TCR signaling (Homo sapiens)

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5, 27, 3350, 518, 32, 363118, 50, 513111, 154438, 4937, 5013, 341717141415019, 4692, 171710, 1430318326, 76, 75110, 146, 7174510, 14, 291722, 39, 41111324, 28, 4316, 21, 23, 25, 4712, 204, 263548, 52T-cell receptor Ubc13UBE2V1 CARMA1 trimer GADSp-5Y-LAT MHC Class II bearing antigen peptide Ub-TRAF6 trimer bound to CBM complex Bcl10 trimer bound to CARMA1 trimer MALT1 trimer CD3 epsilon delta CARMA1 trimer p-S177,S181-IKKBIKKApUb-NEMO TCR chain beta Bcl10 trimer bound to CARMA1 trimer CARMA1 trimer PIP3, PIcytosolPIP3, PIphosphorylated TAK1 bound to TAB2 Antigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4 CARMA1 trimer MHC Class II bearing antigen peptide Activated CARMA1 CD3 zeta dimer with phosphorylated ITAMs HLA II beta chain TCR chain beta p-Y113,Y128,Y145-SLP-76Gads LAT MALT1 trimer p-SLP-76ADAP Antigen-bearing MHC Class II TCR complexCD4 Lck phosphorylated at Tyr394 HLA II beta chain PLCG1p-3Y-SLP-76GadsLAT Ubc13UBE2V1 T-cell receptor complex MHC class II alpha/beta dimer MHC class II alpha/beta dimer Antigen-bearing MHC Class II TCR complexCD4 Lck phosphorylated at Tyr394 PI3K-regulatory subunit TCR chain alpha PIP3, PIT-cell receptor complex Antigen-bearing MHC Class II TCR complexCD4Lck PTENMg2+ PDK1PIP2,PIP3 Active PKC theta bound to DAG MHC Class II bearing antigen peptide TCR chain alpha ITK bound to SLP-76GadsLAT PI3K-regulatory subunit MHC Class II bearing antigen peptide CARMA1 bound to PDK1 p-SLP-76NCKPAK CARMA1 trimer Bcl10 trimer bound to CARMA1 trimer MHC class II alpha/beta dimer Activated ZAP-70 TCR chain alpha HLA II beta chain Activated PLC gamma1 bound to PIP2 T-cell receptor complex with phosphorylated ITAMs MHC Class II bearing antigen peptide PI3K PI3K-catalytic subunit TCR chain alpha PDK1PIP2,PIP3 Bcl10 bound to CARMA1 HLA II alpha chain Antigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4 TAB2/TAK1 complex T-cell receptor complex with phosphorylated ITAMs p-SLP-76NCK1 T-cell receptor complex with phosphorylated ITAMs CD3 zeta dimer with phosphorylated ITAMs PIP3, PINF-kB complex GADSp-5Y-LAT T-cell receptor CD3 epsilon CD3 delta with phosphorylated ITAMs T-cell receptor MHC class II alpha/beta dimer HLA II beta chain PIP3, PIBcl10 trimer bound to CARMA1 trimer CARMA1 trimer p-Y113,Y128,Y145-SLP-76Gads LAT CD3 zeta dimer with phosphorylated ITAMs T-cell receptor Phosphorylated Bcl10 bound to CARMA1 and RIP2 PIP3, PIT-cell receptor MHC Class II bearing antigen peptide HLA II alpha chain PDK1PIP2,PIP3 MALT1 trimer bound to Bcl10 and CARMA1 trimer GADSp-5Y-LAT PDK1PIP2,PIP3 CD3 epsilon delta Antigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4 CD3 epsilon gamma GADSp-5Y-LAT p-SLP-76NCK1 PI3K MALT1 trimer TCR chain alpha MHC class II alpha/beta dimer p-Y90-PKC-thetaDAG PAK PIP3, PIp-S177,S181-IKKBIKKANEMO HLA II beta chain phospho tyrosine ZAP-70 Antigen-bearing MHC Class II TCR complexCD4p-LckT-cell receptor complex HLA II alpha chain PIP3, PIHLA II alpha chain MALT1 trimer bound to Bcl10 and CARMA1 trimer PDK1PIP2,PIP3 HLA II alpha chain T-cell receptor HLA II beta chain SLP-76 bound to GadsLAT T-cell receptor complex with phosphorylated ITAMs TCR chain beta PDK1PIP2,PIP3 CD3 epsilon CD3 gamma with phosphorylated ITAM MALT1 trimer CD3 epsilon CD3 gamma with phosphorylated ITAM CD3 epsilon CD3 delta with phosphorylated ITAMs TRAF6 trimer bound to CBM complex PDK1PIP2,PIP3 T-cell receptor T-cell receptor HLA II alpha chain PIP3, PITCR chain beta IKKAIKKBNEMO p-SLP-76NCK1WASP TCR chain alpha CD3 zeta dimer with phosphorylated ITAMs TCR chain beta MHC class II alpha/beta dimer p-SLP-76NCK1 TCR chain beta p-SLP-76ADAP IkBCARMA1 trimer PIP3, PITCR chain beta PLCG1p-5Y-LAT CD3 epsilon CD3 delta with phosphorylated ITAMs HLA II beta chain CARMA1 trimer MHC class II alpha/beta dimer p-SLP-76ADAPEna/VASP Antigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4 MALT1 trimer CD3 epsilon delta PIP3, PIHLA II alpha chain MHC Class II bearing antigen peptide PDK1PIP2,PIP3 PDK1PIP2,PIP3 phosphorylated PLC-gamma1 bound to LAT MHC Class II bearing antigen peptide PKC-theta Bcl10 trimer bound to CARMA1 trimer CD3 epsilon gamma p-Y113,Y128,Y145-SLP-76Gads LAT phopshorylated PLC-gamma1 bound to SLP-76 CD3 epsilon gamma PDK1PIP2,PIP3 PDK1PIP2,PIP3 T-cell receptor complex CD3 epsilon CD3 delta with phosphorylated ITAMs TCR chain beta TCR chain alpha MALT1 trimer bound to Bcl10 and CARMA1 trimer PI3K bound to TRAT CD3 epsilon CD3 gamma with phosphorylated ITAM CD3 epsilon gamma GADSp-5Y-LAT ZAP-70 bound to phosphorylated ITAM motifs p-Y113,Y128,Y145-SLP-76Gads