="80.0" h="40.0" x="1775.0" y="1130.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5626_sa1211" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CSNK2A1 HUGO:CSNK2A2 HUGO:CSNK2B CASCADE:PD1 CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS PMID:23732914 PD-1 Increases PTEN Phosphatase Activity While Decreasing PTEN Protein Stability by Inhibiting Casein Kinase 2 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β</body> </html> </notes> <label text="CK2*"/> <bbox w="80.0" h="40.0" x="2200.0" y="1435.0"/> </glyph> <glyph class="macromolecule" id="s5627_sa1212" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PTEN CASCADE:TCR CASCADE:PD1 MODULE:TCR_SIGNALING PMID:16982858 An additional level of regulation is provided by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (13), which does not act on PI3K directly, but rather dephosphorylates PIP3 on the 3′ position to regenerate PIP2, thus limiting the amount of available PI3K product PTEN-deficient CD4+ T cells are hyperresponsive to TCR stimulation. Augmented response of PTENΔT T cells is correlated with enhanced activation of the PI3K pathway PTEN regulates anergy induction in vitro and in vivo PMID:23732914 during T cell receptor (TCR)/CD3- and CD28-mediated stimulation, PTEN is phosphorylated by casein kinase 2 (CK2) in the Ser380-Thr382-Thr383 cluster within the C-terminal regulatory domain, which stabilizes PTEN, resulting in increased protein abundance but suppressed PTEN phosphatase activity. PD-1 inhibited the stabilizing phosphorylation of the Ser380-Thr382-Thr383 cluster within the C-terminal domain of PTEN, thereby resulting in ubiquitin-dependent degradation and diminished abundance of PTEN protein but increased PTEN phosphatase activity.</body> </html> </notes> <label text="PTEN"/> <bbox w="80.0" h="40.0" x="4770.0" y="1725.0"/> <glyph class="state variable" id="_87e2f928-91ed-4001-a169-e8143be506fc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4762.5" y="1740.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5630_sa1215" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CSNK2A1 HUGO:CSNK2A2 HUGO:CSNK2B CASCADE:PD1 CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS PMID:23732914 Because our studies showed that T cells displayed a low steady-state level of CK2 protein, which was upregulated by stimulation via TCR/CD3 and CD28, we examined whether CK2 expression was regulated at the level of mRNA. Real-time quantitative PCR showed that CK2 mRNA was increased after T cell activation.</body> </html> </notes> <label text="CK2*"/> <bbox w="90.0" h="25.0" x="2045.0" y="1437.5"/> <glyph class="unit of information" id="_3c950563-0d3d-4b2d-a3c2-93af01f3df46"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2080.0" y="1432.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5631_sa1216" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CSNK2A1 HUGO:CSNK2A2 HUGO:CSNK2B CASCADE:PD1 CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS PMID:23732914 Because our studies showed that T cells displayed a low steady-state level of CK2 protein, which was upregulated by stimulation via TCR/CD3 and CD28, we examined whether CK2 expression was regulated at the level of mRNA. Real-time quantitative PCR showed that CK2 mRNA was increased after T cell activation. However, at all time intervals of culture, CK2 mRNA levels were significantly lower in T cells receiving PD-1 signals than in T cells stimulated by TCR/CD3 and CD28 without PD-1</body> </html> </notes> <label text="CK2"/> <bbox w="70.0" h="25.0" x="2055.0" y="1497.5"/> </glyph> <glyph class="macromolecule" id="s5632_sa1217" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:FOXO1 PMID:25464856 AKT phosphorylation inhibits the nuclear activity of FoxO transcription factors, namely FoxO1, which positively regulates several genes involved in naïve and memory T cell survival and trafficking including Il7ra, Ccr7, Klf2, Sell (CD62L), Tcf7, Eomes and Bcl2 Expression and nuclear retention of the transcription factor, FoxO1, is enhanced in exhausted CD8+ T cells FoxO1 binds to and promotes the expression of PD-1 in CD8+ T cells</body> </html> </notes> <label text="FOXO1"/> <bbox w="80.0" h="40.0" x="1600.0" y="900.0"/> </glyph> <glyph class="nucleic acid feature" id="s5634_sa1219" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:LAG3 PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection. PMID:26013006 IL-27 stimulation of Tregs induced expression of Lag3 qPCR analysis confirmed that IL-27 upregulated Tbx21, Lag3, Ccl3, Ccl4, and Il10 expression PMID:20385810 Expression of LAG-3 and on CD8+ T cells was up-regulated by IL-10, IL-6</body> </html> </notes> <label text="LAG3"/> <bbox w="70.0" h="25.0" x="455.0" y="837.5"/> </glyph> <glyph class="nucleic acid feature" id="s5635_sa1220" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:LAG3 PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection. PMID:26013006 IL-27 stimulation of Tregs induced expression of Lag3 qPCR analysis confirmed that IL-27 upregulated Tbx21, Lag3, Ccl3, Ccl4, and Il10 expression PMID:20385810 Expression of LAG-3 and on CD8+ T cells was up-regulated by IL-10, IL-6</body> </html> </notes> <label text="LAG3"/> <bbox w="90.0" h="25.0" x="445.0" y="777.5"/> <glyph class="unit of information" id="_9f069b0b-b7e7-4c71-9959-4bc506d4b79c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="480.0" y="772.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5636_sa1221" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:BTLA PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection. PMID:12796776 expression of BTLA mRNA is partially dependent on STAT1</body> </html> </notes> <label text="BTLA"/> <bbox w="70.0" h="25.0" x="1065.0" y="1137.5"/> </glyph> <glyph class="nucleic acid feature" id="s5637_sa1222" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:BTLA PMID:12796776 expression of BTLA mRNA is partially dependent on STAT1</body> </html> </notes> <label text="BTLA"/> <bbox w="90.0" h="25.0" x="1055.0" y="1077.5"/> <glyph class="unit of information" id="_ecccaa4b-e189-4f50-a49f-b353fd8394bc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1090.0" y="1072.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5638_sa1223" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD160 PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection.</body> </html> </notes> <label text="CD160"/> <bbox w="70.0" h="25.0" x="1215.0" y="937.5"/> </glyph> <glyph class="nucleic acid feature" id="s5639_sa1224" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD160 PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection</body> </html> </notes> <label text="CD160"/> <bbox w="90.0" h="25.0" x="1205.0" y="877.5"/> <glyph class="unit of information" id="_1935cc91-5adb-499a-ac41-75c292741563"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1240.0" y="872.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5640_sa1225" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 HUGO:KLRG1 MODULE:INHIBITING_CHECKPOINTS PMID:27557510 KLRG1 expression on T cells significantly increased in tumor microenvironment. KLRG1+ T cells exhibited poor proliferative capacity with decreased effector cytokine production. PMID:17307799 KLRG1 contains one ITIM motif in its cytoplasmic domain, which mediates its effects through the recruitment of SHIP-1 and SHP-2 phosphatases and a tyrosine residue at position 7 in the ITIM KLRG1 recruits both SHIP-1 and SHP-2 but not SHP-1 in T cell hybridoma DO11 KLRG1 ligation partially inhibits T cell activation. partial inhibition of IL-2 production and TGFB production PMID:19406987; PMID:19479342 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1 senescence-associated receptor KLRG1 PMID: 27557510 KLRG1 expression on T cells significantly increased in tumor microenvironment. KLRG1+ T cells exhibited poor proliferative capacity with decreased effector cytokine production. Meanwhile, KLRG1+ T cells expressed abundant pro-inflammatory cytokines and demonstrated high level of Foxp3 expression. KLRG1+ T cells showed decreased expression of miRNA-101 and higher expression of CtBP2. We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="KLRG1"/> <bbox w="80.0" h="50.0" x="880.0" y="670.0"/> <glyph class="unit of information" id="_98ba5dee-be6b-484d-b82e-00ce0d517639"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="897.5" y="665.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5641_sa1226" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:KLRG1 PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection.</body> </html> </notes> <label text="KLRG1"/> <bbox w="70.0" h="25.0" x="965.0" y="1137.5"/> </glyph> <glyph class="nucleic acid feature" id="s5642_sa1227" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:KLRG1 PMID: 21623380 T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Increased T-bet expression using the retroviral overexpression approach in P14 cells increased KLRG-1 expression (Fig. 8c), but repressed Lag-3, CD160, and BTLA along with PD-1 during chronic LCMV infection.</body> </html> </notes> <label text="KLRG1"/> <bbox w="90.0" h="25.0" x="955.0" y="1077.5"/> <glyph class="unit of information" id="_d509a37d-cf96-4451-a139-0f0ef1d0189b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="990.0" y="1072.5"/> </glyph> </glyph> <glyph class="complex" id="s5647_csa145" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:21263073 Among the three components of type I IFN-induced ISGF3 (STAT1, STAT2, and cytosolic IRF9), IRF9 contains the DNA-binding motif for ISRE. The chromatin precipitated by anti–IRF-9 was enriched in the PD-1 promoter of IFN-α–treated, but not nontreated, T cells, suggesting that the ISGF3 complex bound directly to the PD-1 promoter in activated primary T cells</body> </html> </notes> <label text="s5647"/> <bbox w="110.0" h="160.0" x="1585.0" y="975.0"/> <glyph class="macromolecule" id="s5633_sa1218"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:IFR9 PMID:21263073 IFN-α enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association IFN-responsive factor 9 (IRF9) to the IFN stimulation response element. Furthermore, PD-1 expression on Ag-specific CD8(+) T cells was augmented by IFN-α in vivo.</body> </html> </notes> <label text="IFR9"/> <bbox w="80.0" h="40.0" x="1595.0" y="1075.0"/> </glyph> <glyph class="macromolecule" id="s5645_sa1232"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:STAT2 PMID:21263073 Among the three components of type I IFN-induced ISGF3 (STAT1, STAT2, and cytosolic IRF9), IRF9 contains the DNA-binding motif for ISRE. The chromatin precipitated by anti–IRF-9 was enriched in the PD-1 promoter of IFN-α–treated, but not nontreated, T cells, suggesting that the ISGF3 complex bound directly to the PD-1 promoter in activated primary T cells</body> </html> </notes> <label text="STAT2"/> <bbox w="80.0" h="40.0" x="1595.0" y="985.0"/> </glyph> <glyph class="macromolecule" id="s5648_sa1233"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:STAT1 PMID:21263073 Among the three components of type I IFN-induced ISGF3 (STAT1, STAT2, and cytosolic IRF9), IRF9 contains the DNA-binding motif for ISRE. The chromatin precipitated by anti–IRF-9 was enriched in the PD-1 promoter of IFN-α–treated, but not nontreated, T cells, suggesting that the ISGF3 complex bound directly to the PD-1 promoter in activated primary T cells PMID:12796776 expression of BTLA mRNA is partially dependent on STAT1</body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="1595.0" y="1035.0"/> <glyph class="state variable" id="_7b66ba14-1838-4228-9c3e-f5473adbad0b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1590.0" y="1050.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5649_sa1234" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CRTAM CELL:TCD8 CELL:NKT CELL:TCD4 MODULE:ACTIVATING_CHECKPOINTS PMID:22285893 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells CD226 and CRTAM promote NK and CD8 T cell function, where as TIGIT has an inhibitory function. PMID:26694968 CRTAM determines the CD4+ cytotoxic T lymphocyte lineage CRTAM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM+ T cells are the precursor of CD4+CTL. http://www.jidonline.org/article/S0022-202X(17)30474-8/fulltext CRTAM (class I restricted T cell associated molecule), a CADM1 ligand, is expressed on activated CD8+ T cells Tumor cells suppress CRTAM expression on CD8+ T cells to evade host immunity in adult T cell leukemia/lymphoma PMID:15811952 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM Stimulation of a human polyclonal T-cell line with PMA/ionomycin induced expression of CRTAM on CD8+ T cells after 4 hours of stimulation CRTAM expression on NK cells and CD8+ T cells is tightly regulated by NK cell–activating receptors and T-cell receptor (TCR) triggering, respectively. Necl-2–CRTAM interaction leads to strong IFN-γ secretion by CD8+ T cells. NK cells play a crucial role in clearing Necl-2–expressing tumors in vivo. Crtam Assembles a Scrib-Containing Complex that Controls T Cell Polarity 12 hr after TCR Activation Crtam interacts with Scrib to provide a scaffolding to colocalize Cdc42 and PKCz Knockdown of Scrib protein resulted in loss of Talin and Crtam polarization 8 hr following anti-CD3/28 mAb crosslinking (Figure 6B) as well as inhibition of TCR-mediated IFNgand IL22, but not IL2, production</body> </html> </notes> <label text="CRTAM"/> <bbox w="80.0" h="50.0" x="5060.0" y="815.0"/> <glyph class="unit of information" id="_6e441a69-791a-4079-b8f1-911c42def864"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5077.5" y="810.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5653_sa227" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 HUGO:CD226 MODULE:ACTIVATING_CHECKPOINTS PMID:22285893 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells CD226 and TIGIT may control CD8 T cell effector function through mechanisms analogous to that of CD28/CTLA-4 interactions with CD80/86. CD226 and CRTAM promote NK and CD8 T cell function, where as TIGIT has an inhibitory function. PMID:12913096 Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule (NK model) DNAM-1 Contributes to NK-mediated Lysis of Tumor Cells. PMID:19029380; PMID:8673704; PMID:26840537 DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. (T-cell models) DNAM-1 blockade inhibits T cell priming PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. multiple Src family kinases, including not only Fyn but also Lyn, Src, and Lck, were able to trigger DNAM-1 tyrosine phosphorylation. PMID:10591186; PMID:14676297 LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. CD226 (DNAM-1) Is Involved in Lymphocyte Function–associated Antigen 1 Costimulatory Signal for Naive T Cell Differentiation and Proliferation Upon antigen recognition by the T cell receptor, lymphocyte function–associated antigen 1 (LFA-1) physically associates with the leukocyte adhesion molecule CD226 (DNAM-1) and the protein tyrosine kinase Fyn. proliferation induced by LFA-1 costimulatory signal was suppressed in mutant (Y-F322) CD226-transduced naive CD4+ and CD8+ T cells in the absence of IL-2. These results suggest that CD226 is involved in LFA-1–mediated costimulatory signals for triggering naive T cell differentiation and proliferation. PMID:24337740 DNAM-1 interacts with LFA-1, a critical molecule for immunological synapse formation between T cells and APCs, and for cytotoxic killing of target cells. Mice that lack DNAM-1 display abnormal T cell responses and antitumor activity; DNAM-1 deficiency results in reduced proliferation of CD8+ T cells after Ag presentation and impaired cytotoxic activity. We also demonstrate that DNAM-1–deficient T cells show reduced conjugations with tumor cells and decreased recruitment of both LFA-1 and lipid rafts to the immunological synapse, which correlates with reduced tumor cell killing in vitro. This synapse defect may explain why DNAM-1–deficient mice cannot clear tumors in vivo, and highlights the importance of DNAM-1 and the immunological synapse in T cell–mediated antitumor immunity. PMID:24658051 CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. PMID:28893624 Frequencies of PD-1+ TIGIT+ CD226− CD8+ T cells are increased in AML patients and correlate with poor clinical prognosis.</body> </html> </notes> <label text="CD226"/> <bbox w="80.0" h="50.0" x="5440.0" y="695.0"/> <glyph class="state variable" id="_b3fd8f4a-5d3d-4fbc-95b1-658ec41db65c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5435.0" y="715.0"/> </glyph> <glyph class="unit of information" id="_794baeb9-296f-4465-ad32-ad9e1c9b2991"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5457.5" y="690.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5654_sa1235" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:NECTIN1 PMID:22285893 CD111</body> </html> </notes> <label text="NECTIN1"/> <bbox w="80.0" h="40.0" x="250.