ENTRY       hsa04660                    Pathway
NAME        T cell receptor signaling pathway - Homo sapiens (human)
DESCRIPTION Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.
CLASS       Organismal Systems; Immune system
PATHWAY_MAP hsa04660  T cell receptor signaling pathway
NETWORK     nt06114  PI3K signaling (viruses)
            nt06120  Calcium signaling (viruses and bacteria)
            nt06169  Measles virus (MV)
  ELEMENT   N00683  CD80/CD86-CD28-PI3K signaling pathway
            N01106  TCR-NFAT signaling pathway
DRUG        D00107  Tacrolimus (USP/INN)
            D00184  Cyclosporine (USP)
            D03420  Cedelizumab (USAN/INN)
            D04603  Ipilimumab (USAN/INN)
            D05092  Muromonab-CD3 (JAN/USAN/INN)
            D05480  Pimecrolimus (JAN/USAN/INN)
            D05610  Priliximab (USAN/INN)
            D05777  Ruplizumab (USAN/INN)
            D06193  Toralizumab (USAN/INN)
            D06314  Visilizumab (USAN/INN)
            D06657  Tremelimumab (USAN/INN)
            D08556  Tacrolimus (INN)
            D08959  Otelixizumab (USAN)
            D08976  Pomalidomide (JAN/USAN/INN)
            D09013  Teplizumab (USAN/INN)
            D09033  Voclosporin (JAN/USAN/INN)
            D09190  Anti-human thymocyte immunoglobulin, rabbit (JAN)
            D09207  Catumaxomab (INN)
            D09325  Blinatumomab (USAN/INN)
            D09575  Ibalizumab (USAN/INN)
            D09671  Sotrastaurin (USAN/INN)
            D09718  Sotrastaurin acetate (USAN)
            D10316  Nivolumab (USAN/INN)
            D10390  Pidilizumab (USAN)
            D10574  Pembrolizumab (USAN)
            D10983  Ruclosporin (USAN/INN)
            D10993  Tucidinostat (JAN/USAN/INN)
            D11108  Cemiplimab (USAN)
            D11122  Letolizumab (USAN/INN)
            D11366  Dostarlimab (USAN)
            D11372  Duvortuxizumab (USAN)
            D11433  Vopratelimab (USAN/INN)
            D11487  Tislelizumab (USAN/INN)
            D11488  Cetrelimab (USAN/INN)
            D11489  Cibisatamab (USAN/INN)
            D11605  Spartalizumab (USAN/INN)
            D11820  Balstilimab (USAN/INN)
            D11823  Zalifrelimab (USAN/INN)
            D11827  Retifanlimab (USAN)
            D11948  Pacmilimab (USAN/INN)
            D11992  Pavurutamab (USAN)
            D11996  Feladilimab (USAN/INN)
            D12007  Ubamatamab (USAN)
            D12058  Elranatamab (USAN)
            D12063  Zimberelimab (USAN)
            D12119  Sintilimab (USAN/INN)
            D12180  Talquetamab (USAN/INN)
            D12186  Vudalimab (USAN)
            D12190  Cadonilimab (USAN)
            D12195  Izuralimab (USAN)
            D12198  Penpulimab (USAN)
            D12202  Toripalimab (USAN/INN)
            D12223  Rosnilimab (USAN)
            D12231  Peresolimab (USAN)
            D12233  Quavonlimab (USAN/INN)
            D12296  Tebentafusp (USAN/INN)
            D12300  Acazicolcept (USAN)
            D12317  Bavunalimab (USAN)
            D12332  Zeluvalimab (USAN/INN)
            D12347  Volrustomig (USAN)
            D12368  Epcoritamab (USAN/INN)
            D12448  Botensilimab (USAN/INN)
DBLINKS     GO: 0050852
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        915  CD3D; CD3 delta subunit of T-cell receptor complex [KO:K06450]
            916  CD3E; CD3 epsilon subunit of T-cell receptor complex [KO:K06451]
            917  CD3G; CD3 gamma subunit of T-cell receptor complex [KO:K06452]
            919  CD247; CD247 molecule [KO:K06453]
            920  CD4; CD4 molecule [KO:K06454]
            925  CD8A; CD8 subunit alpha [KO:K06458]
            926  CD8B; CD8 subunit beta [KO:K06459]
            927  CD8B2; CD8B family member 2 [KO:K06459]
            5788  PTPRC; protein tyrosine phosphatase receptor type C [KO:K06478] [EC:3.1.3.48]
            3932  LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
            2534  FYN; FYN proto-oncogene, Src family tyrosine kinase [KO:K05703] [EC:2.7.10.2]
            7535  ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360] [EC:2.7.10.2]
            3937  LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
            27040  LAT; linker for activation of T cells [KO:K07362]
            3702  ITK; IL2 inducible T cell kinase [KO:K07363] [EC:2.7.10.2]