LAT GADSp-5Y-LAT HLA II beta chain TCR chain alpha HLA II alpha chain CD3 epsilon CD3 gamma with phosphorylated ITAM CD3 epsilon delta Ub-TRAF6 trimer bound to CBM complex MALT1 trimer bound to Bcl10 and CARMA1 trimer Cskp-PAG TAK1/TAB2 complex bound to TRAF6/CBM complex NF-kB complex PI3K-catalytic subunit MHC class II alpha/beta dimer GRAP2 HLA class II histocompatibility antigen, DQ p-5Y-LAT p-S552-CARD11p-S177,S181-IKBKB TRBC1TCRB HLA class II histocompatibility antigen, DRB1-14 beta chain LCP2Ubc13UBE2V1CSKHLA class II histocompatibility antigen, DRB1-4 beta chain TRAF6 trimer bound to CBM complexCD4 TAB2/TAK1 complexHLA class II histocompatibility antigen, DRB1-13 beta chain p-Y160,Y171-CD3G T-cell receptor alpha chain V region HPB-MLT precursor UBE2N PIPDPK1 ATPHLA class II histocompatibility antigen, DR beta 4 chain ADPTRBC1PIHLA class II histocompatibility antigen, DRB1-7 beta chain PI3K bound to TRATPIHLA class II histocompatibility antigen, DRB3-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-11 beta chain CHUK p-BCL10 p-Y394-LCK HLA class II histocompatibility antigen, DRB1-7 beta chain ADPNFKB1HLA class II histocompatibility antigen, DQ PIHLA class II histocompatibility antigen, DP PDPK1 PIK3R2 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor Phosphorylated PLC-gamma1 bound to LAT or SLP-76ATPADPHLA class II histocompatibility antigen, DR beta 5 chain TCRA HLA class II histocompatibility antigen, DRB1-9 beta chain precursor HLA class II histocompatibility antigen, DRB3-1 beta chain precursor HLA class II histocompatibility antigen, DQ p-BCL10 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor RELA NFKBIA HLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DQ p-S552-CARD11p-S552-CARD11HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-15 beta chain ZAP70 PIHLA class II histocompatibility antigen, DQ p-5Y-LAT p-Y90,T538,S676,S695-PRKCQ PITRBV12-3 HLA class II histocompatibility antigen, DRB1-1 beta chain p-Y160,Y171-CD3G p-Y771,Y783,Y1254-PLCG1HLA class II histocompatibility antigen, DRB1-12 beta chain ATPp-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DRB1-8 beta chain PRKQC closed conformationPDPK1 HLA class II histocompatibility antigen, DQ Bcl10 bound to CARMA1HLA class II histocompatibility antigen, DRB3-1 beta chain precursor ATPHLA class II histocompatibility antigen, DQ PDPK1 T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DRB1-8 beta chain ATPp-Y149,Y160-CD3D HLA class II histocompatibility antigen, DRB1-7 beta chain CARD11HLA class II histocompatibility antigen, DR-1 beta chain precursor CD247-1 p-SLP-76NCK1WASPMALT1 ADPPIHLA class II histocompatibility antigen, DQ beta 2 chain T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DQ beta 2 chain PITRACHLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DR alpha chain precursor Cskp-PAGADPCD247-1 PIHLA class II histocompatibility antigen, DQ beta 2 chain IHLA class II histocompatibility antigen, DQB1*0602 beta chain precursor p-S552-CARD11TCRB PLCG1WAS HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DRB1-11 beta chain p-SLP-76ADAPEna/VASPHLA class II histocompatibility antigen, DRB1-9 beta chain precursor HLA class II histocompatibility antigen, DR beta 4 chain phospho tyrosine ZAP-70CD3E PIphosphorylated PLC-gamma1 bound to LATHLA class II histocompatibility antigen, DQ Activated ZAP-70GRAP2 ZAP70HLA class II histocompatibility antigen, DR-1 beta chain precursor HLA class II histocompatibility antigen, DR alpha chain precursor CARMA1 bound to PDK1p-S32,S36-NFKBIANCK1 p-Y505-LCK p-6Y-CD247-1 p-Y317-PAG1 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DQ Phosphorylated Bcl10 bound to CARMA1 and RIP2HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor T-cell receptor alpha chain V region HPB-MLT precursor HLA class II histocompatibility antigen, DRB1-12 beta chain p-Y188,Y199-CD3E GRAP2 RELA HLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DR beta 5 chain PIHLA class II histocompatibility antigen, DRB1-16 beta chain CSK K63polyUb-NEMO PIHLA class II histocompatibility antigen, DR beta 5 chain ZAP-70 and ITK tyrosine kinasesp-5Y-LAT TCRA HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-12 beta chain CD247-1 PITCRB HLA class II histocompatibility antigen, DRB1-9 beta chain precursor HLA class II histocompatibility antigen, DRB1-4 beta chain p-Y771,Y783,Y1254-PLCG1 UBE2V1 H2OHLA class II histocompatibility antigen, DRB1-12 beta chain CHUK PI3KPPiFYBPIUb-TRAF6 trimer bound to CBM complexHLA class II histocompatibility antigen, DRB1-9 beta chain precursor ADPHLA class II histocompatibility antigen, DQ CD4 