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s5656_sa1237" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:NECTIN3 PMID:22285893 CD113</body> </html> </notes> <label text="NECTIN3"/> <bbox w="80.0" h="40.0" x="350.0" y="380.0"/> </glyph> <glyph class="macromolecule" id="s5658_sa1240" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:CADM1 PMID:22285893 NECL2 http://www.jidonline.org/article/S0022-202X(17)30474-8/fulltext CRTAM (class I restricted T cell associated molecule), a CADM1 ligand, is expressed on activated CD8+ T cells Tumor cells suppress CRTAM expression on CD8+ T cells to evade host immunity in adult T cell leukemia/lymphoma PMID:15811952 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM</body> </html> </notes> <label text="CADM1"/> <bbox w="80.0" h="40.0" x="5030.0" y="470.0"/> </glyph> <glyph class="macromolecule" id="s5661_sa228" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 HUGO:CD226 MODULE:ACTIVATING_CHECKPOINTS PMID:22285893 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells CD226 and TIGIT may control CD8 T cell effector function through mechanisms analogous to that of CD28/CTLA-4 interactions with CD80/86. CD226 and CRTAM promote NK and CD8 T cell function, where as TIGIT has an inhibitory function. PMID:12913096 Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule (NK model) DNAM-1 Contributes to NK-mediated Lysis of Tumor Cells. PMID:19029380; PMID:8673704; PMID:26840537 DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. (T-cell models) DNAM-1 blockade inhibits T cell priming PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. multiple Src family kinases, including not only Fyn but also Lyn, Src, and Lck, were able to trigger DNAM-1 tyrosine phosphorylation. PMID:10591186; PMID:14676297 LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. CD226 (DNAM-1) Is Involved in Lymphocyte Function–associated Antigen 1 Costimulatory Signal for Naive T Cell Differentiation and Proliferation Upon antigen recognition by the T cell receptor, lymphocyte function–associated antigen 1 (LFA-1) physically associates with the leukocyte adhesion molecule CD226 (DNAM-1) and the protein tyrosine kinase Fyn. proliferation induced by LFA-1 costimulatory signal was suppressed in mutant (Y-F322) CD226-transduced naive CD4+ and CD8+ T cells in the absence of IL-2. These results suggest that CD226 is involved in LFA-1–mediated costimulatory signals for triggering naive T cell differentiation and proliferation. PMID:24337740 DNAM-1 interacts with LFA-1, a critical molecule for immunological synapse formation between T cells and APCs, and for cytotoxic killing of target cells. Mice that lack DNAM-1 display abnormal T cell responses and antitumor activity; DNAM-1 deficiency results in reduced proliferation of CD8+ T cells after Ag presentation and impaired cytotoxic activity. We also demonstrate that DNAM-1–deficient T cells show reduced conjugations with tumor cells and decreased recruitment of both LFA-1 and lipid rafts to the immunological synapse, which correlates with reduced tumor cell killing in vitro. This synapse defect may explain why DNAM-1–deficient mice cannot clear tumors in vivo, and highlights the importance of DNAM-1 and the immunological synapse in T cell–mediated antitumor immunity. PMID:24658051 CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. PMID:28893624 Frequencies of PD-1+ TIGIT+ CD226− CD8+ T cells are increased in AML patients and correlate with poor clinical prognosis.</body> </html> </notes> <label text="CD226"/> <bbox w="80.0" h="50.0" x="5440.0" y="785.0"/> <glyph class="state variable" id="_eb729c10-ec17-4185-bfbe-e12639977042"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5432.5" y="805.0"/> </glyph> <glyph class="unit of information" id="_ceeb5535-d56f-4562-9e1a-4925dc58bb44"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5457.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5662_sa1243" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:LYN MODULE:ACTIVATING_CHECKPOINTS PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. multiple Src family kinases, including not only Fyn but also Lyn, Src, and Lck, were able to trigger DNAM-1 tyrosine phosphorylation.</body> </html> </notes> <label text="LYN"/> <bbox w="80.0" h="40.0" x="5500.0" y="960.0"/> </glyph> <glyph class="macromolecule" id="s5663_sa1244" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:SRC PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. multiple Src family kinases, including not only Fyn but also Lyn, Src, and Lck, were able to trigger DNAM-1 tyrosine phosphorylation.</body> </html> </notes> <label text="SRC"/> <bbox w="80.0" h="40.0" x="5390.0" y="960.0"/> </glyph> <glyph class="nucleic acid feature" id="s5664_sa1245" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:CRTAM PMID:15811952 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM Stimulation of a human polyclonal T-cell line with PMA/ionomycin induced expression of CRTAM on CD8+ T cells after 4 hours of stimulation CRTAM expression on NK cells and CD8+ T cells is tightly regulated by NK cell–activating receptors and T-cell receptor (TCR) triggering, respectively.</body> </html> </notes> <label text="CRTAM"/> <bbox w="90.0" h="25.0" x="5125.0" y="887.5"/> <glyph class="unit of information" id="_5bc1d21f-2c98-4245-872d-e0adb7cfbb5f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5160.0" y="882.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5665_sa1247" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL22 MODULE:TCR_SIGNALING PMID:18329370 loss of Crtam resulted in decreased secretion of IFNg(a TH1-associated cytokine) as well as IL22 and IL17 (TH17-associated cytokines).</body> </html> </notes> <label text="ILL22"/> <bbox w="90.0" h="25.0" x="1725.0" y="6282.5"/> <glyph class="unit of information" id="_fbbb3734-28d1-47cc-bc38-7e53c8631015"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1760.0" y="6277.5"/> </glyph> </glyph> <glyph class="complex" id="s5667_csa146" compartmentRef="c2_ca2"> <label text="s5667"/> <bbox w="100.0" h="120.0" x="5020.0" y="1010.0"/> <glyph class="macromolecule" id="s5668_sa1236"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CRTAM CELL:TCD8 CELL:NKT CELL:TCD4 MODULE:ACTIVATING_CHECKPOINTS PMID:22285893 Immunoglobulin receptors that bind nectin and nectin-like proteins include CD226, TIGIT, CRTAM and CD96 All of these receptors are expressed on both NK cells and CD8 T cells CD226 and CRTAM promote NK and CD8 T cell function, where as TIGIT has an inhibitory function. PMID:26694968 CRTAM determines the CD4+ cytotoxic T lymphocyte lineage CRTAM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM+ T cells are the precursor of CD4+CTL. http://www.jidonline.org/article/S0022-202X(17)30474-8/fulltext CRTAM (class I restricted T cell associated molecule), a CADM1 ligand, is expressed on activated CD8+ T cells Tumor cells suppress CRTAM expression on CD8+ T cells to evade host immunity in adult T cell leukemia/lymphoma PMID:15811952 The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM Stimulation of a human polyclonal T-cell line with PMA/ionomycin induced expression of CRTAM on CD8+ T cells after 4 hours of stimulation CRTAM expression on NK cells and CD8+ T cells is tightly regulated by NK cell–activating receptors and T-cell receptor (TCR) triggering, respectively. Necl-2–CRTAM interaction leads to strong IFN-γ secretion by CD8+ T cells. NK cells play a crucial role in clearing Necl-2–expressing tumors in vivo. Crtam Assembles a Scrib-Containing Complex that Controls T Cell Polarity 12 hr after TCR Activation Crtam interacts with Scrib to provide a scaffolding to colocalize Cdc42 and PKCz Knockdown of Scrib protein resulted in loss of Talin and Crtam polarization 8 hr following anti-CD3/28 mAb crosslinking (Figure 6B) as well as inhibition of TCR-mediated IFNgand IL22, but not IL2, production</body> </html> </notes> <label text="CRTAM"/> <bbox w="80.0" h="50.0" x="5030.0" y="1015.0"/> <glyph class="unit of information" id="_94415ebf-2fef-485d-932e-7443b9669809"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5047.5" y="1010.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5666_sa1248"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 HUGO:SCRIB MODULE:ACTIVATING_CHECKPOINTS PMID:15811952 Crtam Assembles a Scrib-Containing Complex that Controls T Cell Polarity 12 hr after TCR Activation . Knockdown of Scrib protein resulted in loss of Talin and Crtam polarization 8 hr following anti-CD3/28 mAb crosslinking (Figure 6B) as well as inhibition of TCR-mediated IFNgand IL22, but not IL2, production</body> </html> </notes> <label text="SCRIB"/> <bbox w="80.0" h="40.0" x="5030.0" y="1070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5669_sa1249" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 HUGO:SCRIB MODULE:ACTIVATING_CHECKPOINTS PMID:15811952 Crtam Assembles a Scrib-Containing Complex that Controls T Cell Polarity 12 hr after TCR Activation . Knockdown of Scrib protein resulted in loss of Talin and Crtam polarization 8 hr following anti-CD3/28 mAb crosslinking (Figure 6B) as well as inhibition of TCR-mediated IFNgand IL22, but not IL2, production</body> </html> </notes> <label text="SCRIB"/> <bbox w="80.0" h="40.0" x="4950.0" y="820.0"/> </glyph> <glyph class="complex" id="s5672_csa147" compartmentRef="c2_ca2"> <label text="s5672"/> <bbox w="200.0" h="150.0" x="290.0" y="955.0"/> <glyph class="macromolecule" id="s5671_sa223"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 MODULE:INHIBITING_CHECKPOINTS PMID:26755705 CD112R, Identification of CD112R as a novel checkpoint for human T cells Signal through CD112R inhibits TCR-mediated signal SHIP was strongly associated with CD112R in untreated Molt4 cells, and pervanadate treatment further increased this interaction (Fig. 2 J). SHP-1 and SHP-2 weakly associated with CD112R in untreated Molt4 cells, but these associations were enhanced greatly upon pervanadate treatment when CD112R was used as a competitor, the CD112–CD226 interaction was significantly inhibited even in a relatively low concentration. Thus, our competition studies indicate that CD112R and CD226 share a common binding site on CD112. CD112 interacts with CD112R to suppress T cell response the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ</body> </html> </notes> <label text="PVRIG"/> <bbox w="80.0" h="50.0" x="300.0" y="960.0"/> <glyph class="state variable" id="_b2f0f694-87a8-4278-a633-1d3b8d29dfbe"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="292.5" y="980.0"/> </glyph> <glyph class="unit of information" id="_8c89f244-202f-494b-b9cb-c62db86c4a79"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="317.5" y="955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5674_sa1251"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:PD1 HUGO:PTPN6 MODULE:INHIBITING_CHECKPOINTS PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN6"/> <bbox w="80.0" h="40.0" x="400.0" y="965.0"/> </glyph> <glyph class="macromolecule" id="s5675_sa1252"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:PD1 HUGO:PTPN11 MODULE:INHIBITING_CHECKPOINTS PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement CD247 chain has been reported to be a substrate of SHP-2 in T cells (12), we examined the phosphorylation levels of CD267 in these lines after TCR engagement by immunoprecipitation with anti-CD247 mAb,followed by blotting with anti-PY mAb. As shown in Fig. 3 D, the phosphorylation levels of theCD247 chain were attenuated by Gab2(WT) expression but not by Gab2(Y614F). Therefore, the inhibitory function of Gab2 is mediated, at least in part, through SHP-2-dependent dephosphorylation of the CD247 chain. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="400.0" y="1015.0"/> </glyph> <glyph class="macromolecule" id="s5673_sa1253"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:INPP5D CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS 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:12421919 SHIP is tyrosine phosphorylated in response to CD28 and CD3 ligation in CEM and MOLT-4 cells (The human leukemic T cell lines Jurkat, CEM, MOLT-4, and HUT78) Differential expression of lipid phosphatases correlates with PKB phosphorylation levels availability of SHIP may determine the activity of the PI3K-dependent signaling cascades was confirmed by the expression of constitutively active membrane-localized SHIP construct which was sufficient to reduce both PKB-PH domain membrane localization and phosphorylation.</body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="300.0" y="1015.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5676_sa1254" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 MODULE:TCR_SIGNALING HUGO:IL5 PMID:1825141; PMID:2965306 The stacks contact the plasma membrane (Stinchcombe et al., 2006), which would lead to very focused secretion of cytokines. Interleukin 2 (IL2), IL4, IL5, and interferon-g are all secreted in a polarized manner toward the target APC by T-helpers PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ</body> </html> </notes> <label text="IL5"/> <bbox w="90.0" h="25.0" x="1545.0" y="6087.5"/> <glyph class="unit of information" id="_dc6fc277-24f8-4eb2-b54b-ea4e18c9bdf3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1580.0" y="6082.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5677_sa1255" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:IL13 PMID:26755705 the combinatory blockade of CD112R and TIGIT significantly promoted the secretion of cytokines, including IL-2, IL-5, IL-10, IL-13, and IFN-γ</body> </html> </notes> <label text="IL13"/> <bbox w="90.0" h="25.0" x="1665.0" y="6087.5"/> <glyph class="unit of information" id="_3f702977-4cda-451b-8a58-9a566ec04d50"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1700.0" y="6082.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5691_sa1267" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:HMGB1 PMID:27192565; PMID:22842346 Tim-3 ligands include soluble ligands (galectin-9 and HMGB1) and cell surface ligands (Ceacam-1 and Phosphatidyl serine [PtdSer]). (Data about HMGB frome innat immune module only)</body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="830.0" y="380.0"/> </glyph> <glyph class="simple chemical" id="s5692_sa1268" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS PMID:27192565; PMID:29308307 Tim-3 ligands include soluble ligands (galectin-9 and HMGB1) and cell surface ligands (Ceacam-1 and Phosphatidyl serine [PtdSer]).</body> </html> </notes> <label text="PtdSer"/> <bbox w="70.0" h="25.0" x="615.0" y="387.5"/> </glyph> <glyph class="macromolecule" id="s5693_sa1269" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CEACAM1 PMID:27192565; PMID:25363763 Tim-3 ligands include soluble ligands (galectin-9 and HMGB1) and cell surface ligands (Ceacam-1 and Phosphatidyl serine [PtdSer]).</body> </html> </notes> <label text="CEACAM1"/> <bbox w="80.0" h="40.0" x="720.0" y="380.0"/> </glyph> <glyph class="complex" id="s5694_csa149" compartmentRef="c2_ca2"> <label text="s5694"/> <bbox w="100.0" h="120.0" x="700.0" y="685.0"/> <glyph class="macromolecule" id="s5695_sa206"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:HAVCR2 MODULE:INHIBITING_CHECKPOINTS PMID:22437870; PMID:28900677 TIM3 rew PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 In the absence of ligandmediated Tim-3 signaling, Bat3 is bound to Tim-3 and blocks SH2 domain-binding sites in the Tim-3 tail. In this state, Bat3 recruits the catalytically active form of Lck, thereby forming an intracellular molecular complex with Tim-3 that preserves and potentially promotes T cell signaling.Galectin-9 and Ceacam-1 binding to Tim-3 leads to phosphorylation of Y256 and Y263 and release of Bat-3 from the Tim-3 tail, thereby promoting Tim-3-mediated T cell inhibition by allowing binding of SH2 domain-containing Src kinases and subsequent regulation of TCR signaling , Fyn binds to the same region on the Tim-3 tail as Bat3. Fyn has been implicated in the induction of T cell anergy (Davidson et al., 2007) and is known to be a key kinase to activate phosphoprotein associated with glycosphingolipid microdomains (PAG), which recruits Csk to suppress Lck function (Salmond et al., 2009; Smida et al., 2007). Because Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling PMID:16286920 The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Galectin-9 induces TH1 cell death through Tim-3 Galectin-9 eliminates IFN-γ-producing TH1 cells PMID:20819927 Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.</body> </html> </notes> <label text="HAVCR2"/> <bbox w="80.0" h="50.0" x="710.0" y="740.0"/> <glyph class="state variable" id="_73b27219-d19e-4587-a477-fcb0d9ae4b93"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="705.0" y="760.0"/> </glyph> <glyph class="unit of information" id="_db41c569-cd9c-4554-98dc-c7c4a31ff3cc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="727.5" y="735.