TCR signaling (Homo sapiens)

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13, 30, 33621010602327, 614744, 467, 456019, 361238481014, 1619, 36, 57123, 29, 5119, 3618, 20, 21, 50, 5325256335, 64174, 34, 39, 52101015, 26, 49, 56, 5955, 6364211, 28, 4362, 642, 17, 641, 5289, 2410, 3731, 42324240, 41, 607, 457, 45nucleoplasmcytosolPSMC2 T-cell receptor alpha chain V region HPB-MLT precursor HLA class II histocompatibility antigen, DR beta 4 chain HLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DRB1-7 beta chain PSMB4 HLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DRB1-15 beta chain TRBV12-3 T-cell receptor alpha chain V region PY14 precursor BCL10ENAH HLA class II histocompatibility antigen, DRB1-4 beta chain p-Y315,Y493-ZAP70 p-Y317-PAG1 PPiPRKQC closedconformationTRBC1 HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DP PSMB2 HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DR-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-4 beta chain PIK3R2 26S proteasomePRKCQ HLA class II histocompatibility antigen, DRB1-13 beta chain Activated PLC gamma1bound to PIP2Antigen HLA class II histocompatibility antigen, DR alpha chain precursor HLA class II histocompatibility antigen, DR alpha chain precursor CD4 RELA HLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DRB1-14 beta chain ATPDAGs HLA class II histocompatibility antigen, DQ p-6Y-CD247-1 TRBV12-3 DAGs CARMA1 trimerp-S32,36-IkB-alpha:NF-kB complexPSMB11 TRAC p-SLP-76:NCK1HLA class II histocompatibility antigen, DRB1-8 beta chain HLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DRB1-9 beta chain precursor p-Y160,Y171-CD3G Mg2+ PDPK1HLA class II histocompatibility antigen, DRB1-12 beta chain RIPK2HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DQ Antigen-bearing MHCClass II : TCRcomplex:CD4:LckPDPK1 TRBV12-3 FYB HLA class II histocompatibility antigen, DRB1-15 beta chain ADPHLA class II histocompatibility antigen, DQ NCK1p-Y113,Y128,Y145-LCP2T-cell receptor alpha chain V region HPB-MLT precursor CD3E TRAC CUL1 p-Y188,Y199-CD3E p-6Y-CD247-1 TCRB WAS ATPIKKA NF-kB complexActivated CARMA1CARD11 TCRB HLA class II histocompatibility antigen, DRB3-1 beta chain precursor ATPPAK1 HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-1 beta chain p-SLP-76:ADAP:Ena/VASPHLA class II histocompatibility antigen, DRB1-9 beta chain precursor HLA class II histocompatibility antigen, DRB1-1 beta chain HLA class II histocompatibility antigen, DQ beta 2 chain p-Y160,Y171-CD3G PI(3,4,5)P3 PI(3,4,5)P3 ATPATPAntigen-bearing MHCClass II :TCRcomplex:CD4: Lckphosphorylated atTyr394HLA class II histocompatibility antigen, DQ ATPHLA class II histocompatibility antigen, DP alpha chain precursor RELA HLA class II histocompatibility antigen, DRB1-9 beta chain precursor p-Y149,Y160-CD3D TRBC1 HLA class II histocompatibility antigen, DQ phopshorylatedPLC-gamma1 bound toSLP-76HLA class II histocompatibility antigen, DR alpha chain precursor PTPRC TCRB HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor Ub-48-RPS27A(1-76) p-6Y-CD247-1 FYB PhosphorylatedPLC-gamma1 bound toLAT or SLP-76RELA PI(3,4)P2 phosphorylatedPLC-gamma1 bound toLATHLA class II histocompatibility antigen, DRB1-13 beta chain Csk:p-PAGHLA class II histocompatibility antigen, DR beta 4 chain CDC34 PLCG1p-5Y-LAT HLA class II histocompatibility antigen, DR-1 beta chain precursor Ub-124-UBC(77-152) HLA class II histocompatibility antigen, DR-1 beta chain precursor T-cell receptor alpha chain V region PY14 precursor TRBV12-3 Phosphorylated Bcl10bound to CARMA1 andRIP2HLA class II histocompatibility antigen, DRB1-4 beta chain CD4 HLA class II histocompatibility antigen, DRB1-1 beta chain PSMB10 DAGsHLA class II histocompatibility antigen, DQ Ub-200-UBB(153-228) p-Y90-PRKCQ HLA class II histocompatibility antigen, DRB1-13 beta chain HLA class II histocompatibility antigen, DRB1-16 beta chain Antigen-bearing MHCClass II: TCR withphosphorylatedITAMs:CD4Ub-580-UBC(533-608) p-Y113,Y128,Y145-LCP2 p-S552-CARD11 CD3E TRBC1 PTPRJ HLA class II histocompatibility antigen, DRB1-1 beta chain p-Y493-ZAP70 PSMD1 TCRB HLA class II histocompatibility antigen, DRB1-8 beta chain PIP3, PI(3,4)P2PSMC3 HLA class II histocompatibility antigen, DRB1-12 beta chain CD3G p-Y771,Y783,Y1254-PLCG1 GRAP2 PAK1,2,3p-Y113,Y128,Y145-LCP2 GRAP2 TCRB IKBKB HLA class II histocompatibility antigen, DRB1-4 beta chain PSMA2 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor TAB2 TCRA MALT1 Antigen Ubc13:UBE2V1HLA class II histocompatibility antigen, DP TRAC HLA class II histocompatibility antigen, DR beta 5 chain p-5Y-LAT ITK bound toSLP-76:Gads:LATK48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexPDPK1 HLA class II histocompatibility antigen, DRB1-12 beta chain phospho tyrosineZAP-70IKBKG PI(3,4)P2 Antigen PAK2 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor ADPPI(3,4)P2 TRBV12-3 HLA class II histocompatibility antigen, DR beta 5 chain p-Y188,Y199-CD3E TRAC p-Y149,Y160-CD3D HLA class II histocompatibility antigen, DRB1-9 beta chain precursor p-5Y-LAT H2OMALT1 TRBC1 CARD11p-BCL10 SKP1 ADPp-Y394-LCK p-Y394-LCK VASP K63polyUbHLA class II histocompatibility antigen, DR alpha chain precursor PSME3 ADPATPT-cell receptor alpha chain V region PY14 precursor PSMA4 p-T184,T187-MAP3K7 PI(3,4)P2 PIK3CB UBE2D1 PDPK1 CD3G PSMD3 ZAP-70 and ITKtyrosine kinasesHLA class II histocompatibility antigen, DRB1-15 beta chain CARMA1 bound to PDK1Ub-48-UBC(1-76) CD4 Antigen LCP2CD3D TRBV12-3 PLCG1 T-cell receptor alpha chain V region HPB-MLT precursor HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DR beta 4 chain HLA class II histocompatibility antigen, DRB1-11 beta chain Ub-200-UBC(153-228) TCRA CD247-1 PI(3,4)P2 HLA class II histocompatibility antigen, DRB1-7 beta chain NFKB1(1-433) HLA class II histocompatibility antigen, DQ EVL HLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DP HLA class II histocompatibility antigen, DQ CSK p-S552-CARD11 HLA class II histocompatibility antigen, DR alpha chain precursor K63polyUb-NEMO HLA class II histocompatibility antigen, DQ NFKBIA Antigen p-Y394-LCK HLA class II histocompatibility antigen, DRB1-9 beta chain precursor PTEN:Mg2+HLA class II histocompatibility antigen, DRB1-11 beta chain p-BCL10 PLCG1:p-5Y-LATPSMD4 ATPHLA class II histocompatibility antigen, DRB1-14 beta chain TRBC1 p-Y160,Y171-CD3G PI(3,4,5)P3 HLA class II histocompatibility antigen, DRB1-15 beta chain HLA class II histocompatibility antigen, DR beta 4 chain HLA class II histocompatibility antigen, DQ PKC-theta (open):DAGHLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DRB1-8 beta chain HLA class II histocompatibility antigen, DRB1-7 beta chain PAK1 HLA class II histocompatibility antigen, DRB1-16 beta chain PLCG1:p-3Y-SLP-76:Gads:LATPLC-gamma1 bound toLAT or SLP-76p-S552-CARD11 HLA class II histocompatibility antigen, DRB1-16 beta chain PSMB6 HLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-11 beta chain p-Y160,Y171-CD3G CD4 Activated ZAP-70ATPGRAP2 PSMD5 ITKHLA class II histocompatibility antigen, DRB1-16 beta chain NCK1 HLA class II histocompatibility antigen, DRB1-10 beta chain p-Y317-PAG1HLA class II histocompatibility antigen, DR alpha chain precursor PPiPIK3CA HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DR beta 4 chain HLA class II histocompatibility antigen, DR-1 beta chain precursor ATPHLA class II histocompatibility antigen, DRB3-1 beta chain precursor p-Y394-LCK p-5Y-LAT PAK3 p-5Y-LAT p-SLP-76:NCK:PAKHLA class II histocompatibility antigen, DR-1 beta chain precursor PI(4,5)P2HLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-4 beta chain p-S552-CARD11 TRAC PDPK1 TRBC1 HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-15 beta chain TAK1/TAB2 complexbound to TRAF6/CBMcomplexPI(3,4,5)P3 ADPUBE2N PI(3,4)P2 HLA class II histocompatibility antigen, DRB1-8 beta chain Ubc13:UBE2V1p-Y149,Y160-CD3D p-S552-CARD11 PIK3R2 NCK1 HLA class II histocompatibility antigen, DRB1-13 beta chain CD247-1 HLA class II histocompatibility antigen, DR beta 5 chain HLA class II histocompatibility antigen, DQ beta 2 chain PSMD11 HLA class II histocompatibility antigen, DRB1-1 beta chain CD4 HLA class II histocompatibility antigen, DP alpha chain precursor K63polyUbp-Y771,Y783,Y1254-PLCG1 HLA class II histocompatibility antigen, DP ITK CD4 PDPK1 PSMD7 HLA class II histocompatibility antigen, DR beta 5 chain ATPHLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DRB1-9 beta