p-S177,S181-IKKBIKKANEMOTAB2 p-5Y-LATDAGsCD3E TCRA HLA class II histocompatibility antigen, DRB1-14 beta chain CD3D T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DRB3-1 beta chain precursor PDPK1 p-S552-CARD11PIK3R1 HLA class II histocompatibility antigen, DRB1-13 beta chain p-6Y-CD247-1 Bcl10 trimer bound to CARMA1 trimerHLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DR beta 5 chain PDPK1 p-Y63,Y79,Y110-TRAT1T-cell receptor alpha chain V region PY14 precursor CARMA1 trimerAntigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4CARD11ADPHLA class II histocompatibility antigen, DRB1-12 beta chain TRACIkBBCL10 PIp-BCL10 p-BCL10 HLA class II histocompatibility antigen, DR-1 beta chain precursor PIADPPINCK1 TRACHLA class II histocompatibility antigen, DR beta 5 chain HLA class II histocompatibility antigen, DP alpha chain precursor p-Y188,Y199-CD3E HLA class II histocompatibility antigen, DRB1-9 beta chain precursor T-cell receptor alpha chain V region HPB-MLT precursor RIPK2PTENMg2+HLA class II histocompatibility antigen, DRB1-10 beta chain PICD3D K63polyUb TRAF6 TRACPAK2p-SLP-76NCKPAKTCRA ADPPITRBV12-3 GRAP2 HLA class II histocompatibility antigen, DRB1-13 beta chain ITKp-S552-CARD11T-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DP IKBKG TRACMALT1 TAB2 ZAP-70 bound to phosphorylated ITAM motifsH2OHLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DQ ADPHLA class II histocompatibility antigen, DR alpha chain precursor PIHLA class II histocompatibility antigen, DRB1-8 beta chain p-BCL10HLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DRB1-15 beta chain p-5Y-LAT PICD3G HLA class II histocompatibility antigen, DR-1 beta chain precursor MALT1 p-S177,S181-IKKBIKKApUb-NEMOATPHLA class II histocompatibility antigen, DRB1-7 beta chain CD3E HLA class II histocompatibility antigen, DQ T-cell receptor alpha chain V region HPB-MLT precursor PITRACp-Y160,Y171-CD3G IKKAIKKBNEMOITK bound to SLP-76GadsLATHLA class II histocompatibility antigen, DQ p-Y113,Y128,Y145-LCP2 p-MAP3K7 p-T184,T187-MAP3K7 HLA class II histocompatibility antigen, DRB1-14 beta chain p-BCL10 HLA class II histocompatibility antigen, DRB1-16 beta chain UBE2V1 CD4 p-S552-CARD11p-Y63,Y79,Y110-TRAT1 TRBC1PRKCQ TRAF6HLA class II histocompatibility antigen, DRB1-8 beta chain PKC-theta HLA class II histocompatibility antigen, DRB1-1 beta chain HLA class II histocompatibility antigen, DR alpha chain precursor HLA class II histocompatibility antigen, DRB1-13 beta chain K63polyUbT-cell receptor alpha chain V region HPB-MLT precursor TRBV12-3 HLA class II histocompatibility antigen, DQ TAK1/TAB2 complex bound to TRAF6/CBM complexCD4 CD3G HLA class II histocompatibility antigen, DR beta 5 chain p-Y394-LCK HLA class II histocompatibility antigen, DRB1-1 beta chain GRAP2 HLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DQ TCRB HLA class II histocompatibility antigen, DRB1-9 beta chain precursor LCK LATTRBV12-3 PAKCD247-1 HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DRB1-1 beta chain p-Y317-PAG1TCRA HLA class II histocompatibility antigen, DRB1-14 beta chain p-Y188,Y199-CD3E TCRA HLA class II histocompatibility antigen, DRB1-1 beta chain p-SLP-76ADAPp-Y160,Y171-CD3G PIK3R1 TCRB p-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DP alpha chain precursor p-S552-CARD11HLA class II histocompatibility antigen, DRB1-13 beta chain PDPK1Activated PLC gamma1 bound to PIP2HLA class II histocompatibility antigen, DRB1-16 beta chain TRBC1PDPK1 HLA class II histocompatibility antigen, DRB1-13 beta chain HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DP HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-4 beta chain MALT1 trimer bound to Bcl10 and CARMA1 trimerHLA class II histocompatibility antigen, DP PLCG1HLA class II histocompatibility antigen, DRB1-8 beta chain p-Y113,Y128,Y145-LCP2 p-Y394-LCK HLA class II histocompatibility antigen, DRB3-1 beta chain precursor CD4 CD4 DAGsActivated CARMA1PLCG1p-5Y-LATHLA class II histocompatibility antigen, DR alpha chain precursor PDK1PIP2,PIP3HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DRB1-11 beta chain PTEN HLA class II histocompatibility antigen, DR-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DRB1-10 beta chain T-cell receptor alpha chain V region HPB-MLT precursor ADPADPAntigen-bearing MHC Class II TCR complexCD4p-LckPIK3R2 p-Y394-LCK HLA class II histocompatibility antigen, DR beta 4 chain PDPK1 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DRB1-10 beta chain ADPp-6Y-CD247-1 p-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DRB1-1 beta chain T-cell receptor alpha chain V region PY14 precursor PIHLA class