            7006  TEC; tec protein tyrosine kinase [KO:K07364] [EC:2.7.10.2]
            4690  NCK1; NCK adaptor protein 1 [KO:K07365]
            8440  NCK2; NCK adaptor protein 2 [KO:K19862]
            10451  VAV3; vav guanine nucleotide exchange factor 3 [KO:K05730]
            7409  VAV1; vav guanine nucleotide exchange factor 1 [KO:K05730]
            7410  VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730]
            9402  GRAP2; GRB2 related adaptor protein 2 [KO:K07366]
            2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
            5058  PAK1; p21 (RAC1) activated kinase 1 [KO:K04409] [EC:2.7.11.1]
            5062  PAK2; p21 (RAC1) activated kinase 2 [KO:K04410] [EC:2.7.11.1]
            5063  PAK3; p21 (RAC1) activated kinase 3 [KO:K05733] [EC:2.7.11.1]
            10298  PAK4; p21 (RAC1) activated kinase 4 [KO:K05734] [EC:2.7.11.1]
            57144  PAK5; p21 (RAC1) activated kinase 5 [KO:K05736] [EC:2.7.11.1]
            56924  PAK6; p21 (RAC1) activated kinase 6 [KO:K05735] [EC:2.7.11.1]
            106821730  BUB1B-PAK6; BUB1B-PAK6 readthrough [KO:K05735] [EC:2.7.11.1]
            387  RHOA; ras homolog family member A [KO:K04513]
            998  CDC42; cell division cycle 42 [KO:K04393]
            1739  DLG1; discs large MAGUK scaffold protein 1 [KO:K12076]
            5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
            6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
            5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
            1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
            5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
            5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
            5532  PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
            5533  PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
            5534  PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
            5535  PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268]
            4772  NFATC1; nuclear factor of activated T cells 1 [KO:K04446]
            4773  NFATC2; nuclear factor of activated T cells 2 [KO:K17332]
            4775  NFATC3; nuclear factor of activated T cells 3 [KO:K17333]
            6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
            6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
            10125  RASGRP1; RAS guanyl releasing protein 1 [KO:K04350]
            3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
            3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
            4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
            5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
            5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
            5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
            5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
            5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
            2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
            3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
            5588  PRKCQ; protein kinase C theta [KO:K18052] [EC:2.7.11.13]
            84433  CARD11; caspase recruitment domain family member 11 [KO:K07367]
            8915  BCL10; BCL10 immune signaling adaptor [KO:K07368]
            10892  MALT1; MALT1 paracaspase [KO:K07369] [EC:3.4.22.-]
            6885  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
            5609  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
            5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
            5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
            5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
            1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
            3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
            8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
            4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
            5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
            4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
            4793  NFKBIB; NFKB inhibitor beta [KO:K02581]
            4794  NFKBIE; NFKB inhibitor epsilon [KO:K05872]