chain precursor VASP TCRB p-Y90,T538,S676,S695-PRKCQ HLA class II histocompatibility antigen, DRB1-8 beta chain HLA class II histocompatibility antigen, DP p-BCL10 HLA class II histocompatibility antigen, DRB1-10 beta chain ATPHLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DRB1-15 beta chain p-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-14 beta chain PIK3CA PSMD12 p-5Y-LATATPADPp-Y63,Y79,Y110-TRAT1 HLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DRB1-15 beta chain HLA class II histocompatibility antigen, DR beta 4 chain p-Y113,Y128,Y145-LCP2 TCRA HLA class II histocompatibility antigen, DR beta 5 chain TCRB HLA class II histocompatibility antigen, DR beta 4 chain NFKB1(1-433) PSMD13 p-BCL10 I(1,4,5)P3PDPK1 HLA class II histocompatibility antigen, DR alpha chain precursor MALT1 trimer boundto Bcl10 and CARMA1trimerTRAC PAK3 ADPGRAP2 PDPK1 MALT1 trimerHLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DR alpha chain precursor Ub-TRAF6 trimerbound to CBMcomplexPSMA8 GRAP2 Active PKC thetabound to DAGZAP-70 bound tophosphorylated ITAMmotifsCSKGRAP2 Ub-504-UBC(457-532) Antigen HLA class II histocompatibility antigen, DP alpha chain precursor PDPK1 GRAP2 HLA class II histocompatibility antigen, DP IKKA HLA class II histocompatibility antigen, DR beta 4 chain PI(3,4)P2 ENAH HLA class II histocompatibility antigen, DRB1-8 beta chain p-Y188,Y199-CD3E HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor UBE2N PI(3,4)P2PI(3,4,5)P3 HLA class II histocompatibility antigen, DRB1-15 beta chain TRBV12-3 PSME1 p-Y113,Y128,Y145-LCP2 p-Y771,Y783,Y1254-PLCG1HLA class II histocompatibility antigen, DRB1-4 beta chain ZAP70PI(3,4,5)P3 IkB(alpha):NF-kBcomplexUb-276-UBC(229-304) PDPK1 p-SLP-76:NCK1:WASPp-Y63,Y79,Y110-TRAT1HLA class II histocompatibility antigen, DRB1-1 beta chain PSMA1 HLA class II histocompatibility antigen, DRB1-1 beta chain ATPTCRA HLA class II histocompatibility antigen, DR beta 5 chain HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DRB1-13 beta chain p-Y113,Y128,Y145-LCP2 TRBC1 ADPHLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DRB1-13 beta chain CD3D HLA class II histocompatibility antigen, DRB1-16 beta chain RELA TCRA ADPHLA class II histocompatibility antigen, DR-1 beta chain precursor PI(3,4)P2 HLA class II histocompatibility antigen, DRB1-13 beta chain Bcl10 bound toCARMA1NFKB1(1-433) p-S552-CARD11 HLA class II histocompatibility antigen, DQ T-cell receptor alpha chain V region PY14 precursor PSMA3 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DRB1-12 beta chain p-Y394-LCK TRBC1 p-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DQ beta 2 chain p-Y771,Y783,Y1254-PLCG1 MALT1 HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-4 beta chain p-6Y-CD247-1 PI(3,4)P2 p-S177,S181-IKKB:IKKA:pUb-NEMOSLP-76 bound toGads:LATp-4Y-PLCG1 HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DRB1-8 beta chain Antigen INPP5DPSMD9 PSMB5 HLA class II histocompatibility antigen, DRB1-11 beta chain DAGs UBE2D2 HLA class II histocompatibility antigen, DRB1-10 beta chain p-Y113,Y128,Y145-LCP2 Ub-428-UBC(381-456) ADPp-Y149,Y160-CD3D HLA class II histocompatibility antigen, DQ p-5Y-LAT PI(4,5)P2DAGsCD3G SCF-beta-TRCPITK p-5Y-LAT TCRA TAB2 PSMD8 HLA class II histocompatibility antigen, DRB1-11 beta chain ADPHLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DQ LCK K48-UbTRAC Antigen MALT1 T-cell receptor alpha chain V region PY14 precursor p-BCL10PTEN Ub-124-UBB(77-152) p-S552-CARD11HLA class II histocompatibility antigen, DQ p-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DR-1 beta chain precursor TCRB Ub-48-UBB(1-76) HLA class II histocompatibility antigen, DRB1-1 beta chain PIK3R1 p-Y113,Y128,Y145-SLP-76:Gads: LATTRAF6 HLA class II histocompatibility antigen, DRB1-11 beta chain p-S552-CARD11 T-cell receptor alpha chain V region HPB-MLT precursor Bcl10 trimer boundto CARMA1 trimerp-5Y-LAT T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DR beta 5 chain PDPK1 CD4 ZAP70 UBE2V1 p-5Y-LAT TCRA HLA class II histocompatibility antigen, DRB1-14 beta chain PI(3,4)P2 UBE2D2,UBE2D1,(CDC34)p-S177,S181-IKKB:IKKA:NEMOPSMD6 HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-14 beta chain RELA PI(3,4,5)P3 HLA class II histocompatibility antigen, DRB1-7 beta chain TRAF6PSMA6 PI3K bound to TRATTRAC HLA class II histocompatibility antigen, DP PDPK1 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor HLA class II histocompatibility antigen, DRB3-1 beta chain precursor K63polyUb TRAF6 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor PSMC4 HLA class II histocompatibility antigen, DQ beta 2 chain T-cell receptor alpha chain V region HPB-MLT precursor PSMD2 HLA class II histocompatibility antigen, DRB1-8 beta chain NF-kB complexp-5Y-LAT PI(3,4)P2 PI(4,5)P2 PSMC6 p-Y188,Y199-CD3E p-BCL10 MALT1 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DRB1-1 beta chain TCRB HLA class II histocompatibility antigen, DR-1 beta chain precursor TRBC1 HLA class II histocompatibility antigen, DRB1-16 beta chain GRAP2 p-S552-CARD11 HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DRB1-12 beta chain UBE2V1 HLA class II histocompatibility antigen, DR beta 5 chain CD4 HLA class II histocompatibility antigen, DRB1-13 beta chain Antigen-bearingMHCClassII:TCRcomplex:CD4:p-Lck(Y505)IKKA T-cell receptor alpha chain V region PY14 precursor p-Y113,Y128,Y145-LCP2 PSMA5 PI3KADPHLA class II histocompatibility antigen, DQ PIK3R1 PSMC1 PI(3,4,5)P3ADPCD3D HLA class II histocompatibility antigen, DRB1-15 beta chain p-Y113,Y128,Y145-LCP2 TRBV12-3 K48PolyUb-K21,22-p-S32,S36-IkBA p-BCL10 HLA class II histocompatibility antigen, DRB1-10 beta chain p-Y505-LCK p-SLP-76:ADAPPSME2 T-cell receptor alpha chain V region HPB-MLT precursor p-6Y-CD247-1 HLA class II histocompatibility antigen, DRB1-12 beta chain Ub-48-UBA52(1-76) ADPPIK3CB PI(3,4,5)P3 HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DRB1-9 beta chain precursor PSMB7 HLA class II histocompatibility antigen, DRB1-10 beta chain EVL Antigen-bearing MHCClass II :TCRcomplex:CD4: Lckphosphorylated atTyr394HLA class II histocompatibility antigen, DQ p-S32,S36-NFKBIA PI(4,5)P2HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DP PSMB1 IKKA:IKBKB:IKBKGHLA class II histocompatibility antigen, DR-1 beta chain precursor p-S552-CARD11 ATPEna/VASP proteinsFBXW11 p-S177,S181-IKBKB p-Y149,Y160-CD3D PLCG1 PSMD14 HLA class II histocompatibility antigen, DRB1-13 beta chain IKBKG ADPHLA class II histocompatibility antigen, DRB3-1 beta chain precursor GRAP2 HLA class II histocompatibility antigen, DQ NFKB1(1-433) CD3E p-Y188,Y199-CD3E CD247-1 PI(3,4,5)P3 ADPp-Y394-LCK PSME4 PSMB9 HLA class II histocompatibility antigen, DR alpha chain precursor H2OCD4 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor TCRA PDK1:PIP2,PIP3HLA class II histocompatibility antigen, DRB1-12 beta chain GRAP2TRAF6 trimer boundto CBM complexCD45,CD148NCK1 HLA class II histocompatibility antigen, DR beta 4 chain p-MAP3K7 BCL10 p-5Y-LAT PSMF1 PSMA7 PiHLA class II histocompatibility antigen, DRB3-1 beta chain precursor T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DRB1-7 beta chain Ub-352-UBC(305-380) Antigen HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor TCRA PLCG1 HLA class II histocompatibility antigen, DQ beta 2 chain GADS:p-5Y-LATCD3E p-S177,S181-IKBKB HLA class II histocompatibility antigen, DRB1-8 beta chain PI(3,4,5)P3 CD3D WASHLA class II histocompatibility antigen, DP alpha chain precursor ATPHLA class II histocompatibility antigen, DRB3-1 beta chain precursor T-cell receptor alpha chain V region HPB-MLT precursor HLA class II histocompatibility antigen, DR beta 5 chain PSMD10 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor NFKB1(1-433) HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor LCP2 Ub-656-UBC(609-684) PSMB8 T-cell receptor alpha chain V region HPB-MLT precursor CD247-1 HLA class II histocompatibility antigen, DQ LATHLA class II histocompatibility antigen, DRB1-14 beta chain T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DRB1-4 beta chain CD3G p-Y90-PKC-theta:DAGHLA class II histocompatibility antigen, DP PI(3,4)P2 ADPK63polyUb TRAF6 BTRC TRAC PSMB3 p-Y160,Y171-CD3G p-Y315,Y493-ZAP70 p-Y113,Y128,Y145-LCP2 PAK2 TRBV12-3 HLA class II histocompatibility antigen, DQ PI(3,4,5)P3 PSMC5 T-cell receptor alpha chain V region HPB-MLT precursor PI(3,4,5)P3 FYBp-Y394-LCK TAB2/TAK1 complex318232222225822225423225422