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5696_sa1270"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 In the absence of ligandmediated Tim-3 signaling, Bat3 is bound to Tim-3 and blocks SH2 domain-binding sites in the Tim-3 tail. In this state, Bat3 recruits the catalytically active form of Lck, thereby forming an intracellular molecular complex with Tim-3 that preserves and potentially promotes T cell signaling.Galectin-9 and Ceacam-1 binding to Tim-3 leads to phosphorylation of Y256 and Y263 and release of Bat-3 from the Tim-3 tail, thereby promoting Tim-3-mediated T cell inhibition by allowing binding of SH2 domain-containing Src kinases and subsequent regulation of TCR signaling , Fyn binds to the same region on the Tim-3 tail as Bat3. Fyn has been implicated in the induction of T cell anergy (Davidson et al., 2007) and is known to be a key kinase to activate phosphoprotein associated with glycosphingolipid microdomains (PAG), which recruits Csk to suppress Lck function (Salmond et al., 2009; Smida et al., 2007). Because Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="BAG6"/> <bbox w="80.0" h="40.0" x="710.0" y="690.0"/> </glyph> </glyph> <glyph class="complex" id="s5697_csa150" compartmentRef="c2_ca2"> <label text="s5697"/> <bbox w="100.0" h="120.0" x="700.0" y="915.0"/> <glyph class="macromolecule" id="s94_sa207"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:HAVCR2 MODULE:INHIBITING_CHECKPOINTS PMID:22437870; PMID:28900677 TIM3 rew PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 In the absence of ligandmediated Tim-3 signaling, Bat3 is bound to Tim-3 and blocks SH2 domain-binding sites in the Tim-3 tail. In this state, Bat3 recruits the catalytically active form of Lck, thereby forming an intracellular molecular complex with Tim-3 that preserves and potentially promotes T cell signaling.Galectin-9 and Ceacam-1 binding to Tim-3 leads to phosphorylation of Y256 and Y263 and release of Bat-3 from the Tim-3 tail, thereby promoting Tim-3-mediated T cell inhibition by allowing binding of SH2 domain-containing Src kinases and subsequent regulation of TCR signaling , Fyn binds to the same region on the Tim-3 tail as Bat3. Fyn has been implicated in the induction of T cell anergy (Davidson et al., 2007) and is known to be a key kinase to activate phosphoprotein associated with glycosphingolipid microdomains (PAG), which recruits Csk to suppress Lck function (Salmond et al., 2009; Smida et al., 2007). Because Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling PMID:16286920 The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Galectin-9 induces TH1 cell death through Tim-3 Galectin-9 eliminates IFN-γ-producing TH1 cells PMID:20819927 Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.</body> </html> </notes> <label text="HAVCR2"/> <bbox w="80.0" h="50.0" x="710.0" y="970.0"/> <glyph class="state variable" id="_3602e8b3-c65b-4f7f-bc2e-38a98d770ff2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="702.5" y="990.0"/> </glyph> <glyph class="unit of information" id="_6fd64adf-035d-46e0-99b6-8259b3c8f46b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="727.5" y="965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5698_sa1271"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FYN CASCADE:TCR MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells PMID:10648627 Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="FYN"/> <bbox w="80.0" h="40.0" x="710.0" y="920.0"/> <glyph class="state variable" id="_f2446718-b2c8-4324-ac83-771ce6d955a4"> <state value="" variable="Y417"/> <bbox w="30.0" h="10.0" x="775.0" y="953.2294"/> </glyph> <glyph class="state variable" id="_a87368be-51c4-4d01-b7ab-a667b0af3c5e"> <state value="" variable="Y528"/> <bbox w="30.0" h="10.0" x="698.44604" y="915.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s5701_sa1274" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:JUNB PMID:12818166 the expression of JunB, a component of the AP-1 family induced after T cell activation, was reduced by 49% after B7S1 costimulation. On the other hand, there was little change in c-Jun expression (11% reduction) with B7S1-Ig treatment. JunB has been previously shown to bind to the IL-2 promoter (Boise et al., 1993 and JunB overexpression resulted in greater IL-2 production (our unpublished data). Since JunB is induced after T cell activation (Jain et al., 1995, the mechanism of which is unknown, B7S1 costimulation may result in inefficient JunB induction.</body> </html> </notes> <label text="JUNB"/> <bbox w="80.0" h="40.0" x="1690.0" y="4625.0"/> </glyph> <glyph class="nucleic acid feature" id="s5702_sa1275" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:JUNB PMID:12818166 the expression of JunB, a component of the AP-1 family induced after T cell activation, was reduced by 49% after B7S1 costimulation. On the other hand, there was little change in c-Jun expression (11% reduction) with B7S1-Ig treatment. JunB has been previously shown to bind to the IL-2 promoter (Boise et al., 1993 and JunB overexpression resulted in greater IL-2 production (our unpublished data). Since JunB is induced after T cell activation (Jain et al., 1995, the mechanism of which is unknown, B7S1 costimulation may result in inefficient JunB induction.</body> </html> </notes> <label text="JUNB"/> <bbox w="90.0" h="25.0" x="1685.0" y="4562.5"/> <glyph class="unit of information" id="_c7a3e1d2-dbbf-472c-b178-bb3ffa953969"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1720.0" y="4557.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5703_sa1278" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CDH1 MODULE:INHIBITING_CHECKPOINTS PMID:16424155 E-cadherin is a ligand for the murine killer cell lectin-like receptor G1. E-cadherin expression inhibits Ag-induced cell division and induction of cytolytic activity of CD8 T cells</body> </html> </notes> <label text="CDH1"/> <bbox w="80.0" h="40.0" x="1070.0" y="380.0"/> </glyph> <glyph class="complex" id="s5704_csa151" compartmentRef="c2_ca2"> <label text="s5704"/> <bbox w="100.0" h="170.0" x="870.0" y="810.0"/> <glyph class="macromolecule" id="s5707_sa1279"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 HUGO:KLRG1 MODULE:INHIBITING_CHECKPOINTS PMID:27557510 KLRG1 expression on T cells significantly increased in tumor microenvironment. KLRG1+ T cells exhibited poor proliferative capacity with decreased effector cytokine production. PMID:17307799 KLRG1 contains one ITIM motif in its cytoplasmic domain, which mediates its effects through the recruitment of SHIP-1 and SHP-2 phosphatases and a tyrosine residue at position 7 in the ITIM KLRG1 recruits both SHIP-1 and SHP-2 but not SHP-1 in T cell hybridoma DO11 KLRG1 ligation partially inhibits T cell activation. partial inhibition of IL-2 production and TGFB production PMID:19406987; PMID:19479342 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1 senescence-associated receptor KLRG1 PMID: 27557510 KLRG1 expression on T cells significantly increased in tumor microenvironment. KLRG1+ T cells exhibited poor proliferative capacity with decreased effector cytokine production. Meanwhile, KLRG1+ T cells expressed abundant pro-inflammatory cytokines and demonstrated high level of Foxp3 expression. KLRG1+ T cells showed decreased expression of miRNA-101 and higher expression of CtBP2. We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="KLRG1"/> <bbox w="80.0" h="50.0" x="880.0" y="820.0"/> <glyph class="unit of information" id="_7fdc6ca1-dbbd-4178-a1ea-0d1eb53e1290"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="897.5" y="815.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5705_sa1280"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:INPP5D CASCADE:TCR MODULE:INHIBITING_CHECKPOINTS 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:12421919 SHIP is tyrosine phosphorylated in response to CD28 and CD3 ligation in CEM and MOLT-4 cells (The human leukemic T cell lines Jurkat, CEM, MOLT-4, and HUT78) Differential expression of lipid phosphatases correlates with PKB phosphorylation levels availability of SHIP may determine the activity of the PI3K-dependent signaling cascades was confirmed by the expression of constitutively active membrane-localized SHIP construct which was sufficient to reduce both PKB-PH domain membrane localization and phosphorylation.</body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="880.0" y="875.0"/> </glyph> <glyph class="macromolecule" id="s5706_sa1281"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:PD1 HUGO:PTPN11 MODULE:INHIBITING_CHECKPOINTS PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement CD247 chain has been reported to be a substrate of SHP-2 in T cells (12), we examined the phosphorylation levels of CD267 in these lines after TCR engagement by immunoprecipitation with anti-CD247 mAb,followed by blotting with anti-PY mAb. As shown in Fig. 3 D, the phosphorylation levels of theCD247 chain were attenuated by Gab2(WT) expression but not by Gab2(Y614F). Therefore, the inhibitory function of Gab2 is mediated, at least in part, through SHP-2-dependent dephosphorylation of the CD247 chain. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="880.0" y="920.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5711_sa1285" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CCND2 PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1</body> </html> </notes> <label text="CCND2"/> <bbox w="80.0" h="40.0" x="1900.0" y="6555.0"/> </glyph> <glyph class="macromolecule" id="s5712_sa1286" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CCNE1 HUGO:CCNE2 MODULE:TCR_SIGNALING PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1</body> </html> </notes> <label text="CCNE*"/> <bbox w="80.0" h="40.0" x="2010.0" y="6555.0"/> </glyph> <glyph class="macromolecule" id="s5714_sa1288" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CDKN1B PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1</body> </html> </notes> <label text="CDKN1B"/> <bbox w="80.0" h="40.0" x="2120.0" y="6555.0"/> </glyph> <glyph class="nucleic acid feature" id="s5715_sa1289" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CDKN1B PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1</body> </html> </notes> <label text="CDKN1B"/> <bbox w="90.0" h="25.0" x="2115.0" y="6502.5"/> <glyph class="unit of information" id="_8108f061-cbad-4be2-8fa0-39e8d0fd0749"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2150.0" y="6497.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5716_sa1290" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CCNE1 HUGO:CCNE2 MODULE:TCR_SIGNALING PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1</body> </html> </notes> <label text="CCNE*"/> <bbox w="90.0" h="25.0" x="2005.0" y="6502.5"/> <glyph class="unit of information" id="_aa16b632-4a15-44ae-8a54-e4b54418d028"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2040.0" y="6497.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5717_sa1291" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:CCND2 PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1</body> </html> </notes> <label text="CCND2"/> <bbox w="90.0" h="25.0" x="1895.0" y="6502.5"/> <glyph class="unit of information" id="_28f63143-ca2b-45c6-8531-b7f790fa0b70"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1930.0" y="6497.5"/> </glyph> </glyph> <glyph class="complex" id="s5725_csa152" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID: 25893604 mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation PMID:18566586 Model for Akt regulation by mTORC2. mTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt. In the presence of growth factors, Akt is further phosphorylated at the HM (Ser473) and A-loop (Thr308) sites by mTORC2 and PDK1, respectively, leading to full activation of Akt.</body> </html> </notes> <label text="mTORC2*"/> <bbox w="230.0" h="210.0" x="4955.0" y="2170.0"/> <glyph class="macromolecule" id="s5718_sa1292"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MTOR CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells. two mTOR-dependent pathways that can negatively regulate FoxP3 expression whose loss may explain the increased FoxP3 expression in mTOR null T cells. First, HIF1α is induced by mTORC1 and has been shown to directly bind to FoxP3 protein and promote its ubiquitination and degradation (Dang et al., 2011). Second, the Foxo transcription factors directly bind to and transactivate the FoxP3 promoter, and they are inactivated in an mTORC2-dependent manner following phosphorylation by doubly phosphorylated activated AKT, leading to nuclear export of the Foxos [reviewed in Coffer and Burgering (2004)].</body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="4980.0" y="2195.0"/> <glyph class="state variable" id="_d5617ad9-c3ea-4383-b929-f3c617c87b6d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4975.0" y="2210.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5721_sa1294"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:RICTOR MODULE:TCR_SIGNALING 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="RICTOR"/> <bbox w="80.0" h="40.0" x="4975.0" y="2250.0"/> </glyph> <glyph class="macromolecule" id="s5722_sa1295"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:PRR5 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="PRR5"/> <bbox w="80.0" h="40.0" x="4975.0" y="2310.0"/> </glyph> <glyph class="macromolecule" id="s5723_sa1296"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MLST8 CASCADE:TCR MODULE:TCR_SIGNALING 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 PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="5070.0" y="2255.0"/> </glyph> <glyph class="macromolecule" id="s5724_sa1297"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAPKAP1 MODULE:TCR_SIGNALING 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="MAPKAP1"/> <bbox w="80.0" h="40.0" x="5070.0" y="2310.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1113_sa648" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:AKT1 HUGO:AKT2 HUGO:AKT3 CELL:CD8 MODULE:TH1 CASCADE:TCR CASCADE:CD226 CASCADE:PD1 MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:11135576 Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Phosphorylation of Akt induced by CD28 ligation via PI3K PMID:23087689 PMID:23732914 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1 PMID:16962653; PMID:18566586 TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. (not immune model)</body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="4910.0" y="2555.0"/> <glyph class="state variable" id="_65f6926d-a679-4df4-888a-10ff517a797a"> <state value="" variable="ser473"/> <bbox w="40.0" h="10.0" x="4970.0" y="2551.7705"/> </glyph> <glyph class="state variable" id="_8b8c01e4-f52c-4559-b935-32fae3b69725"> <state value="" variable="Thr308"/> <bbox w="40.0" h="10.0" x="4891.0273" y="2590.0"/> </glyph> <glyph class="state variable" id="_b1e9bce0-04aa-4e6e-bf22-d073c32c518c"> <state value="P" variable="Thr450"/> <bbox w="45.0" h="10.0" x="4967.5" y="2586.2788"/> </glyph> </glyph> <glyph class="macromolecule" id="s5726_sa1298" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:AKT1 HUGO:AKT2 HUGO:AKT3 CELL:CD8 MODULE:TH1 CASCADE:TCR CASCADE:CD226 CASCADE:PD1 MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:11135576 Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Phosphorylation of Akt induced by CD28 ligation via PI3K PMID:23087689 PMID:23732914 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1 PMID:16962653; PMID:18566586 TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. (not immune model)</body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="5050.0" y="2555.0"/> <glyph class="state variable" id="_0f358c12-d4b2-47b1-a843-46d9582fc917"> <state value="" variable="ser473"/> <bbox w="40.0" h="10.0" x="5110.0" y="2551.7705"/> </glyph> <glyph class="state variable" id="_83eba866-667f-4b3a-9422-94c5c8a7f26a"> <state value="" variable="Thr308"/> <bbox w="40.0" h="10.0" x="5031.0273" y="2590.0"/> </glyph> <glyph class="state variable" id="_2092933f-0551-4c3b-81d4-59aa61e20b38"> <state value="" variable="Thr450"/> <bbox w="40.0" h="10.0" x="5110.0" y="2586.2788"/> </glyph> </glyph> <glyph class="macromolecule" id="s5727_sa1301" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:AKT1 HUGO:AKT2 HUGO:AKT3 CELL:CD8 MODULE:TH1 CASCADE:TCR CASCADE:CD226 CASCADE:PD1 MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:11135576 Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Phosphorylation of Akt induced by CD28 ligation via PI3K PMID:23087689 PMID:23732914 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1 PMID:16962653; PMID:18566586 TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. 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Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="IL6"/> <bbox w="70.0" h="25.0" x="1885.0" y="5842.5"/> </glyph> <glyph class="nucleic acid feature" id="s5730_sa1304" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:IL6 MODULE:TCR_SIGNALING PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="IL6"/> <bbox w="90.0" h="25.0" x="1875.0" y="5912.5"/> <glyph class="unit of information" id="_77c06f72-d65f-419f-bc76-a414309852c0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1910.0" y="5907.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5731_sa647" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:AKT1 HUGO:AKT2 HUGO:AKT3 CELL:CD8 MODULE:TH1 CASCADE:TCR CASCADE:CD226 CASCADE:PD1 MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells PMID:11135576 Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Phosphorylation of Akt induced by CD28 ligation via PI3K PMID:23087689 PMID:23732914 Inhibition of CK2 during stimulation via TCR/CD3 and CD28 recapitulated the effects of PD-1 and resulted in diminished PTEN expression and phosphorylation in the C-terminal regulatory region. These events were associated with diminished activation of the PI3K/Akt pathway, as determined by impaired phosphorylation of Akt and its downstream target, GSK3β PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. PMID:19406987 Akt activation is controlled by phosphorylation at 2 different sites, Thr308 and Ser473 The blockade of KLRG1 signaling significantly enhanced the phosphorylation of Akt (ser473) in the CD28−CD27+ cells and CD28−CD27− cells KLRG1 blockade enhances CD8+ T-cell proliferation via the up-regulation of cyclin D2 and E and decrease of p27 expression KLRG1 mediates its effects via the PI3K pathway. Probably via SHIP1 PMID:16962653; PMID:18566586 TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. (not immune model)</body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="4760.0" y="2565.0"/> <glyph class="state variable" id="_9719b74c-2018-48bd-92c9-8bc23b0ea00c"> <state value="" variable="ser473"/> <bbox w="40.0" h="10.0" x="4820.0" y="2561.7705"/> </glyph> <glyph class="state variable" id="_f862f25c-746f-4a0b-9e2d-9a942a8a44d4"> <state value="P" variable="Thr308"/> <bbox w="45.0" h="10.0" x="4738.5273" y="2600.0"/> </glyph> <glyph class="state variable" id="_f4f87477-b78c-4188-be3e-7946c739065e"> <state value="P" variable="Thr450"/> <bbox w="45.0" h="10.0" x="4817.5" y="2596.2788"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5732_sa1306" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:IL18 PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="IL1B"/> <bbox w="70.0" h="25.0" x="1545.0" y="5842.5"/> </glyph> <glyph class="nucleic acid feature" id="s5733_sa1307" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:IL18 PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="IL1B"/> <bbox w="90.0" h="25.0" x="1525.0" y="5912.5"/> <glyph class="unit of information" id="_8fd0dbf1-4e01-42f1-a445-74e6927e2b02"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1560.0" y="5907.