II histocompatibility antigen, DQ TCRA HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DR beta 4 chain TCRB HLA class II histocompatibility antigen, DRB3-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-1 beta chain HLA class II histocompatibility antigen, DR-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-15 beta chain GRAP2 p-Y188,Y199-CD3E TCRB FYBUbc13UBE2V1Antigen-bearing MHC Class II TCR complexCD4 Lck phosphorylated at Tyr394IKBKB DAGs PIK3CB p-Y149,Y160-CD3D TRACHLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DQ p-Y113,Y128,Y145-LCP2 TRACTRBC1HLA class II histocompatibility antigen, DR-1 beta chain precursor CD3E WAST-cell receptor alpha chain V region HPB-MLT precursor CD3D PIT-cell receptor alpha chain V region PY14 precursor HLA class II histocompatibility antigen, DR alpha chain precursor p-Y113,Y128,Y145-LCP2 p-Y315,Y493-ZAP70 NCK1HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DQ beta 2 chain p-S552-CARD11HLA class II histocompatibility antigen, DRB1-15 beta chain HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DRB1-15 beta chain Ena/VASP proteinsp-5Y-LAT PIP3, PIHLA class II histocompatibility antigen, DQ beta 2 chain ITK p-5Y-LAT HLA class II histocompatibility antigen, DRB1-8 beta chain ADPTRBV12-3 HLA class II histocompatibility antigen, DP alpha chain precursor ATPp-Y90-PRKCQ CHUK HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DP alpha chain precursor PIHLA class II histocompatibility antigen, DRB3-1 beta chain precursor Antigen-bearing MHC Class II TCR complexCD4LckHLA class II histocompatibility antigen, DRB1-8 beta chain MALT1 p-Y149,Y160-CD3D TCRB HLA class II histocompatibility antigen, DR beta 4 chain TRBC1HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor TRBC1p-Y113,Y128,Y145-LCP2 HLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DR alpha chain precursor HLA class II histocompatibility antigen, DR-1 beta chain precursor HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DR beta 4 chain PIK3CA PICD4 HLA class II histocompatibility antigen, DP alpha chain precursor PLCG1p-3Y-SLP-76GadsLATHLA class II histocompatibility antigen, DRB1-13 beta chain p-Y771,Y783,Y1254-PLCG1 p-Y149,Y160-CD3D PLC-gamma1 bound to LAT or SLP-76PITRBV12-3 HLA class II histocompatibility antigen, DR beta 5 chain TCRA PPiHLA class II histocompatibility antigen, DR beta 4 chain ADPGADSp-5Y-LATHLA class II histocompatibility antigen, DRB1-10 beta chain p-BCL10 TRBV12-3 p-S552-CARD11p-5Y-LAT PLCG1NCK1 INPP5Dp-5Y-LAT GRAP2ATPMg2+ CD4 TRBV12-3 HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DP DAGs HLA class II histocompatibility antigen, DRB1-9 beta chain precursor ATPHLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DP alpha chain precursor HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor HLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DRB1-4 beta chain TRBC1ADPATPATPHLA class II histocompatibility antigen, DRB1-15 beta chain PDPK1 HLA class II histocompatibility antigen, DRB1-13 beta chain PTPRCHLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DQ p-SLP-76NCK1HLA class II histocompatibility antigen, DR beta 5 chain T-cell receptor alpha chain V region HPB-MLT precursor SLP-76 bound to GadsLATHLA class II histocompatibility antigen, DRB1-8 beta chain LCP2 HLA class II histocompatibility antigen, DRB1-15 beta chain ATPHLA class II histocompatibility antigen, DRB1-1 beta chain p-Y90-PKC-thetaDAGATPp-Y113,Y128,Y145-SLP-76Gads LATHLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DP CD3G HLA class II histocompatibility antigen, DRB1-12 beta chain MALT1 IKBKG K63polyUbPIK3CB PAK1 p-S177,S181-IKBKB BCL10ATPATPp-Y113,Y128,Y145-LCP2 Antigen-bearing MHC Class II TCR complexCD4 Lck phosphorylated at Tyr394PIHLA class II histocompatibility antigen, DQ beta 2 chain p-Y113,Y128,Y145-LCP2p-4Y-PLCG1 HLA class II histocompatibility antigen, DR beta 4 chain CD3G PDPK1 UBE2N MALT1 trimerK63polyUb TRAF6 FYBHLA class II histocompatibility antigen, DRB1-10 beta chain PDPK1 p-Y493-ZAP70 HLA class II histocompatibility antigen, DQ beta 2 chain DAGs PiCD3D HLA class II histocompatibility antigen, DR alpha chain precursor HLA class II histocompatibility antigen, DP p-Y394-LCK ATPHLA class II histocompatibility antigen, DP Active PKC theta bound to DAGp-Y394-LCK p-6Y-CD247-1 HLA class II histocompatibility antigen, DRB1-10 beta chain phopshorylated PLC-gamma1 bound to SLP-76NF-kB complexHLA class II histocompatibility antigen, DRB1-15 beta chain T-cell receptor alpha chain V region PY14 precursor NFKB1PIK3CA TRAF6 HLA class II histocompatibility antigen, DRB1-16 beta chain 4242444215424240444240