Description

The TCR is a multisubunit complex that consists of clonotypic alpha/beta chains noncovalently associated with the invariant CD3 delta/epsilon/gamma and TCR zeta chains. T cell activation by antigen presenting cells (APCs) results in the activation of protein tyrosine kinases (PTKs) that associate with CD3 and TCR zeta subunits and the co-receptor CD4. Members of the Src kinases (Lck), Syk kinases (ZAP-70), Tec (Itk) and Csk families of nonreceptor PTKs play a crucial role in T cell activation. Activation of PTKs following TCR engagement results in the recruitment and tyrosine phosphorylation of enzymes such as phospholipase C gamma1 and Vav as well as critical adaptor proteins such as LAT, SLP-76 and Gads. These proximal activation leads to reorganization of the cytoskeleton as well as transcription activation of multiple genes leading to T lymphocyte proliferation, differentiation and/or effector function. View original pathway at:Reactome.

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Bibliography

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  33. Bruyns E, Marie-Cardine A, Kirchgessner H, Sagolla K, Shevchenko A, Mann M, Autschbach F, Bensussan A, Meuer S, Schraven B.; ''T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-zeta complex, recruits intracellular signaling proteins to the plasma membrane.''; PubMed Europe PMC Scholia
  34. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC Scholia
  35. Galisteo ML, Chernoff J, Su YC, Skolnik EY, Schlessinger J.; ''The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1.''; PubMed Europe PMC Scholia
  36. van Leeuwen JE, Samelson LE.; ''T cell antigen-receptor signal transduction.''; PubMed Europe PMC Scholia
  37. Das S, Dixon JE, Cho W.; ''Membrane-binding and activation mechanism of PTEN.''; PubMed Europe PMC Scholia
  38. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
  39. Yablonski D, Kadlecek T, Weiss A.; ''Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT.''; PubMed Europe PMC Scholia
  40. Rudd CE, Wang H.; ''Hematopoietic adaptors in T-cell signaling: potential applications to transplantation.''; PubMed Europe PMC Scholia
  41. Baldi L, Brown K, Franzoso G, Siebenlist U.; ''Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alpha.''; PubMed Europe PMC Scholia
  42. Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ.; ''The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.''; PubMed Europe PMC Scholia
  43. Boerth NJ, Judd BA, Koretzky GA.; ''Functional association between SLAP-130 and SLP-76 in Jurkat T cells.''; PubMed Europe PMC Scholia
  44. Gilmore TD.; ''Introduction to NF-kappaB: players, pathways, perspectives.''; PubMed Europe PMC Scholia
  45. Rueda D, Thome M.; ''Phosphorylation of CARMA1: the link(er) to NF-kappaB activation.''; PubMed Europe PMC Scholia
  46. Kroll M, Conconi M, Desterro MJ, Marin A, Thomas D, Friguet B, Hay RT, Virelizier JL, Arenzana-Seisdedos F, Rodriguez MS.; ''The carboxy-terminus of I kappaB alpha determines susceptibility to degradation by the catalytic core of the proteasome.''; PubMed Europe PMC Scholia
  47. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
  48. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMed Europe PMC Scholia
  49. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed Europe PMC Scholia
  50. Spencer E, Jiang J, Chen ZJ.; ''Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP.''; PubMed Europe PMC Scholia
  51. Musci MA, Hendricks-Taylor LR, Motto DG, Paskind M, Kamens J, Turck CW, Koretzky GA.; ''Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinases.''; PubMed Europe PMC Scholia
  52. Carter RS, Pennington KN, Ungurait BJ, Arrate P, Ballard DW.; ''Signal-induced ubiquitination of I kappaB Kinase-beta.''; PubMed Europe PMC Scholia
  53. Huang Y, Wange RL.; ''T cell receptor signaling: beyond complex complexes.''; PubMed Europe PMC Scholia
  54. Latres E, Chiaur DS, Pagano M.; ''The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.''; PubMed Europe PMC Scholia
  55. Stepanek O, Kalina T, Draber P, Skopcova T, Svojgr K, Angelisova P, Horejsi V, Weiss A, Brdicka T.; ''Regulation of Src family kinases involved in T cell receptor signaling by protein-tyrosine phosphatase CD148.''; PubMed Europe PMC Scholia
  56. Manicassamy S, Gupta S, Sun Z.; ''Selective function of PKC-theta in T cells.''; PubMed Europe PMC Scholia
  57. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP.; ''Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.''; PubMed Europe PMC Scholia
  58. Lin X, Wang D.; ''The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling.''; PubMed Europe PMC Scholia
  59. Hayden MS, Ghosh S.; ''Signaling to NF-kappaB.''; PubMed Europe PMC Scholia
  60. Chan AC, Iwashima M, Turck CW, Weiss A.; ''ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.''; PubMed Europe PMC Scholia
  61. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
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  64. Kölsch U, Arndt B, Reinhold D, Lindquist JA, Jüling N, Kliche S, Pfeffer K, Bruyns E, Schraven B, Simeoni L.; ''Normal T-cell development and immune functions in TRIM-deficient mice.''; PubMed Europe PMC Scholia
  65. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC Scholia
  66. Brdicka T, Pavlistová D, Leo A, Bruyns E, Korínek V, Angelisová P, Scherer J, Shevchenko A, Hilgert I, Cerný J, Drbal K, Kuramitsu Y, Kornacker B, Horejsí V, Schraven B.; ''Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation.''; PubMed Europe PMC Scholia
  67. Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, Jeffery D, Mortara K, Sampang J, Williams SR, Buggy J, Clark JM.; ''Identification of substrates of human protein-tyrosine phosphatase PTPN22.''; PubMed Europe PMC Scholia
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  69. Rohrschneider LR, Fuller JF, Wolf I, Liu Y, Lucas DM.; ''Structure, function, and biology of SHIP proteins.''; PubMed Europe PMC Scholia
  70. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M.; ''A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB.''; PubMed Europe PMC Scholia
  71. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y.; ''Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway.''; PubMed Europe PMC Scholia
  72. Liu SK, Berry DM, McGlade CJ.; ''The role of Gads in hematopoietic cell signalling.''; PubMed Europe PMC Scholia
  73. Maehama T, Dixon JE.; ''The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.''; PubMed Europe PMC Scholia
  74. Melowic HR, Stahelin RV, Blatner NR, Tian W, Hayashi K, Altman A, Cho W.; ''Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Ctheta.''; PubMed Europe PMC Scholia
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  78. Qi Q, August A.; ''Keeping the (kinase) party going: SLP-76 and ITK dance to the beat.''; PubMed Europe PMC Scholia
  79. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114986view16:51, 25 January 2021ReactomeTeamReactome version 75
113430view11:50, 2 November 2020ReactomeTeamReactome version 74
112632view16:01, 9 October 2020ReactomeTeamReactome version 73
101547view11:41, 1 November 2018ReactomeTeamreactome version 66
101082view21:24, 31 October 2018ReactomeTeamreactome version 65
100611view19:58, 31 October 2018ReactomeTeamreactome version 64
100162view16:43, 31 October 2018ReactomeTeamreactome version 63
99712view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93802view13:37, 16 August 2017ReactomeTeamreactome version 61
93340view11:20, 9 August 2017ReactomeTeamreactome version 61
86427view09:17, 11 July 2016ReactomeTeamreactome version 56
83133view10:06, 18 November 2015ReactomeTeamVersion54
81476view13:00, 21 August 2015ReactomeTeamVersion53
76950view08:22, 17 July 2014ReactomeTeamFixed remaining interactions
76655view12:02, 16 July 2014ReactomeTeamFixed remaining interactions
75984view10:04, 11 June 2014ReactomeTeamRe-fixing comment source
75687view11:02, 10 June 2014ReactomeTeamReactome 48 Update
75043view13:55, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74687view08:45, 30 April 2014ReactomeTeamReactome46
68930view17:33, 8 July 2013MaintBotUpdated to 2013 gpml schema
45094view21:15, 6 October 2011KhanspersOntology Term : 'T cell receptor signaling pathway' added !
42142view22:00, 4 March 2011MaintBotAutomatic update
39953view05:58, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated CARMA1ComplexR-HSA-202440 (Reactome)
Activated PLC gamma1 bound to PIP2ComplexR-HSA-202269 (Reactome)
Activated ZAP-70ComplexR-HSA-202181 (Reactome)
Active PKC theta bound to DAGComplexR-HSA-202442 (Reactome)
Antigen R-NUL-173548 (Reactome)
Antigen-bearing