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5734_sa1308" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:IL18 PMID:27557510 We FACS sorted KLRG1 positive and negative T cells from PBMC and performed RT-PCR analysis. Our results showed significantly less expression of IL-2 and IL-17 in KLRG1+ CD4 T cells (Figure (Figure3B)3B) and IFN-γ and TNF-α in KLRG1+ CD8 T cells compared with their KLRG1− counterparts KLRG1+ T cells secreted significantly higher levels of IL-1b, IL-6 and IL-8 than KLRG1− T cells by RT-PCR analysis</body> </html> </notes> <label text="IL1B"/> <bbox w="80.0" h="40.0" x="1530.0" y="5990.0"/> </glyph> <glyph class="nucleic acid feature" id="s5735_sa1309" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD4 MODULE:TCR_SIGNALING HUGO:IL4 PMID:11160275 T cell prolipheration is dependent on IL2 and IL4 IκBα(ΔN) inhibition of the NF-κB/Rel pathway impairs the competence of T cells to respond to IL-4 growth signaling. the inhibitory effects of IκBα(ΔN) on IL-4 signaling pathways include decreased expression of selected target genes such as c-myc, IL4RA and IL2RB PMID:11371360 GADD45B was also highly expressed in TH1 versus TH2 cells the expression of this gene is both upregulated by TCR signaling and IL-12 but repressed by IL-4. PMID:1825141; PMID:2965306 The stacks contact the plasma membrane (Stinchcombe et al., 2006), which would lead to very focused secretion of cytokines. Interleukin 2 (IL2), IL4, IL5, and interferon-g are all secreted in a polarized manner toward the target APC by T-helpers PMID:12818165 By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. It inhibits IL-2, IL-4, IL-10, and IFN-γ secretion from B7-1 costimulated T cells.</body> </html> </notes> <label text="IL4"/> <bbox w="90.0" h="25.0" x="1585.0" y="6282.5"/> <glyph class="unit of information" id="_b1e8da4e-5ed2-4d29-b096-4c116d89fec1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1620.0" y="6277.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s5736_sa1310"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:22116345 The tumor microenvironment has high levels of adenosine as a result of hypoxia and ectopic expression of enzymes responsible for the generation of extracellular adenosine.</body> </html> </notes> <label text="Adenosine"/> <bbox w="70.0" h="25.0" x="2355.0" y="567.5"/> </glyph> <glyph class="macromolecule" id="s5738_sa622" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 MODULE:SMAC MODULE:TCR_SIGNALING HUGO:PRKCQ CASCADE:TCR PMID:23433459 PKCtheta in tregs. PMID:23886063; PMID:9738502 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta PMID:17544292 ; PMID:23433459 Protein kinase C theta (PKCtheta): a key player in T cell life and death. Mutation of the PKCθ gene leads to impaired receptor-induced stimulation of the transcription factors AP-1, NF-κB and NFAT, which results in defective T cell activation, and to aberrant expression of apoptosis-related proteins, resulting in poor T cell survival. Furthermore, PKCθ-deficient mice display defects in the differentiation of T helper subsets, particularly in Th2 and Th17-mediated inflammatory responses. The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation PMID: 10746729 The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:15536066 Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. PMID:10652356 The C2-like domain contains a tyrosine residue (Tyr-90), which is phosphorylated by the T cell tyrosine kinase Lck PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner PKCθ was required for the survival of both activated CD4 and CD8+ T cells</body> </html> </notes> <label text="PRKCQ"/> <clone/> <bbox w="80.0" h="40.0" x="3670.0" y="2185.0"/> <glyph class="state variable" id="_6b3442dc-c0a9-42f9-b8cb-90b5d8845977"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3665.0" y="2200.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5738_sa924" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TREG CELL:TCD4 CELL:TCD8 MODULE:SMAC MODULE:TCR_SIGNALING HUGO:PRKCQ CASCADE:TCR PMID:23433459 PKCtheta in tregs. PMID:23886063; PMID:9738502 The central region of the SMAC (cSMAC) is enriched in TCRs and one of its downstream signalling effectors, protein kinase C-teta PMID:17544292 ; PMID:23433459 Protein kinase C theta (PKCtheta): a key player in T cell life and death. Mutation of the PKCθ gene leads to impaired receptor-induced stimulation of the transcription factors AP-1, NF-κB and NFAT, which results in defective T cell activation, and to aberrant expression of apoptosis-related proteins, resulting in poor T cell survival. Furthermore, PKCθ-deficient mice display defects in the differentiation of T helper subsets, particularly in Th2 and Th17-mediated inflammatory responses. The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:23474202 The protein kinase PDK1 is considered essential for PKCθ activation GCK-like kinase (GLK), a SLP76-regulated kinase, was recently reported to phosphorylate directly PKCθ both in vitro and in primary T cells and T cell lines in response to TCR stimulation PMID: 10746729 The original analysis of PKCθ−/− T cells25 revealed that two transcription factors, i.e., nuclear factor κB (NF-κB) and activator protein-1 (AP-1) are targets of PKCθ in TCR/CD28-costimulated T cells, but failed to reveal any substantial defect in the activation of another critical transcription factor, i.e., nuclear factor of T cells (NFAT). PMID:15536066 Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. PMID:10652356; PMID:17544292 Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation PMID:15214048 TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta (-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca(2+) mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca(2+) signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells. PKCθ-deficient T cells displayed a reduced basal phosphorylation of Tec on tyrosine, and anti-CD3/CD28 stimulation failed to increase the phospho-tyrosine (pTyr) content of Tec (Fig. 6E). These results indicate that PKCθ is required for optimalTec activation. PMID:10652356 The C2-like domain contains a tyrosine residue (Tyr-90), which is phosphorylated by the T cell tyrosine kinase Lck PMID:15536066 Signal-dependent nuclear translocation of p50 and p65 is impaired in PKCθ–/– cells. NIK and IKKα Are Activated by TCR/CD28 Costimulation anti-CD3 stimulation alone could induce increased NIK autophosphorylation in Jurkat-E6.1 cells after 30 min of stimulation. Importantly, anti-CD3/CD28 costimulation induced NIK activity sooner than anti-CD3 stimulation alone The Non-canonical Pathway for NF-κB Activation Is Not Operative Downstream of TCR/CD28 Signaling PKCθ Operates Independently of NIK to Activate NF-κB kinase activity of NIK following PMA or anti-CD3/CD28 stimulation of PKCθ–/– T cells was identical to that observed in wild-type T cells We found that the TCR/CD28-dependent increase in p100 and p52 expression was impaired in PKCθ–/– T cells (Fig. 7C), indicating that PKCθ activity is required for p52 generation by TCR/CD28 signaling. This requirement most likely reflects an indirect role of PKCθ in up-regulating p100 in an NF-κB-dependent manner PKCθ was required for the survival of both activated CD4 and CD8+ T cells</body> </html> </notes> <label text="PRKCQ"/> <clone/> <bbox w="80.0" h="40.0" x="3670.0" y="2065.0"/> <glyph class="state variable" id="_81a29f3a-9d15-4b99-8a70-14f74e3fc5f6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3665.0" y="2080.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5739_sa644" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG CASCADE:TCR CASCADE:CD226 MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells Ligation of the T cell receptor for antigen (TCR) and/or costimulatory receptor CD28 results in rapid activation of phosphoinositide-3 kinase (PI-3 kinase). The primary mechanism for class IA PI-3 kinase activation by tyrosine kinase-coupled receptors is recruitment of the p85/p110 heterodimer to phosphorylated tyrosine kinase receptors via interaction of p85 Src homology 2 (SH2) domain(s) with phosphotyrosine moieties on the receptors PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="5250.0" y="1995.0"/> </glyph> <glyph class="macromolecule" id="s5739_sa645" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG CASCADE:TCR CASCADE:CD226 MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells Ligation of the T cell receptor for antigen (TCR) and/or costimulatory receptor CD28 results in rapid activation of phosphoinositide-3 kinase (PI-3 kinase). The primary mechanism for class IA PI-3 kinase activation by tyrosine kinase-coupled receptors is recruitment of the p85/p110 heterodimer to phosphorylated tyrosine kinase receptors via interaction of p85 Src homology 2 (SH2) domain(s) with phosphotyrosine moieties on the receptors PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="5250.0" y="1845.0"/> </glyph> <glyph class="macromolecule" id="s5740_sa649" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIK3R1 HUGO:PIK3R2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells Ligation of the T cell receptor for antigen (TCR) and/or costimulatory receptor CD28 results in rapid activation of phosphoinositide-3 kinase (PI-3 kinase). The primary mechanism for class IA PI-3 kinase activation by tyrosine kinase-coupled receptors is recruitment of the p85/p110 heterodimer to phosphorylated tyrosine kinase receptors via interaction of p85 Src homology 2 (SH2) domain(s) with phosphotyrosine moieties on the receptors PMID:11526404 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. The p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) was identified as a substrate for Cbl-b. We have shown that Cbl-b negatively regulated p85 recruitment of p85 to CD28 and T cell antigen receptor through its E3 ubiquitin ligase activity. The enhanced activation of Cbl-b-/- T cells was suppressed by the inhibition of PI3K. PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="PI3KR(p85)*"/> <clone/> <bbox w="80.0" h="40.0" x="5420.0" y="1760.0"/> <glyph class="state variable" id="_f6bb9d58-7c1b-4c4e-9ba2-6e0f6611699b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5415.0" y="1774.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s5740_sa650" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIK3R1 HUGO:PIK3R2 CASCADE:TCR MODULE:TCR_SIGNALING PMID:12670391 PI3K in T cells Ligation of the T cell receptor for antigen (TCR) and/or costimulatory receptor CD28 results in rapid activation of phosphoinositide-3 kinase (PI-3 kinase). The primary mechanism for class IA PI-3 kinase activation by tyrosine kinase-coupled receptors is recruitment of the p85/p110 heterodimer to phosphorylated tyrosine kinase receptors via interaction of p85 Src homology 2 (SH2) domain(s) with phosphotyrosine moieties on the receptors PMID:11526404 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. The p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) was identified as a substrate for Cbl-b. We have shown that Cbl-b negatively regulated p85 recruitment of p85 to CD28 and T cell antigen receptor through its E3 ubiquitin ligase activity. The enhanced activation of Cbl-b-/- T cells was suppressed by the inhibition of PI3K. PMID:23087689 PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells.</body> </html> </notes> <label text="PI3KR(p85)*"/> <clone/> <bbox w="80.0" h="40.0" x="5420.0" y="1910.0"/> <glyph class="state variable" id="_9eaa008e-c753-426a-9187-af0e4aae413f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5415.0" y="1924.9681"/> </glyph> </glyph> <glyph class="simple chemical" id="s5741_sa651" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="4955.0" y="2977.5"/> </glyph> <glyph class="simple chemical" id="s5741_sa712" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="1535.0" y="2482.5"/> </glyph> <glyph class="simple chemical" id="s5741_sa774" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="2825.0" y="2487.5"/> </glyph> <glyph class="simple chemical" id="s5741_sa1192" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="5095.0" y="5557.5"/> </glyph> <glyph class="simple chemical" id="s5741_sa1326" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="2305.0" y="857.5"/> </glyph> <glyph class="simple chemical" id="s5742_sa652" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="4858.75" y="2976.875"/> </glyph> <glyph class="simple chemical" id="s5742_sa711" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="1638.75" y="2481.875"/> </glyph> <glyph class="simple chemical" id="s5742_sa777" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="2718.75" y="2486.875"/> </glyph> <glyph class="simple chemical" id="s5742_sa1193" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="4908.75" y="5561.875"/> </glyph> <glyph class="simple chemical" id="s5742_sa1321" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS MODULE:TCR_SIGNALING</body> </html> </notes> <label text="GDP"/> <clone/> <bbox w="70.0" h="25.0" x="2165.0" y="857.5"/> </glyph> <glyph class="macromolecule" id="s5743_sa680" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:GRB2 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="GRB2"/> <clone/> <bbox w="80.0" h="40.0" x="3950.0" y="1740.0"/> </glyph> <glyph class="macromolecule" id="s5743_sa1242" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:CD226 HUGO:GRB2 MODULE:TCR_SIGNALING PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:26552706 DNAM-1 controls NK cell activation via an ITT-like motif Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization.</body> </html> </notes> <label text="GRB2"/> <clone/> <bbox w="80.0" h="40.0" x="3950.0" y="1660.0"/> </glyph> <glyph class="macromolecule" id="s5744_sa734" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIP5K1A HUGO:PIP5K1B HUGO:PIP5K1C MODULE:TCR_SIGNALING CASCADE:TCR PMID:27242793 Phosphatidylinositol 4-Phosphate 5-Kinases in the Regulation of T Cell Activation. Following engagement by B7, human CD28 binds Vav1 that in turn favors the recruitment of PIP5Kα and PIP5Kβ. PIP5Kα generates PIP2 that favors the recruitment of the WASP/Cdc42/ARP2/3 complex, which, in turn, promotes actin polymerization. PIP5Kβ mediates the recruitment of filamin-A (FLN-A) and lipid rafts to the T:APC contact zone. (B) Upon TCR recognition of peptide–MHC complexes presented on the surface of APCs, Lck and Fyn phosphorylate CD3 and ζ chains, which bind ZAP-70. ZAP-70 phosphorylates LAT that in turn binds PLC-γ1. CD28 mediates the recruitment of Vav-associated PIP5Kα that generates PIP2. PLC-γ1 hydrolyzes PIP2 in IP3 and DAG. IP3 induces the activation of Ca2+/calcineurin (CN) and NF-AT. CD28 also binds class 1A PI3K that phosphorylates PIP2 and generates PIP3 that favors the recruitment and activation of Akt. Akt cooperates with DAG to activate PKCθ/CARMA1/Bcl10/MALT1 complex and NF-κB. PMID:25539813 Vav1 is the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions.</body> </html> </notes> <label text="PIP5K1*"/> <clone/> <bbox w="80.0" h="40.0" x="4390.0" y="2090.0"/> </glyph> <glyph class="macromolecule" id="s5744_sa735" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PIP5K1A HUGO:PIP5K1B HUGO:PIP5K1C MODULE:TCR_SIGNALING CASCADE:TCR PMID:27242793 Phosphatidylinositol 4-Phosphate 5-Kinases in the Regulation of T Cell Activation. Following engagement by B7, human CD28 binds Vav1 that in turn favors the recruitment of PIP5Kα and PIP5Kβ. PIP5Kα generates PIP2 that favors the recruitment of the WASP/Cdc42/ARP2/3 complex, which, in turn, promotes actin polymerization. PIP5Kβ mediates the recruitment of filamin-A (FLN-A) and lipid rafts to the T:APC contact zone. (B) Upon TCR recognition of peptide–MHC complexes presented on the surface of APCs, Lck and Fyn phosphorylate CD3 and ζ chains, which bind ZAP-70. ZAP-70 phosphorylates LAT that in turn binds PLC-γ1. CD28 mediates the recruitment of Vav-associated PIP5Kα that generates PIP2. PLC-γ1 hydrolyzes PIP2 in IP3 and DAG. IP3 induces the activation of Ca2+/calcineurin (CN) and NF-AT. CD28 also binds class 1A PI3K that phosphorylates PIP2 and generates PIP3 that favors the recruitment and activation of Akt. Akt cooperates with DAG to activate PKCθ/CARMA1/Bcl10/MALT1 complex and NF-κB. PMID:25539813 Vav1 is the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions.</body> </html> </notes> <label text="PIP5K1*"/> <clone/> <bbox w="80.0" h="40.0" x="4390.0" y="2000.0"/> </glyph> <glyph class="macromolecule" id="s5745_sa745" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP3K1 MODULE:TCR_SIGNALING 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</body> </html> </notes> <label text="MAP3K1"/> <clone/> <bbox w="80.0" h="40.0" x="1670.0" y="2845.0"/> </glyph> <glyph class="macromolecule" id="s5745_sa747" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:MAP3K1 MODULE:TCR_SIGNALING 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</body> </html> </notes> <label text="MAP3K1"/> <clone/> <bbox w="80.0" h="40.0" x="1670.0" y="2935.0"/> </glyph> <glyph class="macromolecule" id="s5746_sa775" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>son of sevenless homolog 1 (Drosophila) HUGO:SOS1 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 GENECARDS:SOS1 REACTOME:64848 KEGG:6654 ATLASONC:GC_SOS1 WIKI:SOS1 son of sevenless homolog 2 (Drosophila) HUGO:SOS2 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 GENECARDS:SOS2 REACTOME:64850 ATLASONC:GC_SOS2 WIKI:SOS2 GINGF "gingival fibromatosis hereditary 1" "son of sevenless (Drosophilia) homolog 2" CASCADE:TCR MODULE:TCR_SIGNALING PMID:16102570 "LAT signalosome" links the TCR to the main intracellular signalling pathways that regulate T-cell development and T-cell function. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:7510700 A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells. PMID:24027568 Biochemical Synergy between SOS1 and RasGRP1 in Ras activation</body> </html> </notes> <label text="SOS*"/> <clone/> <bbox w="80.0" h="40.0" x="2770.0" y="2386.0"/> </glyph> <glyph class="macromolecule" id="s5746_sa776" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>son of sevenless homolog 1 (Drosophila) HUGO:SOS1 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 GENECARDS:SOS1 REACTOME:64848 KEGG:6654 ATLASONC:GC_SOS1 WIKI:SOS1 son of sevenless homolog 2 (Drosophila) HUGO:SOS2 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 GENECARDS:SOS2 REACTOME:64850 ATLASONC:GC_SOS2 WIKI:SOS2 GINGF "gingival fibromatosis hereditary 1" "son of sevenless (Drosophilia) homolog 2" CASCADE:TCR MODULE:TCR_SIGNALING PMID:16102570 "LAT signalosome" links the TCR to the main intracellular signalling pathways that regulate T-cell development and T-cell function. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:7510700 A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells. PMID:24027568 Biochemical Synergy between SOS1 and RasGRP1 in Ras activation</body> </html> </notes> <label text="SOS*"/> <clone/> <bbox w="90.0" h="50.0" x="2765.0" y="2245.0"/> </glyph> <glyph class="macromolecule" id="s5747_sa824" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:IL18 MODULE:TCR_SIGNALING MODULE:TCELL PMID:19302050; PMID:11148124 NFkB signaling is activated in T-cells downstream of TCR activation. PMID:25648675 T cell-NF-κB activation is required for tumor control in vivo. Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells. PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:10221648 NF-κB/Rel binding sites are present in the promoter regions of several cytokines and cytokine receptors, including IL-2, IL-3, GM-CSF, TNF-α, IL-6, and IL-2Rα chain PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG</body> </html> </notes> <label text="NFkB*"/> <clone/> <bbox w="80.0" h="40.0" x="3530.0" y="5020.0"/> </glyph> <glyph class="macromolecule" id="s5747_sa825" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:IL18 MODULE:TCR_SIGNALING MODULE:TCELL PMID:19302050; PMID:11148124 NFkB signaling is activated in T-cells downstream of TCR activation. PMID:25648675 T cell-NF-κB activation is required for tumor control in vivo. Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells. PMID:21411734 T cell-NF-κB can antagonize iTreg differentiation when strongly induced at high antigen doses when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. NF-κB-dependent inhibition of Foxp3 expression upon high TCR stimulation is secondary to the production of TNF and IFN-γ by the activated T cells. PMID:10221648 NF-κB/Rel binding sites are present in the promoter regions of several cytokines and cytokine receptors, including IL-2, IL-3, GM-CSF, TNF-α, IL-6, and IL-2Rα chain PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG</body> </html> </notes> <label text="NFkB*"/> <clone/> <bbox w="230.0" h="180.0" x="3455.0" y="5130.0"/> </glyph> <glyph class="macromolecule" id="s5748_sa1081" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL18 CASCADE:IL12 CASCADE:TCR MODULE:TCR_SIGNALING PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG</body> </html> </notes> <label text="MAP3K4"/> <clone/> <bbox w="80.0" h="40.0" x="1730.0" y="3325.0"/> </glyph> <glyph class="macromolecule" id="s5748_sa1082" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:IL18 CASCADE:IL12 CASCADE:TCR MODULE:TCR_SIGNALING PMID:24104473; PMID:16799472 Triggering of the T cell receptor (TCR) activates Src family kinases (SFK) and the zeta-chain-associated protein of 70 kDa (ZAP-70). These tyrosine kinases lead to the activation of the transcription factor NF-κB and the p38 mitogen-activated protein kinase. NF-κB induces transcription of the Gadd45b gene. The same applies to the cytokines IL-12 and IL-18 as well as stimulation of the Notch receptor and its cytoplasmic effector Deltex. The cytokine IL-2 activates transcription of the Gadd45g gene. Both Gadd45β and Gadd45γ proteins interact with the kinase MEKK4, which leads to sustained p38 activation and, subsequently, to interferon-γ (IFN-γ) production and Th1 differentiation. PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells. GADD45B significantly increased phosphorylated p38 MAPK compared to the control MEKK4-p38 pathway is requied for INFG transcription activation downstream IL12 and IL18 IL-18 induction of GADD45B by NF-B and a requirement for GADD45 interaction with MEKK4 in the downstream induction of IFNG</body> </html> </notes> <label text="MAP3K4"/> <clone/> <bbox w="80.0" h="40.0" x="1730.0" y="3225.0"/> </glyph> <glyph class="macromolecule" id="s5751_sa1312" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ADCY1 HUGO:ADCY2 HUGO:ADCY3 HUGO:ADCY4 HUGO:ADCY5 HUGO:ADCY6 HUGO:ADCY7 HUGO:ADCY8 HUGO:ADCY9 HUGO:ADCY10 CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:18758473 Short-term agonist exposure induced a rapid desensitization of A2AAR-stimulated adenylyl cyclase activity which was associated with diminished receptor-Gs coupling, and agonist-stimulated phosphorylation of the A2AAR receptor protein.</body> </html> </notes> <label text="Adenylil_cyclase*"/> <bbox w="80.0" h="40.0" x="2140.0" y="960.0"/> </glyph> <glyph class="simple chemical" id="s5758_sa1323" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS</body> </html> </notes> <label text="ATP"/> <bbox w="70.0" h="25.0" x="2095.0" y="1152.5"/> </glyph> <glyph class="simple chemical" id="s5759_sa1324" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS</body> </html> </notes> <label text="cAMP"/> <bbox w="70.0" h="25.0" x="2095.0" y="1212.5"/> </glyph> <glyph class="complex" id="s5760_csa153" compartmentRef="c2_ca2"> <label text="s5760"/> <bbox w="180.0" h="140.0" x="2330.0" y="670.0"/> <glyph class="macromolecule" id="s5763_sa209"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 CASCADE:AR2A HUGO:ADORA2A MODULE:INHIBITING_CHECKPOINTS PMID: 22116345 A2A receptor KO mice reject tumors more efficiently than WT controls PMID:17909080 A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. T cells initially stimulated in the presence of an A(2A)R agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-gamma when rechallenged in the absence of A(2A)R stimulation. Accordingly, treating mice with A(2A)R agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3(+) and LAG-3(+) regulatory T cells. http://cancerres.aacrjournals.org/content/77/13_Supplement/1683 A2A receptor was the main adenosine receptor expressed by CD4 and CD8 T lymphocytes and monocytes, and the only one in mature monocyte-derived dendritic cells and NK cells. A2B receptor was poorly detected in T cells and monocytes, while A1 and A3 receptors were never detected. PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses. PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. Two-way MLR-stimulated T cell proliferation was reduced by ATL313, a selective A(2A)R agonist in a dose-responsive manner</body> </html> </notes> <label text="ADORA2A"/> <bbox w="80.0" h="50.0" x="2340.0" y="675.0"/> <glyph class="unit of information" id="_80bb72ff-ce70-411d-9a89-e5cd65137948"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2357.5" y="670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5753_sa1314"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A HUGO:GNAS PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNAS"/> <bbox w="80.0" h="40.0" x="2430.0" y="680.0"/> </glyph> <glyph class="macromolecule" id="s5754_sa1315"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GNG MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNG*"/> <bbox w="80.0" h="40.0" x="2340.0" y="730.0"/> </glyph> <glyph class="macromolecule" id="s5755_sa1316"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GNB1 HUGO:GNB2 HUGO:GNB3 HUGO:GNB4 HUGO:GNB5 CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNB*"/> <bbox w="80.0" h="40.0" x="2340.0" y="770.0"/> </glyph> <glyph class="simple chemical" id="s5764_sa1327"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 CHEBI:17552, KEGGCOMPOUND:C00035 MODULE:INHIBITING_CHECKPOINTS</body> </html> </notes> <label text="GDP"/> <bbox w="70.0" h="25.0" x="2435.0" y="727.5"/> </glyph> </glyph> <glyph class="complex" id="s5762_csa154" compartmentRef="c2_ca2"> <label text="s5760"/> <bbox w="120.0" h="155.0" x="2000.0" y="822.5"/> <glyph class="macromolecule" id="s5761_sa1325"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 CASCADE:AR2A HUGO:ADORA2A MODULE:INHIBITING_CHECKPOINTS PMID: 22116345 A2A receptor KO mice reject tumors more efficiently than WT controls PMID:17909080 A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. T cells initially stimulated in the presence of an A(2A)R agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-gamma when rechallenged in the absence of A(2A)R stimulation. Accordingly, treating mice with A(2A)R agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3(+) and LAG-3(+) regulatory T cells. http://cancerres.aacrjournals.org/content/77/13_Supplement/1683 A2A receptor was the main adenosine receptor expressed by CD4 and CD8 T lymphocytes and monocytes, and the only one in mature monocyte-derived dendritic cells and NK cells. A2B receptor was poorly detected in T cells and monocytes, while A1 and A3 receptors were never detected. PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses. PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. Two-way MLR-stimulated T cell proliferation was reduced by ATL313, a selective A(2A)R agonist in a dose-responsive manner</body> </html> </notes> <label text="ADORA2A"/> <bbox w="80.0" h="50.0" x="2010.0" y="827.5"/> <glyph class="unit of information" id="_97c9cd45-3129-41a2-b907-737219d52351"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2027.5" y="822.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5768_sa1329"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GNG MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNG*"/> <bbox w="80.0" h="40.0" x="2010.0" y="887.5"/> </glyph> <glyph class="macromolecule" id="s5769_sa1330"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GNB1 HUGO:GNB2 HUGO:GNB3 HUGO:GNB4 HUGO:GNB5 CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNB*"/> <bbox w="80.0" h="40.0" x="2010.0" y="927.5"/> </glyph> </glyph> <glyph class="complex" id="s5766_csa155" compartmentRef="c2_ca2"> <label text="s5766"/> <bbox w="100.0" h="120.0" x="2260.0" y="890.0"/> <glyph class="simple chemical" id="s5767_sa1322"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:DC MODULE:CROSS_ACTIVATION_OF_IMMUNE_CELLS MODULE:ANTIGEN_PRESENTATION_AND_ACTIVATING_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION</body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="2275.0" y="947.5"/> </glyph> <glyph class="macromolecule" id="s5765_sa1328"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A HUGO:GNAS PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNAS"/> <bbox w="80.0" h="40.0" x="2270.0" y="900.0"/> </glyph> </glyph> <glyph class="complex" id="s5770_csa156" compartmentRef="c2_ca2"> <label text="s5770"/> <bbox w="100.0" h="120.0" x="2200.0" y="1145.0"/> <glyph class="macromolecule multimer" id="s5756_sa1319"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRKAR1A HUGO:PRKAR1B CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:11181701 In normal T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the TCR–CD3 complex and inhibits TCR-induced cell proliferation cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 zeta chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on zeta chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion</body> </html> </notes> <label text="PKA1_R"/> <bbox w="86.0" h="46.0" x="2207.0" y="1152.0"/> <glyph class="unit of information" id="_a98d6fee-9a56-4770-810b-69ef38670c7c"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2240.0" y="1147.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s5757_sa1320"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRKACA HUGO:PRKACB HUGO:PRKACG CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:11181701 In normal T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the TCR–CD3 complex and inhibits TCR-induced cell proliferation cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 zeta chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on zeta chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion PMID:17371980 AR2A agonist ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. .</body> </html> </notes> <label text="PKA*"/> <bbox w="86.0" h="46.0" x="2207.0" y="1202.0"/> <glyph class="unit of information" id="_89a30c90-d759-4d3a-9fc7-00b6ee5d6eea"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2240.0" y="1197.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule multimer" id="s5771_sa1331" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRKAR1A HUGO:PRKAR1B CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:11181701 In normal T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the TCR–CD3 complex and inhibits TCR-induced cell proliferation cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 zeta chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on zeta chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion</body> </html> </notes> <label text="PKA1_R"/> <bbox w="86.0" h="46.0" x="1215.0" y="937.5"/> <glyph class="unit of information" id="_d423754c-e22b-4006-a21d-fb374f2031fe"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1248.0" y="932.5"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s5772_sa1332" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:PRKACA HUGO:PRKACB HUGO:PRKACG CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:11181701 In normal T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the TCR–CD3 complex and inhibits TCR-induced cell proliferation cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 zeta chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on zeta chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion PMID:17371980 AR2A agonist ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. .</body> </html> </notes> <label text="PKA*"/> <bbox w="86.0" h="46.0" x="2037.0" y="1327.0"/> <glyph class="unit of information" id="_1692681e-bdb2-4980-8f01-1f8fed347581"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2070.0" y="1322.0"/> </glyph> </glyph> <glyph class="complex" id="s5773_csa157" compartmentRef="c2_ca2"> <label text="s5766"/> <bbox w="100.0" h="150.0" x="1950.0" y="1070.0"/> <glyph class="simple chemical" id="s5774_sa1333"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 CHEBI:15996, KEGGCOMPOUND:C00044, CAS:86-01-1 MODULE:DC MODULE:CROSS_ACTIVATION_OF_IMMUNE_CELLS MODULE:ANTIGEN_PRESENTATION_AND_ACTIVATING_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION</body> </html> </notes> <label text="GTP"/> <bbox w="70.0" h="25.0" x="1965.0" y="1162.5"/> </glyph> <glyph class="macromolecule" id="s5775_sa1334"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A HUGO:GNAS PMID:18758473 A2A receptors are the dominant adenosine receptors in dictating lymphocyte responses.</body> </html> </notes> <label text="GNAS"/> <bbox w="80.0" h="40.0" x="1960.0" y="1120.0"/> </glyph> <glyph class="macromolecule" id="s5776_sa1335"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ADCY1 HUGO:ADCY2 HUGO:ADCY3 HUGO:ADCY4 HUGO:ADCY5 HUGO:ADCY6 HUGO:ADCY7 HUGO:ADCY8 HUGO:ADCY9 HUGO:ADCY10 CASCADE:AR2A MODULE:INHIBITING_CHECKPOINTS PMID:18758473 Short-term agonist exposure induced a rapid desensitization of A2AAR-stimulated adenylyl cyclase activity which was associated with diminished receptor-Gs coupling, and agonist-stimulated phosphorylation of the A2AAR receptor protein.