TCR signaling pathway (Bos taurus)

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DAGRearrangementCytoskeletalMAP4K1MAPK9PMAPK8PMAP2K2PCalmodulinCalcineurinIP3ActinLCP2PWASTRB@CBLBCREB1PNFKB1RELRELAPPPCREB1PJUNCHUKPIKBKBPBIKBAPFYBLHBPCD247FOSPTK2BPRKCDPCARD11ITKPPRKCQPCD247PCDC42FYNPSHC1PMAPK14PSH2B3GAB2PCD3EPAK1GRAP2MAPK3PPTPN11GRB2PCD3DCD3EPLCG1PCD3GNFATC2PSTPIP1NFATC2NCK1RAF1PSOS1MAP2K1PMAPK1PMALT1BCL10UbPVAV3PITPR1VAV1PPIK3R2LATPPIK3R1TRA@CD4CD8AZAP70PCD28AKT1PDPK1CBLSKAP1ICOSATF2MAP3K14MAP3K8HRASGTPMAP3K7IKBKGNFKB1RELPRELAPPNFATC1NFATC1TRAF6CRKCRKLDBNLMAPK9PMAPK8PMAPK14PMAPK3PMAPK1PVIMIL17IL1BFASCD83OPRM1IL15RATGFB1IL1ATNFRSF9GATA3IL6CCR5IRF4IL9NFATC1MAP3K8CYNUCYNUCYNUCYNURIPK2CYNUTCR Signaling PathwayProteinReceptorProteinProteinmRNASmall moleculeLigandInduced activationEnzyme complexInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMoleculeLigand


Description

The T-cell antigen receptor (TCR) complex is composed of a ligand-binding subunit, the α and β chains, and a signaling subunit, namely the CD3ε, γ and δ chains and the TCRζ chain. This complex participates in T-cell activation upon the presentation of the antigen peptide (derived from the foreign antigen) bound to the MHC (Class I and Class II) residing on antigen-presenting cells (APCs), including dendritic cells, macrophages and B cells. Co-stimulatory receptors, such as CD2, CD28, CD4, CD8, and integrin molecules, contribute to signal transduction by modulating the response threshold. All the above components along with accessory proteins essential for MHC are a part of the immunological synapse that initiates T-cell activation.

Protein tyrosine phosphorylation mediated by the Src family kinases Lck and Fyn, in turn regulated by CD45, is the initial event in TCR signaling. Lck is activated by the interaction of MHC and CD4 or CD8. It then induces the phosphorylation and activation of TCR-CD3 complex and eventually mediates Fyn activation. The activated Src kinases phosphorylate ITAMs (Immune receptor tyrosine-based activation motifs) present on CD3γ, δ, ε and ζ chain. The 70-kd ζ chain–associated protein kinase (ZAP70) is then recruited to the ITAMs followed by its phosphorylation and subsequent activation which results in further amplification of the response. These activated PTKs induce tyrosine phosphorylation of several polypeptides, including the transmembrane adaptor LAT (Linker Activator for T-Cells). Protein tyrosine phosphorylation subsequently leads to the activation of multiple pathways, including ERK (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase), NF-κB (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and NFAT(Nuclear Factor of Activated T-Cells) pathways, which ultimately induce effector functions.

CD28 ligation by B7-1 or B7-2 helps in bringing the T-Cell and Antigen Presenting Cell membranes into close proximity. This event also provides a co-stimulatory signal leading to the production of IL-2 and T- cell activation. Besides CD28, many other transmembrane receptors also modulate specific elements of TCR signaling. CD28 and CD45 activate Lck which in turn induces the phosphorylation and activation of the TCR-CD3 complex and consequently, the tyrosine kinases Fyn and ZAP70. CD45 plays a role in antagonizing the effect of inhibitory proteins on T-cell activation. ZAP70 induces activation of LAT (Linker for Activation of T-Cells), an integral membrane adaptor protein which further binds to GADS (Growth Factor Receptor-Bound Protein-2-Related Adaptor Protein-2), SLP76 (SH2 Domain-Containing Leukocyte Protein-76), and ITK (IL-2 inducible T-cell kinase). This complex facilitates the activation of PLCG1 (Phospholipase-C-Gamma1) that is responsible for the production of the second messengers DAG (Diacylglycerol) and IP3 (Inositol Triphosphate). DAG activates proteins including PKCθ (Protein Kinase-C-Theta) and Ras, whereas IP3 leads to Ca2+ release from ER and also facilitates influx of extracellular calcium. Increased intracellular Ca2+ activates the phosphatase Calcineurin that dephosphorylates NFAT which then enters the nucleus and promotes transcription.