MHC Class II

TCR

complex:CD4:p-Lck(Y505)		ComplexR-HSA-202154 (Reactome)
Antigen-bearing MHC

Class II  : TCR

complex:CD4:Lck		ComplexR-HSA-202157 (Reactome)
Antigen-bearing MHC

Class II :TCR complex:CD4: Lck phosphorylated at

Tyr394		ComplexR-HSA-202266 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated

ITAMs:CD4		ComplexR-HSA-203494 (Reactome)
BCL10 ProteinO95999 (Uniprot-TrEMBL)
BCL10ProteinO95999 (Uniprot-TrEMBL)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
Bcl10 bound to CARMA1ComplexR-HSA-202454 (Reactome) Bcl10 interacts with the oligomerized CARMA1 and this is mediated by the CARD-CARD domainn interaction.
Bcl10 trimer bound to CARMA1 trimerComplexR-HSA-202475 (Reactome)
CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
CARD11ProteinQ9BXL7 (Uniprot-TrEMBL)
CARMA1 bound to PDK1ComplexR-HSA-202349 (Reactome)
CARMA1 trimerComplexR-HSA-202445 (Reactome)
CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
CD3D ProteinP04234 (Uniprot-TrEMBL)
CD3E ProteinP07766 (Uniprot-TrEMBL)
CD3G ProteinP09693 (Uniprot-TrEMBL)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CD45,CD148ComplexR-HSA-6785270 (Reactome)
CDC34 ProteinP49427 (Uniprot-TrEMBL)
CSK ProteinP41240 (Uniprot-TrEMBL)
CSKProteinP41240 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
Csk:p-PAGComplexR-HSA-202297 (Reactome)
DAGs MetaboliteCHEBI:18035 (ChEBI)
DAGsMetaboliteCHEBI:18035 (ChEBI)
ENAH ProteinQ8N8S7 (Uniprot-TrEMBL)
EVL ProteinQ9UI08 (Uniprot-TrEMBL)
Ena/VASP proteinsComplexR-HSA-430213 (Reactome)
FBXW11 ProteinQ9UKB1 (Uniprot-TrEMBL)
FYB ProteinO15117 (Uniprot-TrEMBL)
FYBProteinO15117 (Uniprot-TrEMBL)
GADS:p-5Y-LATComplexR-HSA-202177 (Reactome)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRAP2ProteinO75791 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HLA class II histocompatibility antigen, DP ProteinP04440 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DP alpha chain precursor ProteinP20036 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01906 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01909 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01920 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ beta 2 chain ProteinP05538 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor ProteinP01920 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR alpha chain precursor ProteinP01903 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR beta 4 chain ProteinP13762 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR beta 5 chain ProteinQ30154 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR-1 beta chain precursor ProteinP01912 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-1 beta chain ProteinP04229 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-10 beta chain ProteinQ30167 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-11 beta chain ProteinP20039 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-12 beta chain ProteinQ95IE3 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-13 beta chain ProteinQ5Y7A7 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-14 beta chain ProteinQ9GIY3 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-15 beta chain ProteinP01911 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-16 beta chain ProteinQ29974 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-4 beta chain ProteinP13760 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-7 beta chain ProteinP13761 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-8 beta chain ProteinQ30134 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-9 beta chain precursor ProteinQ9TQE0 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB3-1 beta chain precursor ProteinP79483 (Uniprot-TrEMBL)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA ProteinO15111 (Uniprot-TrEMBL)
IKKA:IKBKB:IKBKGComplexR-HSA-168113 (Reactome)
INPP5DProteinQ92835 (Uniprot-TrEMBL)
ITK ProteinQ08881 (Uniprot-TrEMBL)
ITK bound to SLP-76:Gads:LATComplexR-HSA-202359 (Reactome)
ITKProteinQ08881 (Uniprot-TrEMBL)
IkB(alpha):NF-kB complexComplexR-HSA-193938 (Reactome)
K48-UbComplexR-HSA-912722 (Reactome) The most studied polyubiquitin chains - lysine48-linked - target proteins for destruction
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexComplexR-HSA-5607697 (Reactome)
K48PolyUb-K21,22-p-S32,S36-IkBA ProteinP25963 (Uniprot-TrEMBL)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-NEMO ProteinQ9Y6K9 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LATProteinO43561 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCP2 ProteinQ13094 (Uniprot-TrEMBL)
LCP2ProteinQ13094 (Uniprot-TrEMBL)
MALT1 ProteinQ9UDY8 (Uniprot-TrEMBL)
MALT1 trimer bound

to Bcl10 and CARMA1

trimer		ComplexR-HSA-202468 (Reactome)
MALT1 trimerComplexR-HSA-202487 (Reactome)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCK1ProteinP16333 (Uniprot-TrEMBL)
NF-kB complexComplexR-HSA-194043 (Reactome)
NF-kB complexComplexR-HSA-194047 (Reactome)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK1,2,3ComplexR-HSA-390765 (Reactome)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PAK3 ProteinO75914 (Uniprot-TrEMBL)
PDK1:PIP2,PIP3ComplexR-HSA-202311 (Reactome)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI(3,4)P2 MetaboliteCHEBI:16152 (ChEBI)
PI(3,4)P2MetaboliteCHEBI:16152 (ChEBI)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K bound to TRATComplexR-HSA-202283 (Reactome)
PI3KComplexR-HSA-74693 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIP3, PI(3,4)P2ComplexR-HSA-R-ALL-202277 (Reactome)
PKC-theta (open): DAGComplexR-HSA-202187 (Reactome)
PLC-gamma1 bound to LAT or SLP-76ComplexR-HSA-202318 (Reactome)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG1:p-3Y-SLP-76:Gads:LATComplexR-HSA-202279 (Reactome)
PLCG1:p-5Y-LATComplexR-HSA-202240 (Reactome)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
PRKQC closed conformationProteinQ04759 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PTEN ProteinP60484 (Uniprot-TrEMBL)
PTEN:Mg2+ComplexR-HSA-199426 (Reactome)
PTPRC ProteinP08575 (Uniprot-TrEMBL)
PTPRJ ProteinQ12913 (Uniprot-TrEMBL)
Phosphorylated

PLC-gamma1 bound to

LAT or SLP-76		ComplexR-HSA-202193 (Reactome)
Phosphorylated Bcl10

bound to CARMA1 and

RIP2		ComplexR-HSA-202480 (Reactome) Bcl10 interacts with the oligomerized CARMA1 and this is mediated by the CARD-CARD domainn interaction.
PiMetaboliteCHEBI:18367 (ChEBI)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RIPK2ProteinO43353 (Uniprot-TrEMBL)
SCF-beta-TRCPComplexR-HSA-5607687 (Reactome)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SLP-76 bound to Gads:LATComplexR-HSA-202151 (Reactome)
T-cell receptor alpha chain V region HPB-MLT precursor ProteinP04436 (Uniprot-TrEMBL)
T-cell receptor alpha chain V region PY14 precursor ProteinP01737 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB2/TAK1 complexComplexR-HSA-202504 (Reactome)
TAK1/TAB2 complex

bound to TRAF6/CBM

complex		ComplexR-HSA-202507 (Reactome)
TCRA ProteinP04437 (Uniprot-TrEMBL)
TCRB ProteinP04435 (Uniprot-TrEMBL)
TRAC ProteinP01848 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6 trimer bound to CBM complexComplexR-HSA-202471 (Reactome)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRBC1 ProteinP01850 (Uniprot-TrEMBL)
TRBV12-3 ProteinP01733 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D2,UBE2D1,(CDC34)ComplexR-HSA-5607669 (Reactome)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-124-UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-124-UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-200-UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-200-UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-276-UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-352-UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-428-UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-48-RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Ub-48-UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
Ub-48-UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-48-UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-504-UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-580-UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-656-UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-TRAF6 trimer