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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=202403

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  30. Bubeck Wardenburg J, Pappu R, Bu JY, Mayer B, Chernoff J, Straus D, Chan AC.; ''Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76.''; PubMed Europe PMC Scholia
  31. Rudd CE, Schneider H.; ''Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.''; PubMed Europe PMC Scholia
  32. Leo A, Wienands J, Baier G, Horejsi V, Schraven B.; ''Adapters in lymphocyte signaling.''; PubMed Europe PMC Scholia
  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
  62. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
  63. van Oers NS, Weiss A.; ''The Syk/ZAP-70 protein tyrosine kinase connection to antigen receptor signalling processes.''; PubMed Europe PMC Scholia
  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
  68. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK.; ''The lipid phosphatase activity of PTEN is critical for its tumor supressor function.''; PubMed Europe PMC Scholia
  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
  75. Sekiya F, Poulin B, Kim YJ, Rhee SG.; ''Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1. Tyrosine 783 phosphorylation is not sufficient for lipase activation.''; PubMed Europe PMC Scholia
  76. Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC.; ''Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains.''; PubMed Europe PMC Scholia
  77. Sebban-Benin H, Pescatore A, Fusco F, Pascuale V, Gautheron J, Yamaoka S, Moncla A, Ursini MV, Courtois G.; ''Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti.''; PubMed Europe PMC Scholia
  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
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated CARMA1ComplexREACT_13227 (Reactome)
Activated PLC gamma1 bound to PIP2ComplexREACT_13147 (Reactome)
Activated ZAP-70ComplexREACT_13133 (Reactome)
Active PKC theta bound to DAGComplexREACT_12934 (Reactome)
Antigen-bearing MHC Class II 
TCR with phosphorylated ITAMs
CD4		ComplexREACT_12725 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