</body> </html> </notes> <label text="Adenylil_cyclase*"/> <bbox w="80.0" h="40.0" x="1960.0" y="1075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5777_sa1336" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CSK MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues PMID:10790433 PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood alpha/beta T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. PMID:12485116 REW PMID:11181701 Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion.</body> </html> </notes> <label text="CSK"/> <bbox w="80.0" h="40.0" x="2210.0" y="1375.0"/> <glyph class="state variable" id="_d17e9876-c5ec-4ff7-bd1c-f6496f5cb924"> <state value="P" variable="S364"/> <bbox w="35.0" h="10.0" x="2192.5" y="1372.4022"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5778_sa1337" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CTLA4 CELL:CD4 CELL:TREG MODULE:INHIBITING_CHECKPOINTS CASCADE:AR2A PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89.</body> </html> </notes> <label text="CTLA4"/> <bbox w="90.0" h="25.0" x="2525.0" y="967.5"/> <glyph class="unit of information" id="_f9e94c02-8211-44f7-abb5-6d8239a5273b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2560.0" y="962.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s5779_sa1338" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:AR2A HUGO:CD40LG MODULE:ACTIVATING_CHECKPOINTS PMID:17371980 AR2A agonist ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines</body> </html> </notes> <label text="CD40LG"/> <bbox w="90.0" h="25.0" x="5095.0" y="747.5"/> <glyph class="unit of information" id="_87bee1a7-9a38-4647-b5a1-c2c663584c97"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5130.0" y="742.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5782_sa1341" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:CD4 CELL:TREG HUGO:NT5E MODULE:INHIBITING_CHECKPOINTS PMID: 8758473 TReg cells — as defined by their expression of CD4+/CD25+/FOXP3+ and an ability to suppress the proliferation of CD4+/CD25− cells — express high levels of both CD39 (Ref. 56) and CD73 (Refs 56,57), cell surface ectoenzymes that convert extracellular ATP and ADP to adenosine PMID:17502665 the expression of CD39/ENTPD1 in concert with CD73/ecto-5'-nucleotidase distinguishes CD4(+)/CD25(+)/Foxp3(+) T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. PMID:21292811 CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis Using adoptive reconstitution of T regulatory cell (Treg)-depleted DEREG (depletion of regulatory T cells) mice, we demonstrated that part of the protumorigenic effect of Tregs was dependent on their expression of CD73.</body> </html> </notes> <label text="CD73*"/> <bbox w="80.0" h="40.0" x="2170.0" y="650.0"/> </glyph> <glyph class="simple chemical" id="s5783_sa1342"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS</body> </html> </notes> <label text="ATP"/> <bbox w="70.0" h="25.0" x="2095.0" y="567.5"/> </glyph> <glyph class="simple chemical" id="s5784_sa1343"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS</body> </html> </notes> <label text="AMP"/> <bbox w="70.0" h="25.0" x="2235.0" y="567.5"/> </glyph> <glyph class="nucleic acid feature" id="s5785_sa1344" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ENTPD1 CELL:CD4 CELL:TREG MODULE:INHIBITING_CHECKPOINTS PMID:17449799 In mice, the enzyme is present on virtually all CD4(+)CD25(+) cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation.</body> </html> </notes> <label text="CD39*"/> <bbox w="70.0" h="25.0" x="2055.0" y="767.5"/> </glyph> <glyph class="nucleic acid feature" id="s5786_sa1345" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ENTPD1 MODULE:INHIBITING_CHECKPOINTS CELL:CD4 CELL:TREG PMID:17449799 In mice, the enzyme is present on virtually all CD4(+)CD25(+) cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation.</body> </html> </notes> <label text="CD39*"/> <bbox w="90.0" h="25.0" x="2045.0" y="717.5"/> <glyph class="unit of information" id="_b36d7fe3-55df-473e-aaba-717381de1d23"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2080.0" y="712.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5781_sa1340" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:ENTPD1 CELL:CD4 CELL:TREG MODULE:INHIBITING_CHECKPOINTS PMID:8758473 TReg cells — as defined by their expression of CD4+/CD25+/FOXP3+ and an ability to suppress the proliferation of CD4+/CD25− cells — express high levels of both CD39 (Ref. 56) and CD73 (Refs 56,57), cell surface ectoenzymes that convert extracellular ATP and ADP to adenosine PMID:17502665 the expression of CD39/ENTPD1 in concert with CD73/ecto-5'-nucleotidase distinguishes CD4(+)/CD25(+)/Foxp3(+) T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. PMID:17449799 In mice, the enzyme is present on virtually all CD4(+)CD25(+) cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation. PMID:20546740 CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice</body> </html> </notes> <label text="CD39*"/> <bbox w="80.0" h="40.0" x="2050.0" y="650.0"/> </glyph> <glyph class="nucleic acid feature" id="s5787_sa1346" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CTLA4 CELL:CD4 CELL:TREG MODULE:INHIBITING_CHECKPOINTS PMID: 16873067 NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25 Chromatin immunoprecipitation (ChIP) experiments confirmed that NFAT1 and FOXP3 could each occupy the Il2, Ctla4, and Cd25 promoters, both in T cells retrovirally transduced with FOXP3 and in “natural” CD4+CD25+ T regulatory cells that had been expanded with IL-2 PMID:12522256 Foxp3 is known to drive the expression of Treg-associated markers such as CD25, CTLA-4, and GITR</body> </html> </notes> <label text="CTLA4"/> <bbox w="70.0" h="25.0" x="2415.0" y="967.5"/> </glyph> <glyph class="complex" id="s5792_csa158" compartmentRef="c2_ca2"> <label text="s5792"/> <bbox w="110.0" h="160.0" x="1035.0" y="810.0"/> <glyph class="macromolecule" id="s5794_sa195"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CELL:TCD8 CELL:TCD4 MODULE:INHIBITING_CHECKPOINTS HUGO:BTLA PMID:22437870, PMID:20007250 rew PMID: 12796776 BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation PMID:20038811 BTLA activation inhibits the function of human CD8+ cancer-specific T cells Regulation of proliferation and cytokine production of primary CD8+ T cells depending on BTLA expression and interaction with HVEM.</body> </html> </notes> <label text="BTLA"/> <bbox w="80.0" h="50.0" x="1050.0" y="815.0"/> <glyph class="unit of information" id="_22151826-c2c9-4343-b4e0-573342ff4bd3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1067.5" y="810.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5795_sa1348"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR CASCADE:PD1 HUGO:PTPN11 MODULE:INHIBITING_CHECKPOINTS PMID:11572860 Gab2 is phosphorylated by ZAP-70, is associated with the TCR signaling complex, and acts as an inhibitory adaptor molecule via recruitment of SHP-2 upon TCR engagement CD247 chain has been reported to be a substrate of SHP-2 in T cells (12), we examined the phosphorylation levels of CD267 in these lines after TCR engagement by immunoprecipitation with anti-CD247 mAb,followed by blotting with anti-PY mAb. As shown in Fig. 3 D, the phosphorylation levels of theCD247 chain were attenuated by Gab2(WT) expression but not by Gab2(Y614F). Therefore, the inhibitory function of Gab2 is mediated, at least in part, through SHP-2-dependent dephosphorylation of the CD247 chain. PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="1045.0" y="910.0"/> </glyph> <glyph class="macromolecule" id="s5793_sa1349"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:PD1 HUGO:PTPN6 MODULE:INHIBITING_CHECKPOINTS PMID:15240681 SHP-1 and SHP-2 are recruited to the PD-1 ITSM the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.</body> </html> </notes> <label text="PTPN6"/> <bbox w="80.0" h="40.0" x="1045.0" y="870.0"/> </glyph> </glyph> <glyph class="complex" id="s5798_csa159" compartmentRef="c2_ca2"> <label text="s5798"/> <bbox w="100.0" h="120.0" x="1880.0" y="640.0"/> <glyph class="macromolecule" id="s5799_sa1352"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <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: MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS 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:22437870; PMID:12810107 CD80 and CD86 act lic coactivators of T-cells when they interact with CD28 and inhibit T-cells via interactions with CTLA4 PMID:18585785, PMID:17629517 human B7-1(CD80) can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. ligation of PD-L1 on T cells by B7-1 inhibits T cell responses in mouse T-cells References_end</body> </html> </notes> <label text="CD80"/> <bbox w="80.0" h="40.0" x="1890.0" y="650.0"/> <glyph class="unit of information" id="_21b3c20c-d7c2-4e3c-96d8-ee9deb155c15"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1907.5" y="645.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5800_sa1353"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD274 MODULE:INHIBITING_CHECKPOINTS 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. PMID:18585785; PMID:17629517 human B7-1(CD80) can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. ligation of PD-L1 on T cells by B7-1 inhibits T cell responses in mouse T-cells</body> </html> </notes> <label text="PDL1*"/> <bbox w="80.0" h="40.0" x="1890.0" y="700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5803_sa1354" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFSF14 MODULE:ACTIVATING_CHECKPOINTS PMID:20007250; PMID:20038807 TNFSF14(LIGHT) -rew PMID:27192566 REW!!! HVEM expressed in T cells binds to its ligands: LIGHT and LTα expressed on APC to modulate the proliferation and function of effector T cells. LIGHT and LTα bind to HVEM at a topographically distinct site from BTLA and CD160, yet all four ligands can activate the HVEM-TRAF2/3 E3 ligase pathway to promote cell survival and differentiation</body> </html> </notes> <label text="TNFSF14"/> <bbox w="80.0" h="50.0" x="5350.0" y="415.0"/> <glyph class="unit of information" id="_215758b2-6f66-4e8e-a506-6aa2ab7f1376"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5367.5" y="410.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5806_sa192" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:ICOS PMID:20116985 ICOS has diverse functions in CD4+ T cell subsets. Following initial TCR engagement and CD28 costimulation, ICOS is upregulated on CD4+ T cells through NFATc2 and ERK signaling. In the early stages of priming, binding of ICOS to ICOSL promotes Th2 polarization through IL-4 secretion, IL-4 receptor signaling, and upregulation of the transcription factors NFATc1 and c-Maf. However, in a Th1, Th17, or Tfh polarizing environment, activated CD4+ T cells differentiate into the T helper lineages dictated by the environment. Upon differentiation into Th1 or Th2 lineages, ICOS expression is regulated by T-bet and NFATc2 in Th1 cells and GATA-3 and NFATc2 in Th2 cells. In differentiated CD4+ T cells, ICOS signaling through PI3K promotes T helper activity through secretion of the Th1, Th2, and Tfh associated cytokines IFN-γ, IL-4, and IL-21, respectively. In Tfh cells, ICOS regulates development and homeostasis through upregulation of the Tfh associated transcription factor c-Maf and secretion of IL-21, which acts in an autocrine manner to expand Tfh and promote their survival. Likewise, in Th17 cells, ICOS signaling upregulates the IL-23 receptor, which promotes survival and expansion of differentiated Th17 cells. In all CD4+ T cell lineages, activation of the ICOS pathway results in PI3K and Akt signaling, mediating T cell survival, proliferation, and memory. PMID: 11343122 ICOS co-stimulation induces CD40L expression by T cells PMID:21708958 The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy.</body> </html> </notes> <label text="ICOS"/> <clone/> <bbox w="80.0" h="50.0" x="5230.0" y="685.0"/> <glyph class="unit of information" id="_6cd437d9-3195-42da-ba2b-4619da393fe6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5247.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5806_sa193" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:ICOS PMID:20116985 ICOS has diverse functions in CD4+ T cell subsets. Following initial TCR engagement and CD28 costimulation, ICOS is upregulated on CD4+ T cells through NFATc2 and ERK signaling. In the early stages of priming, binding of ICOS to ICOSL promotes Th2 polarization through IL-4 secretion, IL-4 receptor signaling, and upregulation of the transcription factors NFATc1 and c-Maf. However, in a Th1, Th17, or Tfh polarizing environment, activated CD4+ T cells differentiate into the T helper lineages dictated by the environment. Upon differentiation into Th1 or Th2 lineages, ICOS expression is regulated by T-bet and NFATc2 in Th1 cells and GATA-3 and NFATc2 in Th2 cells. In differentiated CD4+ T cells, ICOS signaling through PI3K promotes T helper activity through secretion of the Th1, Th2, and Tfh associated cytokines IFN-γ, IL-4, and IL-21, respectively. In Tfh cells, ICOS regulates development and homeostasis through upregulation of the Tfh associated transcription factor c-Maf and secretion of IL-21, which acts in an autocrine manner to expand Tfh and promote their survival. Likewise, in Th17 cells, ICOS signaling upregulates the IL-23 receptor, which promotes survival and expansion of differentiated Th17 cells. In all CD4+ T cell lineages, activation of the ICOS pathway results in PI3K and Akt signaling, mediating T cell survival, proliferation, and memory. PMID: 11343122 ICOS co-stimulation induces CD40L expression by T cells PMID:21708958 The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy.</body> </html> </notes> <label text="ICOS"/> <clone/> <bbox w="80.0" h="50.0" x="5230.0" y="785.0"/> <glyph class="unit of information" id="_17b22c6b-0bd3-4692-b3fc-c466a333d10c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5247.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5284_sa215" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD48 MODULE:SMAC MODULE:ACTIVATING_CHECKPOINTS PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD48 interactions with CD2 in cis on T cells can promote T cell activation, by facilitating recruitment of signaling components to the TCR. Anti-CD48 also could partially block antigen-specific target cell lysis by CTLs in an in vitro cytotoxicity assay [94]. Both anti-CD2 and anti-CD48 mAbs reduced IL-2Rα expression, IL-2 and IFNγ production, and target lysis by anti-CD3-stimulated bulk T cells in vitro. The reduced target lysis could be rescued by addition of IL-2 [95], suggesting that CD48:CD2 costimulation may stabilize IL-2 mRNA [96]. Thus, CD48:CD2 interactions contribute to both priming and effector functions of CD8 + T cells.</body> </html> </notes> <label text="CD48"/> <bbox w="80.0" h="40.0" x="6170.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s5812_sa1363" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD2 MODULE:ACTIVATING_CHECKPOINTS PMID:23886063 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal link er proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2 PMID:19398758 The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells the binding of CD58 to CD2, even in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR(cis interaction) PMID: 15331323 CD2-CD48 interactions promote interleukin-2 and interferon-gamma synthesis by stabilizing cytokine mRNA (trans interaction)</body> </html> </notes> <label text="CD2"/> <clone/> <bbox w="80.0" h="50.0" x="6090.0" y="685.0"/> <glyph class="unit of information" id="_dbcfd9c2-9abf-417e-94bd-e45588d36bdf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6107.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5812_sa1364" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD2 MODULE:ACTIVATING_CHECKPOINTS PMID:23886063 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal link er proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2 PMID:19398758 The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells the binding of CD58 to CD2, even in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR(cis interaction) PMID: 15331323 CD2-CD48 interactions promote interleukin-2 and interferon-gamma synthesis by stabilizing cytokine mRNA (trans interaction)</body> </html> </notes> <label text="CD2"/> <clone/> <bbox w="80.0" h="50.0" x="6090.0" y="785.0"/> <glyph class="unit of information" id="_9b6a9490-871a-4978-a4c1-0a9b4d221c18"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6107.5" y="780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5814_sa1365" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD48 MODULE:SMAC MODULE:ACTIVATING_CHECKPOINTS PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD48 interactions with CD2 in cis on T cells can promote T cell activation, by facilitating recruitment of signaling components to the TCR. Anti-CD48 also could partially block antigen-specific target cell lysis by CTLs in an in vitro cytotoxicity assay [94]. Both anti-CD2 and anti-CD48 mAbs reduced IL-2Rα expression, IL-2 and IFNγ production, and target lysis by anti-CD3-stimulated bulk T cells in vitro. The reduced target lysis could be rescued by addition of IL-2 [95], suggesting that CD48:CD2 costimulation may stabilize IL-2 mRNA [96]. Thus, CD48:CD2 interactions contribute to both priming and effector functions of CD8 + T cells.