bound to CBM

complex		ComplexR-HSA-202456 (Reactome)
Ubc13:UBE2V1ComplexR-HSA-202463 (Reactome)
VASP ProteinP50552 (Uniprot-TrEMBL)
WAS ProteinP42768 (Uniprot-TrEMBL)
WASProteinP42768 (Uniprot-TrEMBL)
ZAP-70 and ITK tyrosine kinasesComplexR-HSA-202282 (Reactome)
ZAP-70 bound to

phosphorylated ITAM

motifs		ComplexR-HSA-202330 (Reactome)
ZAP70 ProteinP43403 (Uniprot-TrEMBL)
ZAP70ProteinP43403 (Uniprot-TrEMBL)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-5Y-LAT ProteinO43561 (Uniprot-TrEMBL)
p-5Y-LATProteinO43561 (Uniprot-TrEMBL)
p-6Y-CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
p-BCL10 ProteinO95999 (Uniprot-TrEMBL)
p-BCL10ProteinO95999 (Uniprot-TrEMBL)
p-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S177,S181-IKKB:IKKA:NEMOComplexR-HSA-202513 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOComplexR-HSA-202562 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexComplexR-HSA-5607671 (Reactome)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-S552-CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
p-S552-CARD11ProteinQ9BXL7 (Uniprot-TrEMBL)
p-SLP-76:ADAP:Ena/VASPComplexR-HSA-430206 (Reactome)
p-SLP-76:ADAPComplexR-HSA-430124 (Reactome)
p-SLP-76:NCK1:WASPComplexR-HSA-430186 (Reactome)
p-SLP-76:NCK1ComplexR-HSA-430188 (Reactome)
p-SLP-76:NCK:PAKComplexR-HSA-430189 (Reactome)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p-Y113,Y128,Y145-LCP2 ProteinQ13094 (Uniprot-TrEMBL)
p-Y113,Y128,Y145-LCP2ProteinQ13094 (Uniprot-TrEMBL)
p-Y113,Y128,Y145-SLP-76:Gads: LATComplexR-HSA-202162 (Reactome)
p-Y149,Y160-CD3D ProteinP04234 (Uniprot-TrEMBL)
p-Y160,Y171-CD3G ProteinP09693 (Uniprot-TrEMBL)
p-Y188,Y199-CD3E ProteinP07766 (Uniprot-TrEMBL)
p-Y315,Y493-ZAP70 ProteinP43403 (Uniprot-TrEMBL)
p-Y317-PAG1 ProteinQ9NWQ8 (Uniprot-TrEMBL)
p-Y317-PAG1ProteinQ9NWQ8 (Uniprot-TrEMBL)
p-Y394-LCK ProteinP06239 (Uniprot-TrEMBL)
p-Y493-ZAP70 ProteinP43403 (Uniprot-TrEMBL)
p-Y505-LCK ProteinP06239 (Uniprot-TrEMBL)
p-Y63,Y79,Y110-TRAT1 ProteinQ6PIZ9 (Uniprot-TrEMBL)
p-Y63,Y79,Y110-TRAT1ProteinQ6PIZ9 (Uniprot-TrEMBL)
p-Y771,Y783,Y1254-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-Y771,Y783,Y1254-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-Y90,T538,S676,S695-PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
p-Y90-PKC-theta:DAGComplexR-HSA-202300 (Reactome)
p-Y90-PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
phopshorylated

PLC-gamma1 bound to

SLP-76		ComplexR-HSA-202302 (Reactome)
phospho tyrosine ZAP-70ComplexR-HSA-202345 (Reactome)
phosphorylated

PLC-gamma1 bound to

LAT		ComplexR-HSA-202310 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-5607724 (Reactome)
ADPArrowR-HSA-202165 (Reactome)
ADPArrowR-HSA-202168 (Reactome)
ADPArrowR-HSA-202174 (Reactome)
ADPArrowR-HSA-202216 (Reactome)
ADPArrowR-HSA-202222 (Reactome)
ADPArrowR-HSA-202233 (Reactome)
ADPArrowR-HSA-202245 (Reactome)
ADPArrowR-HSA-202248 (Reactome)
ADPArrowR-HSA-202291 (Reactome)
ADPArrowR-HSA-202307 (Reactome)
ADPArrowR-HSA-202365 (Reactome)
ADPArrowR-HSA-202437 (Reactome)
ADPArrowR-HSA-202459 (Reactome)
ADPArrowR-HSA-202500 (Reactome)
ADPArrowR-HSA-202510 (Reactome)
ADPArrowR-HSA-202541 (Reactome)
ATPR-HSA-202165 (Reactome)
ATPR-HSA-202168 (Reactome)
ATPR-HSA-202174 (Reactome)
ATPR-HSA-202216 (Reactome)
ATPR-HSA-202222 (Reactome)
ATPR-HSA-202233 (Reactome)
ATPR-HSA-202245 (Reactome)
ATPR-HSA-202248 (Reactome)
ATPR-HSA-202291 (Reactome)
ATPR-HSA-202307 (Reactome)
ATPR-HSA-202365 (Reactome)
ATPR-HSA-202437 (Reactome)
ATPR-HSA-202459 (Reactome)
ATPR-HSA-202500 (Reactome)
ATPR-HSA-202510 (Reactome)
ATPR-HSA-202541 (Reactome)
Activated CARMA1ArrowR-HSA-202437 (Reactome)
Activated CARMA1R-HSA-202443 (Reactome)
Activated PLC gamma1 bound to PIP2ArrowR-HSA-202354 (Reactome)
Activated PLC gamma1 bound to PIP2mim-catalysisR-HSA-202407 (Reactome)
Activated ZAP-70ArrowR-HSA-202174 (Reactome)
Activated ZAP-70mim-catalysisR-HSA-202216 (Reactome)
Activated ZAP-70mim-catalysisR-HSA-202245 (Reactome)
Active PKC theta bound to DAGArrowR-HSA-202222 (Reactome)
Active PKC theta bound to DAGmim-catalysisR-HSA-202437 (Reactome)
Antigen-bearing

MHC Class II

TCR

complex:CD4:p-Lck(Y505)		ArrowR-HSA-202233 (Reactome)
Antigen-bearing

MHC Class II

TCR

complex:CD4:p-Lck(Y505)		R-HSA-202214 (Reactome)
Antigen-bearing MHC

Class II  : TCR

complex:CD4:Lck		ArrowR-HSA-202214 (Reactome)
Antigen-bearing MHC

Class II  : TCR

complex:CD4:Lck		R-HSA-202233 (Reactome)
Antigen-bearing MHC

Class II  : TCR

complex:CD4:Lck		R-HSA-202291 (Reactome)
Antigen-bearing MHC

Class II  : TCR

complex:CD4:Lck		mim-catalysisR-HSA-202291 (Reactome)
Antigen-bearing MHC

Class II :TCR complex:CD4: Lck phosphorylated at

Tyr394		ArrowR-HSA-202291 (Reactome)
Antigen-bearing MHC

Class II :TCR complex:CD4: Lck phosphorylated at

Tyr394		R-HSA-202165 (Reactome)
Antigen-bearing MHC

Class II :TCR complex:CD4: Lck phosphorylated at

Tyr394		mim-catalysisR-HSA-202165 (Reactome)
Antigen-bearing MHC

Class II :TCR complex:CD4: Lck phosphorylated at

Tyr394		mim-catalysisR-HSA-202168 (Reactome)
Antigen-bearing MHC

Class II :TCR complex:CD4: Lck phosphorylated at

Tyr394		mim-catalysisR-HSA-202307 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated

ITAMs:CD4		ArrowR-HSA-202165 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated

ITAMs:CD4		R-HSA-202344 (Reactome)
BCL10R-HSA-202466 (Reactome)
Bcl10 bound to CARMA1ArrowR-HSA-202466 (Reactome)
Bcl10 bound to CARMA1R-HSA-202459 (Reactome)
Bcl10 trimer bound to CARMA1 trimerArrowR-HSA-202489 (Reactome)
Bcl10 trimer bound to CARMA1 trimerR-HSA-202478 (Reactome)
CARD11R-HSA-202394 (Reactome)
CARMA1 bound to PDK1ArrowR-HSA-202394 (Reactome)
CARMA1 bound to PDK1R-HSA-202437 (Reactome)
CARMA1 trimerArrowR-HSA-202443 (Reactome)
CARMA1 trimerR-HSA-202466 (Reactome)
CD45,CD148TBarR-HSA-202233 (Reactome)
CD45,CD148mim-catalysisR-HSA-202214 (Reactome)
CSKR-HSA-203774 (Reactome)
Csk:p-PAGArrowR-HSA-203774 (Reactome)
Csk:p-PAGmim-catalysisR-HSA-202233 (Reactome)
DAGsArrowR-HSA-202407 (Reactome)
DAGsR-HSA-202328 (Reactome)
Ena/VASP proteinsR-HSA-430201 (Reactome)
FYBR-HSA-430135 (Reactome)
GADS:p-5Y-LATArrowR-HSA-202325 (Reactome)
GADS:p-5Y-LATR-HSA-202241 (Reactome)
GRAP2R-HSA-202325 (Reactome)
H2OR-HSA-202214 (Reactome)
H2OR-HSA-202407 (Reactome)
I(1,4,5)P3ArrowR-HSA-202407 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-202500 (Reactome)
INPP5Dmim-catalysisR-HSA-202237 (Reactome)
ITK bound to SLP-76:Gads:LATArrowR-HSA-202375 (Reactome)
ITKR-HSA-202375 (Reactome)
IkB(alpha):NF-kB complexR-HSA-202541 (Reactome)
K48-UbR-HSA-5607728 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexArrowR-HSA-5607728 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexR-HSA-5607724 (Reactome)
K63polyUbR-HSA-202453 (Reactome)
K63polyUbR-HSA-202534 (Reactome)
LATR-HSA-202245 (Reactome)
LCP2R-HSA-202241 (Reactome)
MALT1 trimer bound

