KEGG   PATHWAY: hsa04660
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
hsa04660

Network
nt06169  Measles virus (MV)
nt06183  Yersinia
nt06537  TCR/BCR signaling
  Element
N00683  CD80/CD86-CD28-PI3K signaling pathway
N01106  TCR-PLCG-ITPR signaling pathway
N01165  PDL/PD1-SHP-PI3K signaling pathway
N01579  CD80/CD86-CTLA4-PP2A signaling pathway
N01696  ICOSLG/ICOS-PI3K signaling pathway
Drug
D00107  Tacrolimus (USP/INN)
D00184  Cyclosporine (USP)
D03420  Cedelizumab (USAN/INN)
D04603  Ipilimumab (USAN/INN)
D04923  Mepolizumab (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/INN)
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/INN)
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/INN)
D12317  Bavunalimab (USAN/INN)
D12332  Zeluvalimab (USAN/INN)
D12347  Volrustomig (USAN)
D12368  Epcoritamab (USAN/INN)
D12448  Botensilimab (USAN/INN)
D12620  Frexalimab (USAN/INN)
D12625  Pegenzileukin (USAN/INN)
D12709  Marlotamig (USAN)
D12721  Avitotamig (USAN)
D12724  Forimtamig (USAN/INN)
D12751  Serplulimab (USAN/INN)
D12762  Soquelitinib (USAN)
D12764  Rilvegostomig (USAN/INN)
D12791  Eciskafusp alfa (USAN/INN)
D12808  Ivonescimab (USAN/INN)
D12833  Lifileucel (USAN/INN)
D12839  Sasanlimab (USAN/INN)
D12850  Imneskibart (USAN)
D12961  Tobemstomig (USAN/INN)
D12990  Etentamig (USAN/INN)
D13005  Vilastobart (USAN/INN)
D13064  Gotistobart (USAN/INN)
Other DBs
GO: 0050852
Organism
Homo sapiens (human) [GN:hsa]
Gene
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
10125  RASGRP1; RAS guanyl releasing protein 1 [KO:K04350]
1019  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
10298  PAK4; p21 (RAC1) activated kinase 4 [KO:K05734] [EC:2.7.11.1]
10451  VAV3; vav guanine nucleotide exchange factor 3 [KO:K05730]
106821730  BUB1B-PAK6; BUB1B-PAK6 readthrough [KO:K05735] [EC:2.7.11.1]
10892  MALT1; MALT1 paracaspase [KO:K07369] [EC:3.4.22.-]
110117499  P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
1326  MAP3K8; mitogen-activated protein kinase kinase kinase 8 [KO:K04415] [EC:2.7.11.25]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
1437  CSF2; colony stimulating factor 2 [KO:K05427]
1493  CTLA4; cytotoxic T-lymphocyte associated protein 4 [KO:K06538]
1739  DLG1; discs large MAGUK scaffold protein 1 [KO:K12076]
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]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
2534  FYN; FYN proto-oncogene, Src family tyrosine kinase [KO:K05703] [EC:2.7.10.2]
27040  LAT; linker for activation of T cells [KO:K07362]
28227  PPP2R3B; protein phosphatase 2 regulatory subunit B''beta [KO:K11583]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
29851  ICOS; inducible T cell costimulator [KO:K06713]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3458  IFNG; interferon gamma [KO:K04687]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
3558  IL2; interleukin 2 [KO:K05429]
3565  IL4; interleukin 4 [KO:K05430]
3567  IL5; interleukin 5 [KO:K05428]
3586  IL10; interleukin 10 [KO:K05443]
3702  ITK; IL2 inducible T cell kinase [KO:K07363] [EC:2.7.10.2]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
387  RHOA; ras homolog family member A [KO:K04513]
3932  LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
3937  LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
4690  NCK1; NCK adaptor protein 1 [KO:K07365]
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]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4793  NFKBIB; NFKB inhibitor beta [KO:K02581]
4794  NFKBIE; NFKB inhibitor epsilon [KO:K05872]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
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]
5133  PDCD1; programmed cell death 1 [KO:K06744]
5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [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]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
55012  PPP2R3C; protein phosphatase 2 regulatory subunit B''gamma [KO:K11583]
5515  PPP2CA; protein phosphatase 2 catalytic subunit alpha [KO:K04382] [EC:3.1.3.16]
5516  PPP2CB; protein phosphatase 2 catalytic subunit beta [KO:K04382] [EC:3.1.3.16]
5518  PPP2R1A; protein phosphatase 2 scaffold subunit Aalpha [KO:K03456]
5519  PPP2R1B; protein phosphatase 2 scaffold subunit Abeta [KO:K03456]
5520  PPP2R2A; protein phosphatase 2 regulatory subunit Balpha [KO:K04354]
5521  PPP2R2B; protein phosphatase 2 regulatory subunit Bbeta [KO:K04354]
5522  PPP2R2C; protein phosphatase 2 regulatory subunit Bgamma [KO:K04354]
5523  PPP2R3A; protein phosphatase 2 regulatory subunit B''alpha [KO:K11583]
5525  PPP2R5A; protein phosphatase 2 regulatory subunit B'alpha [KO:K11584]
5526  PPP2R5B; protein phosphatase 2 regulatory subunit B'beta [KO:K11584]
5527  PPP2R5C; protein phosphatase 2 regulatory subunit B'gamma [KO:K11584]
5528  PPP2R5D; protein phosphatase 2 regulatory subunit B'delta [KO:K11584]
5529  PPP2R5E; protein phosphatase 2 regulatory subunit B'epsilon [KO:K11584]
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]
55844  PPP2R2D; protein phosphatase 2 regulatory subunit Bdelta [KO:K04354]
5588  PRKCQ; protein kinase C theta [KO:K18052] [EC:2.7.11.13]
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]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
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]
5609  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
56924  PAK6; p21 (RAC1) activated kinase 6 [KO:K05735] [EC:2.7.11.1]
57144  PAK5; p21 (RAC1) activated kinase 5 [KO:K05736] [EC:2.7.11.1]
5777  PTPN6; protein tyrosine phosphatase non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
5781  PTPN11; protein tyrosine phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
5788  PTPRC; protein tyrosine phosphatase receptor type C [KO:K06478] [EC:3.1.3.48]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
6885  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
7006  TEC; tec protein tyrosine kinase [KO:K07364] [EC:2.7.10.2]
7124  TNF; tumor necrosis factor [KO:K03156]
7409  VAV1; vav guanine nucleotide exchange factor 1 [KO:K05730]
7410  VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730]
7535  ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360] [EC:2.7.10.2]
8440  NCK2; NCK adaptor protein 2 [KO:K19862]
84433  CARD11; caspase recruitment domain family member 11 [KO:K07367]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
868  CBLB; Cbl proto-oncogene B [KO:K22517] [EC:2.3.2.27]
8915  BCL10; BCL10 immune signaling adaptor [KO:K07368]
9020  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
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]
940  CD28; CD28 molecule [KO:K06470]
9402  GRAP2; GRB2 related adaptor protein 2 [KO:K07366]
959  CD40LG; CD40 ligand [KO:K03161]
998  CDC42; cell division cycle 42 [KO:K04393]
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
Related
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   

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