</body> </html> </notes> <label text="CD48"/> <bbox w="80.0" h="40.0" x="4070.0" y="735.0"/> </glyph> <glyph class="complex" id="s5815_csa160" compartmentRef="c9_ca9"> <label text="s5815"/> <bbox w="100.0" h="120.0" x="4090.0" y="865.0"/> <glyph class="macromolecule" id="s5816_sa1366"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD48 MODULE:SMAC MODULE:ACTIVATING_CHECKPOINTS PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD48 interactions with CD2 in cis on T cells can promote T cell activation, by facilitating recruitment of signaling components to the TCR. Anti-CD48 also could partially block antigen-specific target cell lysis by CTLs in an in vitro cytotoxicity assay [94]. Both anti-CD2 and anti-CD48 mAbs reduced IL-2Rα expression, IL-2 and IFNγ production, and target lysis by anti-CD3-stimulated bulk T cells in vitro. The reduced target lysis could be rescued by addition of IL-2 [95], suggesting that CD48:CD2 costimulation may stabilize IL-2 mRNA [96]. Thus, CD48:CD2 interactions contribute to both priming and effector functions of CD8 + T cells.</body> </html> </notes> <label text="CD48"/> <bbox w="80.0" h="40.0" x="4100.0" y="875.0"/> </glyph> <glyph class="macromolecule" id="s5817_sa1367"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC HUGO:CD2 MODULE:ACTIVATING_CHECKPOINTS PMID:23886063 For a successful T cell activation the TcR signal alone is insufficient, a second, co-stimulatory signaling is also necessary The immunological synapse (A.Kupfer and M. Dustin) is the attachment surface between the T cell and the APC; a Supramolecular Activation Complex (SMAC) consisting of a central (c) region containing the TcR complex, CD4 CD8, CD28 peripheral (p) region containing adhesion molecules e.g. LFA-1 and many cytoskeletal link er proteins (such as talin) . Proteins with large extracellular domains, including protein-tyrosine phosphatase CD45 and glycoproteins CD44 and CD43, accumulate in the distal SMAC (d). PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function CD58 (LFA-3) is the high affinity ligand for CD2 PMID:19398758 The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells the binding of CD58 to CD2, even in the absence of TCR activation, also induces signaling through the actin-dependent coalescence of signaling molecules (including TCR-zeta chain, Lck, and LAT) into microdomains. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR(cis interaction) PMID: 15331323 CD2-CD48 interactions promote interleukin-2 and interferon-gamma synthesis by stabilizing cytokine mRNA (trans interaction)</body> </html> </notes> <label text="CD2"/> <bbox w="80.0" h="50.0" x="4100.0" y="920.0"/> <glyph class="unit of information" id="_53426490-8f76-44be-bc81-e05aa465f91b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4117.5" y="915.0"/> </glyph> </glyph> </glyph> <glyph class="phenotype" id="s5819_sa1369"> <label text="CYTOTOXICITY"/> <bbox w="340.0" h="65.0" x="4530.0" y="6947.5"/> </glyph> <glyph class="nucleic acid feature" id="s5820_sa1370" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:24484736 In Tregs, Foxp3 modulates GITR expression: ectopic expression of Foxp3 in initially GITRlo CD4+CD25− cells confers both suppressive activity and high-level GITR expression [17]. In conventional T cells, GITR is reciprocally regulated by classical nuclear factor κB (NF-κB; RelA most critical, but cRel and p50 are also important) and nuclear factor of activated T cells (NFAT), with NF-κB inducing and NFAT repressing GITR expression downstream of TCR signals</body> </html> </notes> <label text="TNFRSF18"/> <bbox w="70.0" h="25.0" x="5735.0" y="977.5"/> </glyph> <glyph class="nucleic acid feature" id="s5821_sa1371" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:24484736 In Tregs, Foxp3 modulates GITR expression: ectopic expression of Foxp3 in initially GITRlo CD4+CD25− cells confers both suppressive activity and high-level GITR expression [17]. In conventional T cells, GITR is reciprocally regulated by classical nuclear factor κB (NF-κB; RelA most critical, but cRel and p50 are also important) and nuclear factor of activated T cells (NFAT), with NF-κB inducing and NFAT repressing GITR expression downstream of TCR signals</body> </html> </notes> <label text="TNFRSF18"/> <bbox w="90.0" h="25.0" x="5725.0" y="897.5"/> <glyph class="unit of information" id="_12dc46cd-1b8d-43d3-9225-2a8ad0e86c56"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5760.0" y="892.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5822_sa1372" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRAF1 HUGO:TRAF2 HUGO:TRAF3 HUGO:TRAF4 HUGO:TRAF5 HUGO:TRAF6 MODULE:ACTIVATING_CHECKPOINTS PMID: 24484736 GITR recruits signaling adaptors, TNFR associated factors (TRAFs), of which there are six in mammals, TRAF1-6 (reviewed in [26]). TRAFs 2 and 5 are required downstream of GITR for maximal activation of the MAPK and canonical NF-κB pathways and up-regulation of the anti-apoptotic molecule Bcl-xL PMID:23758787 The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily [1-3]. There are six known members of the TRAF family (TRAF1 to 6) in mammals. Although a novel protein was named TRAF7 [4], this claim is controversial as the protein does not have the TRAF homology domain that defines the TRAF family PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and downmodulation of BIM protein</body> </html> </notes> <label text="TRAFs*"/> <clone/> <bbox w="80.0" h="40.0" x="5680.0" y="1090.0"/> </glyph> <glyph class="macromolecule" id="s5822_sa1374" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TRAF1 HUGO:TRAF2 HUGO:TRAF3 HUGO:TRAF4 HUGO:TRAF5 HUGO:TRAF6 MODULE:ACTIVATING_CHECKPOINTS PMID: 24484736 GITR recruits signaling adaptors, TNFR associated factors (TRAFs), of which there are six in mammals, TRAF1-6 (reviewed in [26]). TRAFs 2 and 5 are required downstream of GITR for maximal activation of the MAPK and canonical NF-κB pathways and up-regulation of the anti-apoptotic molecule Bcl-xL PMID:23758787 The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily [1-3]. There are six known members of the TRAF family (TRAF1 to 6) in mammals. Although a novel protein was named TRAF7 [4], this claim is controversial as the protein does not have the TRAF homology domain that defines the TRAF family PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and downmodulation of BIM protein</body> </html> </notes> <label text="TRAFs*"/> <clone/> <bbox w="80.0" h="40.0" x="5680.0" y="1200.0"/> </glyph> <glyph class="nucleic acid feature" id="s5823_sa1375" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2L11 PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and down modulation of BIM protein</body> </html> </notes> <label text="BCL2L11"/> <bbox w="70.0" h="25.0" x="3495.0" y="5642.5"/> </glyph> <glyph class="nucleic acid feature" id="s5824_sa1376" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2L11 PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and down modulation of BIM protein</body> </html> </notes> <label text="BCL2L11"/> <bbox w="90.0" h="25.0" x="3495.0" y="5702.5"/> <glyph class="unit of information" id="_ffc879bf-8567-44e4-81e3-021b0aefce22"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3530.0" y="5697.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5825_sa1377" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2L11 PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and down modulation of BIM protein</body> </html> </notes> <label text="BCL2L11"/> <bbox w="80.0" h="40.0" x="3490.0" y="5780.0"/> </glyph> <glyph class="nucleic acid feature" id="s5826_sa1378" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2A1 PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and down modulation of BIM protein</body> </html> </notes> <label text="BCL2A1"/> <bbox w="70.0" h="25.0" x="3365.0" y="5642.5"/> </glyph> <glyph class="nucleic acid feature" id="s5827_sa1379" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2A1 PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and down modulation of BIM protein</body> </html> </notes> <label text="BCL2A1"/> <bbox w="90.0" h="25.0" x="3355.0" y="5712.5"/> <glyph class="unit of information" id="_aef691bc-a8ca-455e-87c0-018ef1f9c9e6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3390.0" y="5707.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5828_sa1380" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:TCR_SIGNALING HUGO:BCL2A1 PMID: 22017440 TRAF1 and TRAF2 are required for maximal MAPK and NFjB activation downstream of 4-1BB in T cells, resulting in upregulation of Bcl-xL and Bﬂ-1 and down modulation of BIM protein</body> </html> </notes> <label text="BCL2A1"/> <bbox w="80.0" h="40.0" x="3360.0" y="5775.0"/> </glyph> <glyph class="nucleic acid feature" id="s5829_sa1381" compartmentRef="c2_ca2"> <label text="ICOS"/> <bbox w="70.0" h="25.0" x="5235.0" y="967.5"/> </glyph> <glyph class="nucleic acid feature" id="s5830_sa1382" compartmentRef="c2_ca2"> <label text="ICOS"/> <bbox w="90.0" h="25.0" x="5225.0" y="887.5"/> <glyph class="unit of information" id="_7fc4e125-a340-47e7-98c2-53b1f9d2ec48"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5260.0" y="882.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5833_sa679" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING HUGO:LAT PMID:23620508 LAT (linker for activation of T cells) is a scaffold protein that assembles key effectors of T cell activation, such as SLP-76, PLCγ1, Grb2 and others. After its phosphorylation by ZAP70 and Lck, LAT recruits many other signaling proteins to form protein microclusters that are distinct from TCR microclusters PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:25137453; PMID:16102570 LAT as a signaling hub in TCR signaling Subsequent biochemical studies helped define the binding partners of phosphorylated LAT molecules and showed that in T cells most of the signalling activity of LAT is funnelled through the four COOH‐terminal tyrosine residues found at positions 136, 175, 195, and 235 of the mouse LAT sequence (Figure 1 ; Figure 2) (Lin 2001; Paz 2001; Zhang 2000 ; Zhu 2003). After TCR‐induced phosphorylation, these four tyrosines manifest some specialization in the SH2‐domain‐containing proteins they recruit. For instance, mutation of tyrosine (Y) 136 primarily eliminates binding of phospholipase C‐γ1 (PLC‐γ1), whereas the simultaneous mutation of Y175 and Y195, or of Y175, Y195, and Y235 results in loss of binding of the Gads and Grb2/Grap adaptors, respectively Gads interacts constitutively with the adaptor SLP‐76, thereby recruiting it to LAT, together with its constellation of associated molecules (Vav, Nck, Itk, adhesion and degranulation promoting adaptor protein (ADAP)). SLP‐76 contributes to PLC‐γ1 activation by stabilizing the LAT‐PLC‐γ1 association and by bringing the Tec family PTK Itk in the vicinity of its PLC‐γ1‐substrate In addition to PLC‐γ1, another major effector molecule functioning downstream of LAT is the Ras GTPase, whose activation is defective in both Lat‐ and Slp‐76‐deficient T cells. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. In Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR.</body> </html> </notes> <label text="LAT"/> <clone/> <bbox w="80.0" h="40.0" x="3670.0" y="1720.0"/> <glyph class="state variable" id="_15492e33-16cf-440f-bc2d-414b7cd253c2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3665.0" y="1735.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5833_sa1368" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:TCR MODULE:TCR_SIGNALING HUGO:LAT PMID:23620508 LAT (linker for activation of T cells) is a scaffold protein that assembles key effectors of T cell activation, such as SLP-76, PLCγ1, Grb2 and others. After its phosphorylation by ZAP70 and Lck, LAT recruits many other signaling proteins to form protein microclusters that are distinct from TCR microclusters PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. PMID:25137453; PMID:16102570 LAT as a signaling hub in TCR signaling Subsequent biochemical studies helped define the binding partners of phosphorylated LAT molecules and showed that in T cells most of the signalling activity of LAT is funnelled through the four COOH‐terminal tyrosine residues found at positions 136, 175, 195, and 235 of the mouse LAT sequence (Figure 1 ; Figure 2) (Lin 2001; Paz 2001; Zhang 2000 ; Zhu 2003). After TCR‐induced phosphorylation, these four tyrosines manifest some specialization in the SH2‐domain‐containing proteins they recruit. For instance, mutation of tyrosine (Y) 136 primarily eliminates binding of phospholipase C‐γ1 (PLC‐γ1), whereas the simultaneous mutation of Y175 and Y195, or of Y175, Y195, and Y235 results in loss of binding of the Gads and Grb2/Grap adaptors, respectively Gads interacts constitutively with the adaptor SLP‐76, thereby recruiting it to LAT, together with its constellation of associated molecules (Vav, Nck, Itk, adhesion and degranulation promoting adaptor protein (ADAP)). SLP‐76 contributes to PLC‐γ1 activation by stabilizing the LAT‐PLC‐γ1 association and by bringing the Tec family PTK Itk in the vicinity of its PLC‐γ1‐substrate In addition to PLC‐γ1, another major effector molecule functioning downstream of LAT is the Ras GTPase, whose activation is defective in both Lat‐ and Slp‐76‐deficient T cells. In T cells, the functional coupling between LAT and Ras occurs mainly through an SLP‐76‐PLC‐γ1‐RasGRP1 pathway, and secondarily via a Grb2‐Sos axis PMID:12640133 Gads/Grb2-Mediated Association with LAT Is Critical for the Inhibitory Function of Gab2 in T Cells LAT is required for Gab2 phosphorylation upon TCR engagement. PMID:14764585 Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1* pathway. In Vav1-deficient cells there is a failure to form a LAT-Grb2-Sos complex following TCR stimulation, probably because of reduced phosphorylation of key tyrosine residues on LAT. This in turn may contribute to the profound defect in TCR-induced Ras and ERK activation. PMID:19494291 when either CD2 or CD48 were lacking from the T cell, there was reduced linker for activation of T cells (LAT) recruitment to the TCR, LAT phosphorylation, calcium flux, and IL-2 production. CD2 was required for CD48 to associate with the TCR and CD3, and CD48 was required for LAT association with the TCR.</body> </html> </notes> <label text="LAT"/> <clone/> <bbox w="80.0" h="40.0" x="3670.0" y="1640.0"/> <glyph class="state variable" id="_70d67dea-619a-414b-93e2-a20bbd722fd6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3665.0" y="1655.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5835_sa219" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD200R1 PMID:22264927 CD200 has a short intracellular tail devoid of any known signaling motifs and functions as a ligand for CD200R CD200-positive chronic lymphocytic leukemia (CLL) cells suppress pro-inflammatory cytokine production and tumor cell lysis in mixed lymphocyte cultures, which can be reversed by blocking CD200 antibodies [28,35,36••]. Similarly, CD200 blocking antibodies increase IL-2 and IFNγ production in allogeneic mixed lymphocyte reactions of T cells and dendritic cells (DCs) with melanoma and ovarian cancer cell lines [30]. Knock down of CD200 in melanoma cells also results in enhanced T cell responses in vitro [37,38]. Of note, all these studies are based on mixed lymphocyte cultures and it is difficult to dissect if the inhibition is direct or through antigen presenting cells. Indirect inhibition of T cells by CD200R was initially shown in antigen-specific T cell stimulations in vitro, where CD200R-block on monocytes but not on T cells was essential for inhibition [39]. These results were reproduced in a tumor model where CD200-expressing plasmacytoma cells are unable to inhibit cytotoxic T lymphocytes activity directly, but influence T cell function by changing the cytokine profile of tumor associated macrophages</body> </html> </notes> <label text="CD200R1"/> <clone/> <bbox w="80.0" h="50.0" x="1330.0" y="665.0"/> <glyph class="unit of information" id="_dc23a5a2-4c19-430a-a05c-65a81b903cc0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1347.5" y="660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5835_sa220" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:CD200R1 PMID:22264927 CD200 has a short intracellular tail devoid of any known signaling motifs and functions as a ligand for CD200R CD200-positive chronic lymphocytic leukemia (CLL) cells suppress pro-inflammatory cytokine production and tumor cell lysis in mixed lymphocyte cultures, which can be reversed by blocking CD200 antibodies [28,35,36••]. Similarly, CD200 blocking antibodies increase IL-2 and IFNγ production in allogeneic mixed lymphocyte reactions of T cells and dendritic cells (DCs) with melanoma and ovarian cancer cell lines [30]. Knock down of CD200 in melanoma cells also results in enhanced T cell responses in vitro [37,38]. Of note, all these studies are based on mixed lymphocyte cultures and it is difficult to dissect if the inhibition is direct or through antigen presenting cells. Indirect inhibition of T cells by CD200R was initially shown in antigen-specific T cell stimulations in vitro, where CD200R-block on monocytes but not on T cells was essential for inhibition [39]. These results were reproduced in a tumor model where CD200-expressing plasmacytoma cells are unable to inhibit cytotoxic T lymphocytes activity directly, but influence T cell function by changing the cytokine profile of tumor associated macrophages</body> </html> </notes> <label text="CD200R1"/> <clone/> <bbox w="80.0" h="50.0" x="1330.0" y="765.0"/> <glyph class="unit of information" id="_5d6f66dd-dc19-4b03-a205-061e8ba58fee"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1347.5" y="760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5847_sa216" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD244 MODULE:ACTIVATING_CHECKPOINTS PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function PMID:12734329 2B4 is expressed on all NK and a subset of memory/effector CD8(+) T cells. 