to Bcl10 and CARMA1

trimer		ArrowR-HSA-202478 (Reactome)
MALT1 trimer bound

to Bcl10 and CARMA1

trimer		R-HSA-202472 (Reactome)
MALT1 trimerR-HSA-202478 (Reactome)
NCK1R-HSA-430190 (Reactome)
NF-kB complexArrowR-HSA-2730894 (Reactome)
NF-kB complexArrowR-HSA-5607724 (Reactome)
NF-kB complexR-HSA-2730894 (Reactome)
PAK1,2,3R-HSA-430183 (Reactome)
PDK1:PIP2,PIP3ArrowR-HSA-202164 (Reactome)
PDK1:PIP2,PIP3R-HSA-202394 (Reactome)
PDK1:PIP2,PIP3mim-catalysisR-HSA-202222 (Reactome)
PDPK1R-HSA-202164 (Reactome)
PI(3,4)P2ArrowR-HSA-202237 (Reactome)
PI(3,4,5)P3ArrowR-HSA-202365 (Reactome)
PI(3,4,5)P3R-HSA-202237 (Reactome)
PI(3,4,5)P3R-HSA-202371 (Reactome)
PI(4,5)P2ArrowR-HSA-202371 (Reactome)
PI(4,5)P2R-HSA-202354 (Reactome)
PI(4,5)P2R-HSA-202365 (Reactome)
PI(4,5)P2R-HSA-202407 (Reactome)
PI3K bound to TRATArrowR-HSA-202203 (Reactome)
PI3K bound to TRATmim-catalysisR-HSA-202365 (Reactome)
PI3KR-HSA-202203 (Reactome)
PIP3, PI(3,4)P2R-HSA-202164 (Reactome)
PKC-theta (open): DAGArrowR-HSA-202328 (Reactome)
PKC-theta (open): DAGR-HSA-202307 (Reactome)
PLC-gamma1 bound to LAT or SLP-76R-HSA-202248 (Reactome)
PLCG1:p-3Y-SLP-76:Gads:LATArrowR-HSA-202331 (Reactome)
PLCG1:p-5Y-LATArrowR-HSA-202212 (Reactome)
PLCG1R-HSA-202212 (Reactome)
PLCG1R-HSA-202331 (Reactome)
PPiArrowR-HSA-202237 (Reactome)
PPiArrowR-HSA-202371 (Reactome)
PRKQC closed conformationR-HSA-202328 (Reactome)
PTEN:Mg2+mim-catalysisR-HSA-202371 (Reactome)
Phosphorylated

PLC-gamma1 bound to

LAT or SLP-76		ArrowR-HSA-202248 (Reactome)
Phosphorylated Bcl10

bound to CARMA1 and

RIP2		ArrowR-HSA-202459 (Reactome)
Phosphorylated Bcl10

bound to CARMA1 and

RIP2		R-HSA-202489 (Reactome)
PiArrowR-HSA-202214 (Reactome)
R-HSA-202164 (Reactome) PI3K activation results in recruitment of the serine/threonine kinase PDK1, (3-phosphoinositide-dependent kinase 1) to the plasma membrane where PDK1 subsequently phosphorylates and activates AKT. PDK1 with its PH domain binds to either PIP3 or PIP2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions (Vanhaesebroeck & Alessi 2000).
R-HSA-202165 (Reactome) The autophosphorylated, active Lck is now proximally positioned to phosphorylate specific tyrosine residues within ITAMs (immunoreceptor tyrosine-based activation motifs) located within the CD3 and the TCR zeta signaling chains of the TCR. ITAMs consist of evolutionarily conserved amino-acid sequence motifs of D/ExYxxLx(6-8)YxxL. Both the tyrosine residues in the motif are phosphorylated by Lck and the TCR complex include 10 ITAMs with one ITAM in each of the CD3 chains including the three tandem ITAMs in each zeta chains.
R-HSA-202168 (Reactome) In ZAP-70 there are multiple phosphorylation sites (Y292, Y315, Y319, Y492, Y493) which have both positive and negative regulatory effect on its catalytic activity. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck. This phosphorylation contribute to the active conformation of the catalytic domain.
R-HSA-202174 (Reactome) Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319. These sites appear to be positive regulatory sites. ZAP-70 achieve its full activation after the trans-autophosphorylation. Activated ZAP-70 phosphorylates T-cell-specific adaptors, such as LAT and SLP-76 leading to the recruitment and activation of other kinase families and enzymes, resulting in secondary messenger generation and culminating in T cell activation.
R-HSA-202203 (Reactome) In response to the TCR stimulation, phsophoinositides are phosphorylated on the 3-position of the inositol ring by PI3K to generate lipid second messengers that serve as membrane docking sites for a variety of downstream effector proteins such as PDK1 and PKB. PI3K is a heterodimer comprising a regulatory subunit p85 and a catalytic subunit p110 which associate constitutively and are activated upon interaction with tyrosine-phosphorylated proteins at the plasma membrane. The p85 subunit contains two SH2 domains and an SH3 domain. p85 subunit is involved in interaction with two phsophotyrosine residues of the adaptor protein TRIM with its two SH2 domains. This interaction is important in recruiting the p110 subunit to the plasma membrane and activate the p110 kinase activity, which is normally inhibited in the p85-p110 complex.
R-HSA-202212 (Reactome) PLC-gamma1 interacts with its SH2 domain to the pY132 residue of LAT.
R-HSA-202214 (Reactome) TCR stimulation induce the transient dephosphorylation of PAG thereby release the Csk from its plasma membrane anchor. The release of Csk from its proximity with Lck may serve to facilitate the activation of Lck.Protein tyrosine phosphtase CD45 (PTPRC) and CD148 (PTPRJ) have dual function in TCR signalling. They act both in activation as well as inactivation of Src family kinases (SFKs) which are involved in the initiation of TCR signal transduction (Stepanek et al. 2011). The activatory role is to dephosphorylate an inhibitory site tyrosine 505 (Y505) at the C-terminal end of Lck, which is needed to enable Lck to an open conformation and expose the activation loop (A-loop) containing the activating tyrosine 394 (Y394) (Xu et al. 1993. McNeill et al. 2007, Zikherman et al. 2010, Stepanek et al. 2011, Salmond et al. 2009).
R-HSA-202216 (Reactome) Once SLP-76 is recruited to Gads its rapidly phosphorylated on the tyrosine residues in the N-terminal acidic domain. This domain contains three tyrosine phosphorylation sites, Y113, Y128 and Y145. These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 and these phosphorylated tyrosine residues provide the binding site for the SH2 domains of the incoming signaling proteins like Vav, Itk and PLC-gamma1.
R-HSA-202222 (Reactome) Raft localized PKC theta is further phosphorylated and activated by PDK1. The threonine residue (T538) in the kinase domain is the potential target of PDK1. Phosphorylation of this site is critical for the PKC theta kinase activity, and its ability to activate NF-kB pathway. PKC theta is later trans-autophopshorylated on putative phosphorylation sites (S676, S695) for the fine-tuning of its kinase activity.
R-HSA-202233 (Reactome) Lck is a member of the Src family tyrosine kinases and these members have the following domains in common: N-terminal Myristoylation site for saturated fatty acid addition, a unique region, a Src-homology 3 (SH3) domain, an SH2 domain, a tyrosine kinase domain (SH1), and a C-terminal negative regulatory domain. Myristoylation engenders Lck with the ability to attach to cellular membranes. This interaction is mediated by both myristic acid and palmitic acid that are bound to the amino terminal glycine and Cys-3 and/or Cys-5.

The unique region of Lck is thought to be involved in the interaction with the cytoplasmic tails of coreceptors CD4 and CD8. The Lck/CD4 interaction require conserved cysteine motifs: a CxCP motif in CD4 and a CxxC motif in the Lck unique domain. The SH3 and SH2 domains of Lck are involved in intramolecular and intermolecular regulation by mediating protein-protein interactions via poly-proline and phosphotyrosine-specific interactions, respectively.