Activated LAT also binds multiple adaptor proteins including GRB2, GRAP (GRB2- Related Adaptor Protein) and GADS to facilitate activation of serine/threonine kinases such as Raf1, MEK (MAPK/ERK Kinase) and dual-specificity kinases ERK1/2 that are involved in activation of MAPKs (Mitogen activated protein kinases) resulting in the induction of transcription factor Elk1.

ZAP70 also activates IKKs via the CARD11 (Caspase recruitment domain family, member 11) -BCL10 (B-Cell CLL/lymphoma-10)-MALT1 (Mucosa Associated Lymphoid Tissue Lymphoma Translocation Gene-1) complex and MAP3K (activated by PKCθ) which in turn relieve NF-κB of IκB (NF-kappa-B inhibitor beta) and allow its nuclear translocation and transcriptional activation. ZAP70 also activates p38 via Vav, Rac and MKK3/6 (Mitogen-Activated Protein Kinase Kinase-3 / Mitogen-Activated Protein Kinase Kinase-6). p38 then activates the transcription factor ATF2 (Activating Transcription Factor-2). Activated Rac also activates JNK via MEKK1 and MKK4/7 (MKK4 (Mitogen-Activated Protein Kinase Kinase-4/ Mitogen-Activated Protein Kinase Kinase-7) which eventually leads to activation of c-Jun mediated transcription.

SIT (SHP2-Interacting Transmembrane Adaptor Protein) and CTLA4 (Cytotoxic T-Lymphocyte Antigen-4) are transmembrane adaptor proteins that interact with the SHP2 (SH2-containing Protein tyrosine Phosphatase-2) and negatively regulate T-cell activation by inhibiting the phosphorylation of Fyn and CD28 respectively. CTLA4 has a greater affinity for its B7-1/B7-2ligands in comparison toCD28 and thus competes for them. During T-cell activation CTLA4 is endocytosed to quicken the response. ZAP70 facilitates translocation of CTLA4 to the membrane when the response needs to be controlled. PAG (Phosphoprotein Associated with Glycosphingolipid Microdomains), a transmembrane adaptor molecule is associated with CSK (c-Src Tyrosine Kinase), an inhibitor of Src-related protein tyrosine kinases. Overexpression of PAG inhibits TCR-mediated responses. Dual specificity phosphatase 3 (DUSP3) or VHR is also induced by ZAP70 which consequently down regulates ERK activation and thus controls T-cell response.