            940  CD28; CD28 molecule [KO:K06470]
            29851  ICOS; inducible T cell costimulator [KO:K06713]
            959  CD40LG; CD40 ligand [KO:K03161]
            5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
            5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
            8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
            5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
            5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
            5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
            5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
            207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
            208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
            10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
            1326  MAP3K8; mitogen-activated protein kinase kinase kinase 8 [KO:K04415] [EC:2.7.11.25]
            9020  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
            2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
            5133  PDCD1; programmed cell death 1 [KO:K06744]
            1493  CTLA4; cytotoxic T-lymphocyte associated protein 4 [KO:K06538]
            5777  PTPN6; protein tyrosine phosphatase non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
            868  CBLB; Cbl proto-oncogene B [KO:K22517] [EC:2.3.2.27]
            3558  IL2; interleukin 2 [KO:K05429]
            3565  IL4; interleukin 4 [KO:K05430]
            3567  IL5; interleukin 5 [KO:K05428]
            3586  IL10; interleukin 10 [KO:K05443]
            3458  IFNG; interferon gamma [KO:K04687]
            1437  CSF2; colony stimulating factor 2 [KO:K05427]
            7124  TNF; tumor necrosis factor [KO:K03156]
            1019  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
COMPOUND    C00076  Calcium cation
            C00165  Diacylglycerol
            C01245  D-myo-Inositol 1,4,5-trisphosphate
            C05981  Phosphatidylinositol-3,4,5-trisphosphate
REFERENCE   PMID:15122199
  AUTHORS   Chen L.
  TITLE     Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity.
  JOURNAL   Nat Rev Immunol 4:336-47 (2004)
            DOI:10.1038/nri1349
REFERENCE   PMID:15928679
  AUTHORS   Macian F.
  TITLE     NFAT proteins: key regulators of T-cell development and function.
  JOURNAL   Nat Rev Immunol 5:472-84 (2005)
            DOI:10.1038/nri1632
REFERENCE   PMID:15771581
  AUTHORS   Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL.
  TITLE     Tec family kinases in T lymphocyte development and function.
  JOURNAL   Annu Rev Immunol 23:549-600 (2005)
            DOI:10.1146/annurev.immunol.22.012703.104743
REFERENCE   PMID:15084594
  AUTHORS   Huang Y, Wange RL.
  TITLE     T cell receptor signaling: beyond complex complexes.
  JOURNAL   J Biol Chem 279:28827-30 (2004)
            DOI:10.1074/jbc.R400012200
REFERENCE   PMID:14656980
  AUTHORS   Schmitz ML, Bacher S, Dienz O.
  TITLE     NF-kappaB activation pathways induced by T cell costimulation.
  JOURNAL   FASEB J 17:2187-93 (2003)
            DOI:10.1096/fj.02-1100rev
REFERENCE   PMID:11905831
  AUTHORS   Alegre ML, Frauwirth KA, Thompson CB.
  TITLE     T-cell regulation by CD28 and CTLA-4.
  JOURNAL   Nat Rev Immunol 1:220-8 (2001)
            DOI:10.1038/35105024
REFERENCE   PMID:15286727
  AUTHORS   Horejsi V, Zhang W, Schraven B.
  TITLE     Transmembrane adaptor proteins: organizers of immunoreceptor signalling.
  JOURNAL   Nat Rev Immunol 4:603-16 (2004)
            DOI:10.1038/nri1414
REFERENCE   PMID:15343367
  AUTHORS   Baniyash M.
  TITLE     TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response.
  JOURNAL   Nat Rev Immunol 4:675-87 (2004)
            DOI:10.1038/nri1434
REFERENCE   PMID:15099566
  AUTHORS   Sechi AS, Wehland J.
  TITLE     Interplay between TCR signalling and actin cytoskeleton dynamics.
  JOURNAL   Trends Immunol 25:257-65 (2004)
            DOI:10.1016/j.it.2004.03.003
REFERENCE   PMID:12669022
  AUTHORS   Okkenhaug K, Vanhaesebroeck B.
  TITLE     PI3K in lymphocyte development, differentiation and activation.
  JOURNAL   Nat Rev Immunol 3:317-30 (2003)
            DOI:10.1038/nri1056
REFERENCE   PMID:15489916
  AUTHORS   Palacios EH, Weiss A.