Lck adopts specific conformation that largely dictate its level of activity. The C-ter tail has an autoinhibitory phosphorylation site (tyr 505). When the Y505 is phosphorylated, Lck adopts a closed conformation, where the pY505 residue creates an intramolecular binding motif for the SH2 domain, effectively inactivating the kinase domain. The inactivating phosphorylation on Y505 is carried out by the Src-specific kinase Csk.
R-HSA-202237 (Reactome) After the generation of PIP3 by PI3K, a part of it is further dephosphorylated to generate other forms of PI which are also involved in signaling. Two major routes for the degradation of PIP3 exists: dephosphorylation by the haematopoietic-specific SH2 domain-containing inositol 5' phosphatase SHIP-1 and dephosphorylation by the 3' phosphoinositide phosphatase PTEN.
SHIP-1 appears to set an activation threshold on T cell signaling. SHIP-1 phosphatase activity removes the 5' phosphate of PIP3 and generate phosphatidylinositol 3,4-bisphosphate. PI(3,4)P2 along with PIP3 preferentially binds to the PH domains of PKB and PDK1.
R-HSA-202241 (Reactome) SLP-76 is an adaptor protein that links proximal and distal T cell receptor signaling events through its function as a molecular scaffold in the assembly of multi molecular signaling complexes. SLP-76 consists of three domains that mediate interactions with many different signaling proteins: an N-terminal acidic domain containing three tyrosine phosphorylation sites, a large central proline-rich region, and a C-terminal SH2 domain. The function of SLP-76 is dependent on its association with Gads. SLP-76 constitutively binds through its 'RxxK' motif in the proline rich region to the SH3 domain of Gads upon TCR activation.
R-HSA-202245 (Reactome) The adaptor molecule LAT (Linker for the Activation of T cells) is a membrane protein that links the TCR signal to the cell activation. It has a total 10 (Y36, Y45, Y64, Y110, Y156, Y161, Y200, Y220, and Y255) conserved TBSMs (tyrosine based signaling motifs) in its cytoplasmic region. These tyrosine residues are phosphorylated by the activated ZAP-70 upon TCR/CD3 complex engagement. Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2 and Gads, and indirectly binds SOS, Vav, SLP-76, and Itk. The residues Y200, Y220 and Y255 are responsible for Grb2 binding, Y200 and Y220 but not Y255, are necessary for Gads binding and Y161 for the PLC-gamma1 binding (numbering based on Uniprot isoform 1).
R-HSA-202248 (Reactome) Three tyrosine residues at positions 771, 783 and 1254 in PLC-gamma1 have been identified as the sites of receptor tyrosine kinase phosphorylation. Of these Y783 and Y1254 are required for activation of PLC-gamma1. The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK.
R-HSA-202291 (Reactome) The binding of CD4/CD8 to non-polymorphic regions of MHC brings Lck in to proximity with TCR subunits phosphorylation. Lck is further phosphorylated to promote the active conformation and to increase their catalytic activity. The C-term domain contain a regulatory activation loop, which is the site of activating Tyr 394 phosphorylation. This tyrosine is auto-phosphorylated to attain an active conformation on TCR stimulation. Now Lck through its kinase activity phosphorylates the ITAMs in TCR zeta and CD3 members.
R-HSA-202307 (Reactome) PKC theta localizes at the interface between T cells and antigen presenting cells. Upon the T cell activation and release of the second messengers Ca++ and DAG by PLC-gamma1, DAG binds to the C1 domain of the PKC theta thereby enhances the attachment to the plasma membrane. Upon membrane translocation, PKC theta is phosphorylated at tyrosine 90 in the C2 like domain. This phosphorylation is mediated by the tyrosine kinase Lck. These association and, most likely, other regulatory interactions, lead to a change in PKC theta conformation into an open, active state whereby it can now access its substrates and phosphorylate them.
R-HSA-202325 (Reactome) Gads is a member of the Grb2 family containing SH2 and SH3 domains with the arrangement SH3-SH2-SH3. Gads binds to the tyrosine phosphorylated residues Y171 and Y191 of LAT through its SH2 domain. It plays a critical role in signaling from the T cell receptor by promoting the formation of a complex between SLP-76 and LAT.
R-HSA-202328 (Reactome) PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.
R-HSA-202331 (Reactome) PLC-gamma1 plays an important role in transducing the external signal in to second messengers by hydrolysing PIP2. PLC-gamma1 contains an N-term PH domain, a catalytic domain 'X' followed by two SH2 domains and an SH3 domain, a C-term catalytic domain 'Y' and a C2 domain (Ca++ binding). PLC-gamma1 interacts with both SLP-76 aswell as LAT. It interacts with its SH3 domain to the proline rich sequence of SLP-76. This interaction aids in localizing PLC-gamma1 to the membrane. This recruitment of PLC-gamma1 to LAT and SLP-76 is essential for its TCR induced tyrosine phosphorylation and activation.
R-HSA-202344 (Reactome) Phosphorylation of the ITAMs by Lck is followed by the recruitment of the ZAP-70 a member of Syk family PTK, to the receptor complex. ZAP-70 is exclusively expressed in T cells and NK cells. The dually phosphorylated ITAMs provide a high-affinity docking site for the tandem SH2-domains of the ZAP-70. Once recruited, ZAP-70 is activated by phosphorylation and will be responsible for the phosphorylation of further downstream molecules. Due to the presence of 10 ITAMs in the TCR complex, up to 10 ZAP-70 molecules may cluster on the fully phosphorylated receptors.
R-HSA-202354 (Reactome) Activated PLA-gamma1 translocates to the plasmamembrane and interacts with the inositol ring of the membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) with its PH domain.
R-HSA-202365 (Reactome) PI3K enzyme bound to adaptor protein TRIM, uses phosphatidylinositol 4,5-bisphosphate (PIP2) as its substrate and phosphorylates it to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and PKB.
R-HSA-202371 (Reactome) PTEN dephosphorylates 3' position of PIP3 to generate PIP2 and negatively regulates the PI3K pathway and PKB activation.
R-HSA-202375 (Reactome) ITK is a member of the Tec protein tyrosine kinase family which forms a complex with SLP-76 after TCR activation. ITK has N-terminal pleckstrin homology (PH) domain, a Tec homology (TH) domain, a proline rich domain, a SH3 domain, an SH2 domain and a C-term kinase domain. The SH2 domain of ITK may interact with Y145 within the N-ter acidic domain of SLP-76 and the SH3 domain of the ITK binds the proline rich region of SLP-76. ITK plays an important role in phosphorylating and activating PLC-gamma-1, leading to the development of second-messenger molecules.
R-HSA-202394 (Reactome) CARMA1 and Bcl10 are the possible link between PKC theta and IKK activation. PDK1 is also required for PKC theta mediated activation of IKK. CARMA1 has a N-terminal CARD motif, a coiled coiled region, a linker region, and a MAGUK-typical PDZ, SH3 and a GUK domains. The linker region is proposed to contain a hinge region and a CARD binding domain. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. CARMA1 is recruited to the plasma membrane by binding to the 'PxxP' motif of membrane bound PDK1 with its SH3 domain.
R-HSA-202407 (Reactome) On recruitment to plasma membrane PLC-gamma1 then hydrolyses PIP2 producing two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 induces a transient increase in intracellular free Ca++, while DAG is a direct activator of protein kinase C (PKC theta). These process have been implicated in many cellular physiological functions like cell proliferation, cell growth and differentiation.
R-HSA-202437 (Reactome) Antigen receptor triggered PKC theta dependent linker phosphorylation of S552 residue is required to release this inhibition and expose the CARD motif for downstream Bcl10 recruitment. PDK1 and maybe other unknown adapter proteins bring PKC theta and CARMA1 into close proximity, facilitating PKC theta mediated CARMA1 phosphorylation and consequent activation.
R-HSA-202443 (Reactome) After the phosphorylation and activation CARMA1 undergoes oligomerization, likely through its CC domain. CARMA1 is thought to oligomerize first as a trimer which triggers downstream oligomerization cascade that is ultimately necessary for the subsequent activation of the IKK complex.
R-HSA-202453 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
R-HSA-202459 (Reactome) Upon interaction with CARMA1, Bcl10 undergoes phosphorylation and oligomerization. The oligomerized Bcl10 acts as a adaptor for the incoming MALT1 and TRAF6. Phosphorylation events of Bcl10 can both positively and negatively regulate the NF-kB pathway. Phosphorylation of Bcl10 that depends on the Ser/Thr kinase RIP2 and correlated with the physical association of Bcl10 with RIP2 has a activation effect on the NF-kB pathway. The target sites of RIP2-mediated phosphorylation has not yet been identified.
R-HSA-202466 (Reactome) Bcl10 is recruited to activated, oligomeric CARMA1 through a CARD-CARD interaction. Bcl10 is characterized by an N-terminal CARD motif and a C-terminal extension of ~130 amino acids rich in serine and threonine residues that serve as targets for multiple phosphorylation events.
R-HSA-202472 (Reactome) TRAF6, which plays central role in innate immune responses, is implicated as proximal downstream effector of MALT1. TRAF6 is a member of the TRAF proteins. It contains an N-term RING domain, followed by several Zn finger domains and C-term MATH domain. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization and thereby activate the ubiquitin ligase activity of TRAF6 to polyubiquitinate itself and NEMO.
R-HSA-202478 (Reactome) Oligomerized Bcl10 facilitates the association with MALT1 to form the CBM signalosome. MALT1 possesses one death domain (DD) and 2 immunoglobulin-like domains (Ig-like) in its N-terminal region and a caspase like domain (CLD) in its C-terminal region. The region between amino acids 107 and 119 of Bcl10 bind to the two Ig-like domains of MALT1. After binding to CARMA1 and Bcl10 complex, MALT1 also undergoes oligomerization. Only the oligomerized forms of Bcl10 and MALT1 are capable of activating IKK.
R-HSA-202489 (Reactome) Association with RIP2 and its phosphorylation allows subsequent trimerization of Bcl10.
R-HSA-202500 (Reactome) The IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex.
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on serine residues (S177 and S181) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
R-HSA-202510 (Reactome) Ubiquitinated TRAF6 recruits TAB2 and activates the TAB2-associated TAK1 kianse by promoting the autophosphorylation of TAK1. TAB2 contains an N-term pseudophosphatase domain, which is indispensable for TAK1 activation, and a C-term domain that binds to and activates TAK1. The activation of TAK1/TAB2 complex requires a ubiquitination reaction catalysed by E1, Ubc13/Uev1A (E2) and TRAF6 (E3). TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 then phosphorylates and activates IKK beta.
R-HSA-202534 (Reactome) During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).
R-HSA-202541 (Reactome) NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin & Ben-Neriah 2000)
R-HSA-203774 (Reactome) Csk is a tyrosine kinase that phosphorylates the negative regulatory C-terminal tyrosine residue Y505 of Lck to maintain Lck in an inactive state. In resting T cells, Csk is targeted to lipid rafts through engagement of its SH2 domain with phosphotyrosine residue pY317 of PAG. PAG is expressed as a tyrosine phosphorylated protein in nonstimulated T-cells. This interaction of Csk and PAG allows activation of Csk and inhibition of Lck. Given that PAG-1 T cell knock out show a weak phenotype, some other protein may substitute in activating Csk.
R-HSA-213406 (Reactome) The activated PLC-gamma1 detaches from its substrate LAT and translocates to the membrane.
R-HSA-213407 (Reactome) The activated PLC-gamma1 detaches from its substrate SLP-76 and translocates to the membrane.
R-HSA-2730894 (Reactome) The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) then moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
R-HSA-430135 (Reactome) SLP-76 inducibly-associates with ADAP (also known as FYN-binding protein or SLAP-130) a hematopoietic-specific adapter protein. ADAP has been implicated in T cell migration and rearrangement of the actin cytoskeleton. In platelets, adhesion to fibrinogen stimulates the association of SLP-76 with ADAP and VASP (Obergfell et al. 2001). ADAP knockout mice exhibit mild thrombocytopenia (Kasirer-Friede et al. 2007).
R-HSA-430180 (Reactome) The second SH3 domain of NCK interacts with the carboxy-terminal SH3 domain of WASP. WASP family proteins bind the Arp2/3 complex, stimulating its ability to nucleate actin filaments and induce filament branching.
R-HSA-430183 (Reactome) NCK binds to PAK through its second SH3 domain. PAK interacts with NCK via the amino terminal SH3 binding domain. This interaction leads to the phosphorylation of NCK at multiple sites.
R-HSA-430190 (Reactome) SLP-76 interacts with the adaptor protein NCK1. This interaction involved the SH2 domain of NCK1, leaving 3 three SH3 domains free to interact with other proteins, notably PAK1, N-WASP and Sos.
R-HSA-430201 (Reactome) ADAP (FYB) is an adaptor protein containing multiple binding motifs including an enabled protein vasodilator-stimulated phosphoprotein homology domain 1 (EVH1)-binding domain. This domain binds Ena-VASP family proteins that regulate actin dynamics. The Ena-VASP family member EVL is found in regions of dynamic actin polymerization, such as F-actin rich patches and the distal tips of microspikes.
R-HSA-5607724 (Reactome) Following ubiquitination Ikappa B-alpha (IKBA) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).
R-HSA-5607728 (Reactome) Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995).
RIPK2mim-catalysisR-HSA-202459 (Reactome)
SCF-beta-TRCPArrowR-HSA-5607728 (Reactome)
SCF-beta-TRCPR-HSA-5607728 (Reactome)
SLP-76 bound to Gads:LATArrowR-HSA-202241 (Reactome)
SLP-76 bound to Gads:LATR-HSA-202216 (Reactome)
TAB2/TAK1 complexR-HSA-202510 (Reactome)
TAB2/TAK1 complexmim-catalysisR-HSA-202510 (Reactome)
TAK1/TAB2 complex

