KEGG PATHWAY: hsa04660

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

Disease

H00408	Type I diabetes mellitus
H00540	Osteoporosis, lymphedema, anhydrotic ectodermal dysplasia with immunodeficiency (OLEDAID)
H00645	Incontinentia pigmenti
H00882	Cocoon syndrome

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:

83080

GO:

0050852

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; lymphocyte-specific protein tyrosine kinase [KO:K05856] [EC:2.7.10.2]
2534	FYN; FYN oncogene related to SRC, FGR, YES [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]
11261	CHP1; calcineurin-like EF-hand protein 1 [KO:K06268]
63928	CHP2; calcineurin-like EF-hand protein 2 [KO:K06268]
4776	NFATC4; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 [KO:K04446]
4772	NFATC1; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 [KO:K04446]
10725	NFAT5; nuclear factor of activated T-cells 5, tonicity-responsive [KO:K04446]
4773	NFATC2; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 [KO:K04446]
4775	NFATC3; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3 [KO:K04446]
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; v-Ha-ras Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845	KRAS; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893	NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
5894	RAF1; v-raf-1 murine leukemia viral oncogene homolog 1 [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]
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 reticuloendotheliosis viral oncogene homolog A (avian) [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]
5163	PDK1; pyruvate dehydrogenase kinase, isozyme 1 [KO:K12077] [EC:2.7.11.2]
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 (protein kinase B, gamma) [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, E3 ubiquitin protein ligase C [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, E3 ubiquitin protein ligase B [KO:K04707] [EC:6.3.2.19]
3558	IL2; interleukin 2 [KO:K05429]
3565	IL4; interleukin 4 [KO:K05430]
3567	IL5; interleukin 5 (colony-stimulating factor, eosinophil) [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]
5588	PRKCQ; protein kinase C, theta [KO:K06068] [EC:2.7.11.13]
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

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)

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)

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)

Reference

PMID:15084594

Authors

Huang Y, Wange RL.

Title

T cell receptor signaling: beyond complex complexes.

Journal

J Biol Chem 279:28827-30 (2004)

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)

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)

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)

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)

Reference

PMID:15099566

Authors

Sechi AS, Wehland J.

Title

Interplay between TCR signalling and actin cytoskeleton dynamics.

Journal

Trends Immunol 25:257-65 (2004)

Reference

PMID:12669022

Authors

Okkenhaug K, Vanhaesebroeck B.

Title

PI3K in lymphocyte development, differentiation and activation.

Journal

Nat Rev Immunol 3:317-30 (2003)

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)

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)

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)

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)

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)

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)

Reference

PMID:19132916

Authors

Smith-Garvin JE, Koretzky GA, Jordan MS

Title

T Cell Activation.

Journal

Annu Rev Immunol (2009)

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)

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)

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)

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)

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)

KO pathway

ko04660

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Ontology (3)   
   KEGG BRITE (3)   
Pathway (1)   
   BioSystems (1)   
Disease (4)   
   KEGG DISEASE (4)   
Drug (22)   
   KEGG DRUG (22)   
Genome (1)   
   KEGG GENOME (1)   
Gene (108)   
   KEGG GENES (108)   
All databases (139)   

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