2B4 binds to CD48 and activates NK cytotoxicity, but its function on CD8(+) T cells is not clear. 2B4/CD48 interaction on adjacent T cells appeared to be critical for cytotoxicity but 2B4 costimulates T cell cytotoxicity even against CD48-negative tumor targets PMID:11739483 Expression of 2B4 is induced on CD8+ T cells after activation in vitro and in vivo. blocking 2B4/CD48 interaction impaired CD48+ 2B4+ T cell proliferation in response to activation.</body> </html> </notes> <label text="CD244"/> <clone/> <bbox w="80.0" h="50.0" x="6190.0" y="685.0"/> <glyph class="unit of information" id="_f417ee4e-a7e8-486a-9504-0188b27c9d5b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6207.5" y="680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5847_sa217" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD244 MODULE:ACTIVATING_CHECKPOINTS PMID:26794910 CD48:CD2 interactions promote immune synapse organization, adhesion, and TCR signaling CD48:CD244 interactions control NK and CTL activation and cytolytic function PMID:12734329 2B4 is expressed on all NK and a subset of memory/effector CD8(+) T cells. 2B4 binds to CD48 and activates NK cytotoxicity, but its function on CD8(+) T cells is not clear. 2B4/CD48 interaction on adjacent T cells appeared to be critical for cytotoxicity but 2B4 costimulates T cell cytotoxicity even against CD48-negative tumor targets PMID:11739483 Expression of 2B4 is induced on CD8+ T cells after activation in vitro and in vivo. blocking 2B4/CD48 interaction impaired CD48+ 2B4+ T cell proliferation in response to activation.</body> </html> </notes> <label text="CD244"/> <clone/> <bbox w="80.0" h="50.0" x="6190.0" y="785.0"/> <glyph class="unit of information" id="_11acce79-3956-43fd-8f0e-0cc0db620db5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6207.5" y="780.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s5848_sa1383" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:SMAC PMID:22566907 The interactions of CD44, primarily with its major ligand, the extra-cellular matrix (ECM) component hyaluronic acid (HA), can be crucial for the recruitment and function of effector and memory T cells into/within inflamed tissues</body> </html> </notes> <label text="Hyaluronic_acid"/> <bbox w="70.0" h="25.0" x="4755.0" y="437.5"/> </glyph> <glyph class="phenotype" id="s4881_sa635" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:11148124 T cell receptor signalling.</body> </html> </notes> <label text="TCR_signaling_induction"/> <bbox w="270.0" h="95.0" x="3215.0" y="132.5"/> </glyph> <glyph class="macromolecule" id="s5852_sa1388" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:ACTIVATING_CHECKPOINTS HUGO:LTA PMID:27192566 HVEM expressed in T cells binds to its ligands: LIGHT and LTα expressed on APC to modulate the proliferation and function of effector T cells.</body> </html> </notes> <label text="LTA"/> <bbox w="80.0" h="40.0" x="5450.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s5853_sa1386" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFRSF14 MODULE:INHIBITING_CHECKPOINTS MODULE:ACTIVATING_CHECKPOINTS PMID:18097025 HVEM is expressed in DCs. PMID:18193050 Binding of HVEM to BTLA or CD160 inhibited T cell activation. PMID:20038811 expression of HVEM by melanoma cells PMID:27192566 HVEM expressed in T cells binds to its ligands: LIGHT and LTα expressed on APC to modulate the proliferation and function of effector T cells via TRAF2 and TRAF3 PMID:19332782 The herpesvirus entry mediator (HVEM; TNFRSF14) activates NF-kappaB through the canonical TNF-related cytokine LIGHT, serving as a costimulatory pathway during activation of T cells. HVEM also functions as a ligand for the Ig superfamily members B and T lymphocyte attenuator (BTLA) and CD160, both of which limit inflammatory responses initiated by T cells.</body> </html> </notes> <label text="HVEM*"/> <clone/> <bbox w="80.0" h="40.0" x="5330.0" y="700.0"/> <glyph class="unit of information" id="_f37402b1-eada-48f6-8df4-541719cee97a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5347.5" y="695.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5853_sa1387" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:TNFRSF14 MODULE:INHIBITING_CHECKPOINTS MODULE:ACTIVATING_CHECKPOINTS PMID:18097025 HVEM is expressed in DCs. PMID:18193050 Binding of HVEM to BTLA or CD160 inhibited T cell activation. PMID:20038811 expression of HVEM by melanoma cells PMID:27192566 HVEM expressed in T cells binds to its ligands: LIGHT and LTα expressed on APC to modulate the proliferation and function of effector T cells via TRAF2 and TRAF3 PMID:19332782 The herpesvirus entry mediator (HVEM; TNFRSF14) activates NF-kappaB through the canonical TNF-related cytokine LIGHT, serving as a costimulatory pathway during activation of T cells. HVEM also functions as a ligand for the Ig superfamily members B and T lymphocyte attenuator (BTLA) and CD160, both of which limit inflammatory responses initiated by T cells.</body> </html> </notes> <label text="HVEM*"/> <clone/> <bbox w="80.0" h="40.0" x="5330.0" y="790.0"/> <glyph class="unit of information" id="_15a3efcc-31e1-41e8-9c95-12862ed2371d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5347.5" y="785.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5854_sa1389" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:VSIR PMID:24691993 VISTA is an immune checkpoint molecule for human T cells. approximately 20% of CD4 and CD8 T cells showed low density VISTA staining VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. VISTA enhances conversion of human naïve T cells into FoxP3+ T cells</body> </html> </notes> <label text="VSIR"/> <clone/> <bbox w="80.0" h="50.0" x="1630.0" y="665.0"/> <glyph class="unit of information" id="_69a61795-3e6c-4af7-89fa-63c9ce515abf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1647.5" y="660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5854_sa1390" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:VSIR PMID:24691993 VISTA is an immune checkpoint molecule for human T cells. approximately 20% of CD4 and CD8 T cells showed low density VISTA staining VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. VISTA enhances conversion of human naïve T cells into FoxP3+ T cells</body> </html> </notes> <label text="VSIR"/> <clone/> <bbox w="80.0" h="50.0" x="1630.0" y="765.0"/> <glyph class="unit of information" id="_a7980ccb-ca69-49ca-918e-468b3616b874"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1647.5" y="760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5855_sa1391" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS HUGO:IGSF11 PMID:29180896 http://www.jimmunol.org.gate2.inist.fr/content/198/1_Supplement/154.1 VSIG-3/IGSF11 is a ligand of VISTA/PD-1H and inhibits human T cell function</body> </html> </notes> <label text="IGSF11"/> <bbox w="80.0" h="40.0" x="1550.0" y="380.0"/> </glyph> <glyph class="phenotype" id="s2246_sa176" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:22437870</body> </html> </notes> <label text="Ligands_of_Inhibiting_immune checkpoints"/> <bbox w="290.0" h="75.0" x="875.0" y="122.5"/> </glyph> <glyph class="macromolecule" id="s5857_sa1392" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:CD274 MODULE:INHIBITING_CHECKPOINTS 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. PMID:18585785; PMID:17629517 human B7-1(CD80) can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. ligation of PD-L1 on T cells by B7-1 inhibits T cell responses in mouse T-cells</body> </html> </notes> <label text="PDL1*"/> <bbox w="80.0" h="40.0" x="1890.0" y="810.0"/> </glyph> <glyph class="phenotype" id="s2245_sa138" compartmentRef="c3_ca3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>PMID:22437870</body> </html> </notes> <label text="Ligands_of_activating_immune checkpoints"/> <bbox w="295.0" h="80.0" x="5552.5" y="170.0"/> </glyph> <glyph class="macromolecule" id="s5858_sa1393" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>MODULE:INHIBITING_CHECKPOINTS PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 In the absence of ligandmediated Tim-3 signaling, Bat3 is bound to Tim-3 and blocks SH2 domain-binding sites in the Tim-3 tail. In this state, Bat3 recruits the catalytically active form of Lck, thereby forming an intracellular molecular complex with Tim-3 that preserves and potentially promotes T cell signaling.Galectin-9 and Ceacam-1 binding to Tim-3 leads to phosphorylation of Y256 and Y263 and release of Bat-3 from the Tim-3 tail, thereby promoting Tim-3-mediated T cell inhibition by allowing binding of SH2 domain-containing Src kinases and subsequent regulation of TCR signaling , Fyn binds to the same region on the Tim-3 tail as Bat3. Fyn has been implicated in the induction of T cell anergy (Davidson et al., 2007) and is known to be a key kinase to activate phosphoprotein associated with glycosphingolipid microdomains (PAG), which recruits Csk to suppress Lck function (Salmond et al., 2009; Smida et al., 2007). Because Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="BAG6"/> <bbox w="80.0" h="40.0" x="630.0" y="850.0"/> </glyph> <glyph class="macromolecule" id="s5859_sa249" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FYN CASCADE:TCR MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells PMID:10648627 Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="FYN"/> <clone/> <bbox w="80.0" h="40.0" x="1215.0" y="937.5"/> <glyph class="state variable" id="_dd6465ad-2678-43bd-8f92-846c070b3cb3"> <state value="" variable="Y417"/> <bbox w="30.0" h="10.0" x="1280.0" y="970.7294"/> </glyph> <glyph class="state variable" id="_12b8ff0d-cc4e-4a74-83d5-882fad08fc05"> <state value="" variable="Y528"/> <bbox w="30.0" h="10.0" x="1203.446" y="932.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s5859_sa1394" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:FYN CASCADE:TCR MODULE:SMAC MODULE:INHIBITING_CHECKPOINTS PMID:19290918 Both Lck and Fyn have C-terminal tyrosine residues (Tyr505 for Lck and Tyr528 for Fyn) that, when phosphorylated by C-terminal src kinase (Csk), act to inhibit kinase function and are therefore referred to as regulatory or inhibitory Tyr residues the CD45 tyrosine phosphatase is key in maintaining the inhibitory C-terminal residues of Lck and Fyn in a dephosphorylated form, allowing the proteins to preserve an open, basally active conformation An additional critical tyrosine residue in the kinase domains of Lck and Fyn (Tyr394 and Tyr417, respectively) facilitates enzymatic activity and is commonly referred to as the activating Tyr residue. This residue is sited in a region called the activation loop (A-loop) of the kinase and in its dephosphorylated state this loop assumes an α-helical conformation which obscures the catalytic cleft, restricting kinase activity (15). Upon activation of src family kinases, via interactions through their SH2/SH3 domains and dephosphorylation of the inhibitory Tyr, their kinase domains are opened up displacing the A-loop helix and making the A-loop accessible to transphosphorylation by the src family kinases themselves. PMID:9738502 Three-dimensional analysis indicated that, as early as 5–13 min after cell conjugation, the Src-family kinases Lck and Fyn were also enriched in the c-SMAC PMID:12218089 Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells PMID:10648627 Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. PMID:27192565; PMID:22863785; PMID: 21807895 BAG6=BAT3 Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, it is possible that a switch between Tim-3-Bat3 and Tim-3- Fyn might trigger the switch of Tim-3 function from being permissive to TCR signaling to inhibition of upstream TCR signaling</body> </html> </notes> <label text="FYN"/> <clone/> <bbox w="80.0" h="40.0" x="770.0" y="820.0"/> <glyph class="state variable" id="_ce4a0259-1066-4324-91dd-51b70c0f204b"> <state value="" variable="Y417"/> <bbox w="30.0" h="10.0" x="835.0" y="853.2294"/> </glyph> <glyph class="state variable" id="_16794699-1daa-4192-8a09-368d289ba6c1"> <state value="" variable="Y528"/> <bbox w="30.0" h="10.0" x="758.44604" y="815.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s5860_sa1395" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:BAD MODULE:TCR_SIGNALING PMID:11342610 Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD.</body> </html> </notes> <label text="BAD"/> <bbox w="80.0" h="40.0" x="3620.0" y="5770.0"/> <glyph class="state variable" id="_328848e2-5a5e-4c9b-8563-d25cc3f6ea29"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3612.5" y="5785.0"/> </glyph> </glyph> <glyph class="phenotype" id="s5187_sa930" compartmentRef="c2_ca2"> <label text="Regulation_of_T-cell_apoptosis"/> <bbox w="170.0" h="35.0" x="3175.0" y="6022.5"/> </glyph> <glyph class="nucleic acid feature" id="s5414_sa1106" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GADD45G CASCADE:IL2 CASCADE:IL12 CASCADE:IL18 MODULE:TCR_SIGNALING MODULE:TH1 PMID:7681987 GADD45G was induced by IL-2 in a T cell line, which suggested a role in T cell activation PMID:11371360 GADD45G was highly expressed in TH1 versus TH2 cells p38 kinase activity was induced when TH1 cells were activated by α-CD3 antibody. However, it was not induced in GADD45γ−/− TH1 effector cells GADD45γ protein therefore mediates TCR-stimulated p38 MAP kinase activation in TH1 effector cells. JNK activity was induced in wild-type TH1 effector cells upon α-CD3 antibody treatment, it was not induced in GADD45γ−/− TH1 effector cells (Figure 4B). Therefore, GADD45γ is required for both p38 and JNK MAP kinase activation through TCR stimulation in TH1 effector cells. The reduction in IFN-γ secretion was the result of reduced expression of IFN-γ mRNA by GADD45γ−/− CD4+ T cells PMID:11175814 IL-12 + IL-18 induces expression of GADD45B and GADD45G mRNA in TH1 cells.</body> </html> </notes> <label text="GADD45G"/> <bbox w="70.0" h="25.0" x="2785.0" y="5452.5"/> </glyph> <glyph class="source and sink" id="s5861_sa1397" compartmentRef="c2_ca2"> <label text="sa1133_degraded"/> <bbox w="30.0" h="30.0" x="5550.0" y="1655.0"/> </glyph> <glyph class="macromolecule" id="s5862_sa1398" compartmentRef="c2_ca2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>HUGO:GRAP MODULE:TCR_SIGNALING CASCADE:TCR PMID:8995379; PMID:9489702 The Grb2‐like adaptor Grap is specifically expressed in lymphocytes. GRAP itreacts with LAT. T cell activation effects an increase in Grap association with p36/38, Shc, Sos, and dynamin.</body> </html> </notes> <label text="GRAP"/> <bbox w="80.0" h="40.0" x="3672.0" y="1776.5"/> </glyph> <glyph class="simple chemical" id="s5863_sa693" compartmentRef="c16_ca16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>CASCADE:CD226 CASCADE:TCR PMID:10811803 The linker for activation of T cells (LAT) is a critical adaptor molecule required for T cell antigen receptor (TCR)-mediated signaling and thymocyte development. Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-γ1 bind LAT via Src homology-2 domains. In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca2+ flux, and activation of AP-1 and NF-AT. 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:15214048 AP-1 activation by Tec is largely dependent on PLCγ1 function. 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id="pr_7d950f4d-a7bc-4af3-9e29-6de6d49c10ba"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>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 induce JNK activation and downstrean c-jun phosphorylation.</body> </html> </notes> <bbox w="10.0" h="10.0" x="1505.0" y="4440.0"/> <port id="pr_7d950f4d-a7bc-4af3-9e29-6de6d49c10ba_p1" x="1510.0" y="4430.0"/> <port id="pr_7d950f4d-a7bc-4af3-9e29-6de6d49c10ba_p2" x="1510.0" y="4460.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5e453ad0-6ad2-4fdf-adc1-fccc5edc93df"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: 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. 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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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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="3425.0" y="4330.0"/> <port id="pr_05fa370c-23f8-4fb7-ac2a-fbdc146a3bd3_p1" x="3430.0" y="4320.0"/> <port id="pr_05fa370c-23f8-4fb7-ac2a-fbdc146a3bd3_p2" x="3430.0" y="4350.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d4c56a5e-3126-49b2-8b21-d6aab1650045"> <bbox w="10.0" h="10.0" x="3783.75" y="4317.5"/> <port id="pr_d4c56a5e-3126-49b2-8b21-d6aab1650045_p1" x="3788.75" y="4307.5"/> <port id="pr_d4c56a5e-3126-49b2-8b21-d6aab1650045_p2" x="3788.75" y="4337.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ad428881-89e4-4d8d-b052-b24124c4dd46"> <bbox w="10.0" h="10.0" x="3195.0" y="4317.5"/> <port id="pr_ad428881-89e4-4d8d-b052-b24124c4dd46_p1" x="3200.0" y="4307.5"/> <port id="pr_ad428881-89e4-4d8d-b052-b24124c4dd46_p2" x="3200.0" y="4337.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c62c1976-88bd-429a-a754-8ce5883b7d40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end 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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