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Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP69(79955) with a 96.0% conversion rate.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
117623view11:43, 21 May 2021EweitzModified title
89939view13:49, 6 October 2016MkutmonOntology Term : 'T cell receptor signaling pathway' added !
89938view13:49, 6 October 2016MkutmonModified description
80877view15:29, 30 June 2015Mkutmonhomology conversion
63335view21:13, 9 May 2013MaintBotUpdated to 2013 gpml schema
40515view19:29, 1 March 2011MaintBotRemoved redundant pathway information and comments
33758view00:02, 9 December 2009MaintBotAutomatic update of empty xrefs
32490view12:46, 17 August 2009MaintBotFixed text labels
31188view19:29, 13 August 2009MaintBotFixed text labels
30580view22:08, 29 July 2009MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1ProteinENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
ATF2ProteinENSBTAG00000002295 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1386
BCL10ProteinENSBTAG00000013851 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8915
BIKBAProteinENSBTAG00000016683 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
CARD11ProteinENSBTAG00000014698 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:84433
CBLBProteinENSBTAG00000013057 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:868
CBLProteinENSBTAG00000006817 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:867
CCR5RnaENSBTAG00000008099 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1234
CD247ProteinENSBTAG00000012700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:919
CD28ProteinENSBTAG00000007445 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:940
CD3DProteinENSBTAG00000006452 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:915
CD3EProteinENSBTAG00000015710 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:916
CD3GProteinENSBTAG00000006453 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:917
CD4ProteinENSBTAG00000003255 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:920
CD83RnaENSBTAG00000031430 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9308
CD8AProteinENSBTAG00000021141 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:925
CDC42ProteinENSBTAG00000001700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
CHUKProteinENSBTAG00000007591 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
CREB1ProteinENSBTAG00000005474 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1385
CRKProteinENSBTAG00000005665 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1398
CRKLProteinENSBTAG00000045548 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1399
DBNLProteinENSBTAG00000017547 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:28988
FASRnaENSBTAG00000010785 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:355
FOSProteinENSBTAG00000004322 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2353
FYBProteinENSBTAG00000001492 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2533
FYNProteinENSBTAG00000011851 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2534
GAB2Protein
GATA3RnaENSBTAG00000017243 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2625
GRAP2ProteinENSBTAG00000015157 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9402
GRB2ProteinENSBTAG00000004736 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2885
HRASProteinENSBTAG00000046644 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3265
ICOSProteinENSBTAG00000021596 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:29851
IKBKBProteinENSBTAG00000007599 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
IKBKGProteinENSBTAG00000006268 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
IL15RARnaENSBTAG00000006078 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3601
IL17RnaENSBTAG00000002150 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3605
IL1ARnaENSBTAG00000010349 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3552
IL1BRnaENSBTAG00000001321 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3553
IL6RnaENSBTAG00000014921 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3569
IL9RnaENSBTAG00000018290 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3578
IRF4RnaENSBTAG00000002929 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3662
ITKProteinENSBTAG00000000306 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3702
ITPR1ProteinENSBTAG00000020455 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3708
JUNProteinENSBTAG00000004037 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
LATProteinENSBTAG00000021249 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:27040
LCP2ProteinENSBTAG00000009381 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3937
LHBProteinENSBTAG00000038735 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3972
MALT1ProteinENSBTAG00000027916 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10892
MAP2K1ProteinENSBTAG00000033983 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
MAP2K2ProteinENSBTAG00000024450 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5605
MAP3K14ProteinENSBTAG00000007084 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000006062
MAP3K7ProteinENSBTAG00000002625 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6885
MAP3K8RnaENSBTAG00000011600 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1326
MAP4K1ProteinENSBTAG00000021145 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11184
MAPK14ProteinENSBTAG00000020783 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAPK1ProteinENSBTAG00000010312 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3ProteinENSBTAG00000016156 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK8ProteinENSBTAG00000007876 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9ProteinENSBTAG00000004709 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
NCK1ProteinENSBTAG00000018427 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4690
NFATC1RnaENSBTAG00000000656 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4772
NFATC2ProteinENSBTAG00000018270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4773
NFKB1ProteinENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
OPRM1RnaENSBTAG00000019719 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4988
PAK1ProteinENSBTAG00000010191 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5058
PDPK1ProteinENSBTAG00000034436 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5170
PIK3R1ProteinENSBTAG00000010989 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
PIK3R2ProteinHomologyConvert: Multiple homologues found: En:ENSBTAG00000002350;En:ENSBTAG00000002350;
PLCG1ProteinENSBTAG00000017584 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
PRKCDProteinENSBTAG00000008719 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5580
PRKCQProteinENSBTAG00000010664 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5588
PSTPIP1ProteinENSBTAG00000021144 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9051
PTK2BProteinENSBTAG00000005958 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2185
PTPN11ProteinENSBTAG00000002048 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5781
RAF1ProteinENSBTAG00000045748 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
RELAProteinENSBTAG00000013895 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
RELProteinENSBTAG00000015386 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
RIPK2ProteinENSBTAG00000015271 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8767
SH2B3ProteinENSBTAG00000009101 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10019
SHC1ProteinENSBTAG00000019838 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6464
SKAP1ProteinENSBTAG00000000641 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8631
SOS1ProteinENSBTAG00000011643 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6654
TGFB1RnaENSBTAG00000020457 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7040
TNFRSF9RnaENSBTAG00000003313 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3604
TRA@Protein
TRAF6ProteinENSBTAG00000036009 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7189
TRB@Protein
VAV1ProteinENSBTAG00000039160 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7409
VAV3ProteinENSBTAG00000031575 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10451
VIMRnaENSBTAG00000018463 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7431
WASProteinENSBTAG00000046555 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7454
ZAP70ProteinENSBTAG00000005892 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7535

Annotated Interactions

No annotated interactions
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