  TITLE     Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation.
  JOURNAL   Oncogene 23:7990-8000 (2004)
            DOI:10.1038/sj.onc.1208074
REFERENCE   PMID:12133805
  AUTHORS   Kane LP, Lin J, Weiss A.
  TITLE     It's all Rel-ative: NF-kappaB and CD28 costimulation of T-cell activation.
  JOURNAL   Trends Immunol 23:413-20 (2002)
            DOI:10.1016/S1471-4906(02)02264-0
REFERENCE   PMID:14647476
  AUTHORS   Acuto O, Michel F.
  TITLE     CD28-mediated co-stimulation: a quantitative support for TCR signalling.
  JOURNAL   Nat Rev Immunol 3:939-51 (2003)
            DOI:10.1038/nri1248
REFERENCE   PMID:15308211
  AUTHORS   Finkelstein LD, Schwartzberg PL.
  TITLE     Tec kinases: shaping T-cell activation through actin.
  JOURNAL   Trends Cell Biol 14:443-51 (2004)
            DOI:10.1016/j.tcb.2003.07.001
REFERENCE   PMID:15345216
  AUTHORS   Duan L, Reddi AL, Ghosh A, Dimri M, Band H.
  TITLE     The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling.
  JOURNAL   Immunity 21:7-17 (2004)
            DOI:10.1016/j.immuni.2004.06.012
REFERENCE   PMID:14617194
  AUTHORS   Schrum AG, Turka LA, Palmer E.
  TITLE     Surface T-cell antigen receptor expression and availability for long-term antigenic signaling.
  JOURNAL   Immunol Rev 196:7-24 (2003)
            DOI:10.1046/j.1600-065X.2003.00083.x
REFERENCE   PMID:19132916
  AUTHORS   Smith-Garvin JE, Koretzky GA, Jordan MS
  TITLE     T cell activation.
  JOURNAL   Annu Rev Immunol 27:591-619 (2009)
            DOI:10.1146/annurev.immunol.021908.132706
REFERENCE   PMID:12195013
  AUTHORS   Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, Crabtree GR, Brown PO
  TITLE     Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation.
  JOURNAL   Proc Natl Acad Sci U S A 99:11796-801 (2002)
            DOI:10.1073/pnas.092284399
REFERENCE   PMID:19290929
  AUTHORS   Blonska M, Lin X
  TITLE     CARMA1-mediated NF-kappaB and JNK activation in lymphocytes.
  JOURNAL   Immunol Rev 228:199-211 (2009)
            DOI:10.1111/j.1600-065X.2008.00749.x
REFERENCE   PMID:17395537
  AUTHORS   Rebeaud F, Hailfinger S, Thome M
  TITLE     Dlgh1 and Carma1 MAGUK proteins contribute to signal specificity downstream of TCR activation.
  JOURNAL   Trends Immunol 28:196-200 (2007)
            DOI:10.1016/j.it.2007.03.004
REFERENCE   PMID:16799472
  AUTHORS   Ashwell JD
  TITLE     The many paths to p38 mitogen-activated protein kinase activation in the immune system.
  JOURNAL   Nat Rev Immunol 6:532-40 (2006)
            DOI:10.1038/nri1865
REFERENCE   PMID:17187070
  AUTHORS   Round JL, Humphries LA, Tomassian T, Mittelstadt P, Zhang M, Miceli MC
  TITLE     Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappaB transcription factors.
  JOURNAL   Nat Immunol 8:154-61 (2007)
            DOI:10.1038/ni1422
REL_PATHWAY hsa04010  MAPK signaling pathway
            hsa04020  Calcium signaling pathway
            hsa04064  NF-kappa B signaling pathway
            hsa04120  Ubiquitin mediated proteolysis
            hsa04151  PI3K-Akt signaling pathway
            hsa04514  Cell adhesion molecules
            hsa04810  Regulation of actin cytoskeleton
KO_PATHWAY  ko04660
///
