KEGG   PATHWAY: hsa04660Help
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
BRITE hierarchy
Pathway map
hsa04660  T cell receptor signaling pathway
hsa04660

Ortholog table
Disease
H00408  Type I diabetes mellitus
H00540  Osteoporosis, lymphedema, anhydrotic ectodermal dysplasia with immunodeficiency (OLEDAID)
H00645  Incontinentia pigmenti
H00882  Cocoon syndrome
H01387  Activated PI3K-delta syndrome (APDS)
H01812  Rasmussen encephalitis
H01970  Lymphoproliferative syndrome 1
Drug
D00107  Tacrolimus (USAN/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)
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 (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)
D10574  Pembrolizumab (USAN)
D10983  Ruclosporin (USAN/INN)
D10993  Tucidinostat (USAN/INN)
Other DBs
BSID: 83080
GO: 0050852
Organism
Homo sapiens (human) [GN:hsa]
Gene
915  CD3D; CD3d molecule [KO:K06450]
916  CD3E; CD3e molecule [KO:K06451]
917  CD3G; CD3g molecule [KO:K06452]
919  CD247; CD247 molecule [KO:K06453]
920  CD4; CD4 molecule [KO:K06454]
925  CD8A; CD8a molecule [KO:K06458]
926  CD8B; CD8b molecule [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; B cell CLL/lymphoma 10 [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]
1147  CHUK; conserved helix-loop-helix ubiquitous kinase [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 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]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
KO pathway
ko04660   

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