bound to TRAF6/CBM

complex		ArrowR-HSA-202510 (Reactome)
TAK1/TAB2 complex

bound to TRAF6/CBM

complex		mim-catalysisR-HSA-202500 (Reactome)
TRAF6 trimer bound to CBM complexArrowR-HSA-202472 (Reactome)
TRAF6 trimer bound to CBM complexR-HSA-202453 (Reactome)
TRAF6 trimer bound to CBM complexmim-catalysisR-HSA-202453 (Reactome)
TRAF6R-HSA-202472 (Reactome)
UBE2D2,UBE2D1,(CDC34)ArrowR-HSA-5607728 (Reactome)
UBE2D2,UBE2D1,(CDC34)R-HSA-5607728 (Reactome)
Ub-TRAF6 trimer

bound to CBM

complex		ArrowR-HSA-202453 (Reactome)
Ub-TRAF6 trimer

bound to CBM

complex		R-HSA-202510 (Reactome)
Ub-TRAF6 trimer

bound to CBM

complex		mim-catalysisR-HSA-202534 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-202453 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-202534 (Reactome)
Ubc13:UBE2V1R-HSA-202453 (Reactome)
Ubc13:UBE2V1R-HSA-202534 (Reactome)
WASR-HSA-430180 (Reactome)
ZAP-70 and ITK tyrosine kinasesmim-catalysisR-HSA-202248 (Reactome)
ZAP-70 bound to

phosphorylated ITAM

motifs		ArrowR-HSA-202344 (Reactome)
ZAP-70 bound to

phosphorylated ITAM

motifs		R-HSA-202168 (Reactome)
ZAP70R-HSA-202344 (Reactome)
p-5Y-LATArrowR-HSA-202245 (Reactome)
p-5Y-LATArrowR-HSA-213406 (Reactome)
p-5Y-LATR-HSA-202212 (Reactome)
p-5Y-LATR-HSA-202325 (Reactome)
p-BCL10R-HSA-202489 (Reactome)
p-S177,S181-IKKB:IKKA:NEMOArrowR-HSA-202500 (Reactome)
p-S177,S181-IKKB:IKKA:NEMOR-HSA-202534 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOArrowR-HSA-202534 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOmim-catalysisR-HSA-202541 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexArrowR-HSA-202541 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexR-HSA-5607728 (Reactome)
p-S552-CARD11R-HSA-202443 (Reactome)
p-SLP-76:ADAP:Ena/VASPArrowR-HSA-430201 (Reactome)
p-SLP-76:ADAPArrowR-HSA-430135 (Reactome)
p-SLP-76:ADAPR-HSA-430201 (Reactome)
p-SLP-76:NCK1:WASPArrowR-HSA-430180 (Reactome)
p-SLP-76:NCK1ArrowR-HSA-430190 (Reactome)
p-SLP-76:NCK1R-HSA-430180 (Reactome)
p-SLP-76:NCK1R-HSA-430183 (Reactome)
p-SLP-76:NCK:PAKArrowR-HSA-430183 (Reactome)
p-Y113,Y128,Y145-LCP2R-HSA-430135 (Reactome)
p-Y113,Y128,Y145-LCP2R-HSA-430190 (Reactome)
p-Y113,Y128,Y145-SLP-76:Gads: LATArrowR-HSA-202216 (Reactome)
p-Y113,Y128,Y145-SLP-76:Gads: LATArrowR-HSA-213407 (Reactome)
p-Y113,Y128,Y145-SLP-76:Gads: LATR-HSA-202331 (Reactome)
p-Y113,Y128,Y145-SLP-76:Gads: LATR-HSA-202375 (Reactome)
p-Y317-PAG1R-HSA-203774 (Reactome)
p-Y63,Y79,Y110-TRAT1R-HSA-202203 (Reactome)
p-Y771,Y783,Y1254-PLCG1ArrowR-HSA-213406 (Reactome)
p-Y771,Y783,Y1254-PLCG1ArrowR-HSA-213407 (Reactome)
p-Y771,Y783,Y1254-PLCG1R-HSA-202354 (Reactome)
p-Y90-PKC-theta:DAGArrowR-HSA-202307 (Reactome)
p-Y90-PKC-theta:DAGR-HSA-202222 (Reactome)
phopshorylated

PLC-gamma1 bound to

SLP-76		R-HSA-213407 (Reactome)
phospho tyrosine ZAP-70ArrowR-HSA-202168 (Reactome)
phospho tyrosine ZAP-70R-HSA-202174 (Reactome)
phospho tyrosine ZAP-70mim-catalysisR-HSA-202174 (Reactome)
phosphorylated

PLC-gamma1 bound to

LAT		R-HSA-213406 (Reactome)
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