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
T cell receptor signaling pathway
hsa04660

All organismsOrtholog 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)
Drug
D00107  
Tacrolimus hydrate (JP16)
D00184  
Ciclosporin (JP16)
D03222  
Belatacept (USAN/INN)
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)
D06356  
Zanolimumab (USAN/INN)
D06657  
Tremelimumab (USAN/INN)
D08556  
Tacrolimus (INN)
D08959  
Otelixizumab (USAN)
D09013  
Teplizumab (USAN/INN)
D09033  
Voclosporin (USAN/INN)
D09207  
Catumaxomab (INN)
D09325  
Blinatumomab (USAN/INN)
D09575  
Ibalizumab (USAN/INN)
D09671  
Sotrastaurin (USAN/INN)
D09718  
Sotrastaurin acetate (USAN)
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
915  
CD3D; CD3d molecule, delta (CD3-TCR complex) [KO:K06450]
916  
CD3E; CD3e molecule, epsilon (CD3-TCR complex) [KO:K06451]
917  
CD3G; CD3g molecule, gamma (CD3-TCR complex) [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 (TCR) associated protein kinase 70kDa [KO:K07360] [EC:2.7.10.2]
3937  
LCP2; lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa) [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:K07365]
10451  
VAV3; vav 3 guanine nucleotide exchange factor [KO:K05730]
7409  
VAV1; vav 1 guanine nucleotide exchange factor [KO:K05730]
7410  
VAV2; vav 2 guanine nucleotide exchange factor [KO:K05730]
9402  
GRAP2; GRB2-related adaptor protein 2 [KO:K07366]
2885  
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
5058  
PAK1; p21 protein (Cdc42/Rac)-activated kinase 1 [KO:K04409] [EC:2.7.11.1]
5062  
PAK2; p21 protein (Cdc42/Rac)-activated kinase 2 [KO:K04410] [EC:2.7.11.1]
5063  
PAK3; p21 protein (Cdc42/Rac)-activated kinase 3 [KO:K05733] [EC:2.7.11.1]
10298  
PAK4; p21 protein (Cdc42/Rac)-activated kinase 4 [KO:K05734] [EC:2.7.11.1]
56924  
PAK6; p21 protein (Cdc42/Rac)-activated kinase 6 [KO:K05735] [EC:2.7.11.1]
57144  
PAK7; p21 protein (Cdc42/Rac)-activated kinase 7 [KO:K05736] [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 homolog 1 (Drosophila) [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 isozyme [KO:K04348] [EC:3.1.3.16]
5532  
PPP3CB; protein phosphatase 3, catalytic subunit, beta isozyme [KO:K04348] [EC:3.1.3.16]
5533  
PPP3CC; protein phosphatase 3, catalytic subunit, gamma isozyme [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, cytoplasmic, calcineurin-dependent 1 [KO:K04446]
4773  
NFATC2; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 [KO:K17332]
4775  
NFATC3; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3 [KO:K17333]
6654  
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655  
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
10125  
RASGRP1; RAS guanyl releasing protein 1 (calcium and DAG-regulated) [KO:K04350]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [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; FBJ murine osteosarcoma viral oncogene homolog [KO:K04379]
3725  
JUN; jun proto-oncogene [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; mucosa associated lymphoid tissue lymphoma translocation gene 1 [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 kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
8517  
IKBKG; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma [KO:K07210]
4790  
NFKB1; nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 [KO:K02580]
5970  
RELA; v-rel avian reticuloendotheliosis viral oncogene homolog A [KO:K04735]
4792  
NFKBIA; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha [KO:K04734]
4793  
NFKBIB; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, beta [KO:K02581]
4794  
NFKBIE; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon [KO:K05872]
940  
CD28; CD28 molecule [KO:K06470]
29851  
ICOS; inducible T-cell co-stimulator [KO:K06713]
959  
CD40LG; CD40 ligand [KO:K03161]
5295  
PIK3R1; phosphoinositide-3-kinase, regulatory subunit 1 (alpha) [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [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]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5170  
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
207  
AKT1; v-akt murine thymoma viral oncogene homolog 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; v-akt murine thymoma viral oncogene homolog 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; v-akt murine thymoma viral oncogene homolog 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]
23624  
CBLC; Cbl proto-oncogene C, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
867  
CBL; Cbl proto-oncogene, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
868  
CBLB; Cbl proto-oncogene B, E3 ubiquitin protein ligase [KO:K04707] [EC:6.3.2.19]
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 (granulocyte-macrophage) [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)
Reference
  Authors
Macian F.
  Title
NFAT proteins: key regulators of T-cell development and function.
  Journal
Nat Rev Immunol 5:472-84 (2005)
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)
Reference
  Authors
Huang Y, Wange RL.
  Title
T cell receptor signaling: beyond complex complexes.
  Journal
J Biol Chem 279:28827-30 (2004)
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)
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)
Reference
  Authors
Horejsi V, Zhang W, Schraven B.
  Title
Transmembrane adaptor proteins: organizers of immunoreceptor signalling.
  Journal
Nat Rev Immunol 4:603-16 (2004)
Reference
  Authors
Baniyash M.
  Title
TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response.
  Journal
Nat Rev Immunol 4:675-87 (2004)
Reference
  Authors
Sechi AS, Wehland J.
  Title
Interplay between TCR signalling and actin cytoskeleton dynamics.
  Journal
Trends Immunol 25:257-65 (2004)
Reference
  Authors
Okkenhaug K, Vanhaesebroeck B.
  Title
PI3K in lymphocyte development, differentiation and activation.
  Journal
Nat Rev Immunol 3:317-30 (2003)
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)
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)
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)
Reference
  Authors
Finkelstein LD, Schwartzberg PL.
  Title
Tec kinases: shaping T-cell activation through actin.
  Journal
Trends Cell Biol 14:443-51 (2004)
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)
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)
Reference
  Authors
Smith-Garvin JE, Koretzky GA, Jordan MS
  Title
T Cell Activation.
  Journal
Annu Rev Immunol (2009)
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)
Reference
  Authors
Blonska M, Lin X
  Title
CARMA1-mediated NF-kappaB and JNK activation in lymphocytes.
  Journal
Immunol Rev 228:199-211 (2009)
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)
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)
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)
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