p-Lck		ComplexREACT_12773 (Reactome)
Antigen-bearing MHC Class II

TCR complex CD4

Lck phosphorylated at Tyr394		ComplexREACT_12817 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

Lck		ComplexREACT_13095 (Reactome)
BCL10 ProteinO95999 (Uniprot-TrEMBL)
BCL10ProteinO95999 (Uniprot-TrEMBL)
Bcl10 bound to CARMA1ComplexREACT_13143 (Reactome) Bcl10 interacts with the oligomerized CARMA1 and this is mediated by the CARD-CARD domainn interaction.
Bcl10 trimer bound to CARMA1 trimerComplexREACT_12824 (Reactome)
CARD11ProteinQ9BXL7 (Uniprot-TrEMBL)
CARMA1 bound to PDK1ComplexREACT_13330 (Reactome)
CARMA1 trimerComplexREACT_13044 (Reactome)
CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
CD3D ProteinP04234 (Uniprot-TrEMBL)
CD3E ProteinP07766 (Uniprot-TrEMBL)
CD3G ProteinP09693 (Uniprot-TrEMBL)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CSK ProteinP41240 (Uniprot-TrEMBL)
CSKProteinP41240 (Uniprot-TrEMBL)
Csk p-PAGComplexREACT_13273 (Reactome)
DAGs MetaboliteCHEBI:18035 (ChEBI)
DAGsMetaboliteCHEBI:18035 (ChEBI)
Ena/VASP proteinsProteinREACT_20983 (Reactome)
FYBProteinO15117 (Uniprot-TrEMBL)
GADS p-5Y-LATComplexREACT_13309 (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)
IMetaboliteCHEBI:16595 (ChEBI)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA

IKKB

NEMO		ComplexREACT_7693 (Reactome)
INPP5DProteinQ92835 (Uniprot-TrEMBL)
ITK ProteinQ08881 (Uniprot-TrEMBL)
ITK bound to SLP-76

Gads

LAT		ComplexREACT_13016 (Reactome)
ITKProteinQ08881 (Uniprot-TrEMBL)
IkBComplexREACT_12767 (Reactome)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-NEMO ProteinQ9Y6K9 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (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 trimerComplexREACT_13172 (Reactome)
MALT1 trimerComplexREACT_12682 (Reactome)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCK1ProteinP16333 (Uniprot-TrEMBL)
NF-kB complexComplexREACT_12832 (Reactome)
NFKB1ProteinP19838 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK2ProteinQ13177 (Uniprot-TrEMBL)
PAKProteinREACT_19640 (Reactome)
PDK1 PIP2,PIP3ComplexREACT_12991 (Reactome)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI3K bound to TRATComplexREACT_13152 (Reactome)
PI3KComplexREACT_4240 (Reactome)
PIMetaboliteCHEBI:16152 (ChEBI)
PIMetaboliteCHEBI:16618 (ChEBI)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIP3, PIMetaboliteREACT_12804 (Reactome)
PKC-theta ComplexREACT_13197 (Reactome)
PLC-gamma1 bound to LAT or SLP-76ComplexREACT_13341 (Reactome)
PLCG1

p-3Y-SLP-76 Gads

LAT		ComplexREACT_13137 (Reactome)
PLCG1 p-5Y-LATComplexREACT_13281 (Reactome)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
PRKQC closed conformationProteinQ04759 (Uniprot-TrEMBL)
PTEN Mg2+ComplexREACT_12877 (Reactome)
PTEN ProteinP60484 (Uniprot-TrEMBL)
PTPRCProteinP08575 (Uniprot-TrEMBL)
Phosphorylated Bcl10 bound to CARMA1 and RIP2ComplexREACT_12759 (Reactome) Bcl10 interacts with the oligomerized CARMA1 and this is mediated by the CARD-CARD domainn interaction.
Phosphorylated PLC-gamma1 bound to LAT or SLP-76ComplexREACT_13004 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RIPK2ProteinO43353 (Uniprot-TrEMBL)
SLP-76 bound to Gads LATComplexREACT_13131 (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 complexComplexREACT_13271 (Reactome)
TAK1/TAB2 complex bound to TRAF6/CBM complexComplexREACT_12884 (Reactome)
TCRA ProteinP04437 (Uniprot-TrEMBL)
TCRB ProteinP04435 (Uniprot-TrEMBL)
TRACProteinP01848 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6 trimer bound to CBM complexComplexREACT_12970 (Reactome)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRBC1ProteinP01850 (Uniprot-TrEMBL)
TRBV12-3 ProteinP01733 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-TRAF6 trimer bound to CBM complexComplexREACT_12752 (Reactome)
Ubc13 UBE2V1ComplexREACT_12995 (Reactome)
WAS ProteinP42768 (Uniprot-TrEMBL)
WASProteinP42768 (Uniprot-TrEMBL)
ZAP-70 and ITK tyrosine kinasesREACT_12862 (Reactome)
ZAP-70 bound to phosphorylated ITAM motifsComplexREACT_13388 (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

NEMO		ComplexREACT_13373 (Reactome)
p-S177,S181-IKKB

IKKA

pUb-NEMO		ComplexREACT_12853 (Reactome)
p-S32,S36-NFKBIAProteinP25963 (Uniprot-TrEMBL)
p-S552-CARD11ProteinQ9BXL7 (Uniprot-TrEMBL)
p-SLP-76

ADAP

Ena/VASP		ComplexREACT_20995 (Reactome)
p-SLP-76 ADAPComplexREACT_20709 (Reactome)
p-SLP-76

NCK

PAK		ComplexREACT_21232 (Reactome)
p-SLP-76

NCK1

WASP		ComplexREACT_21025 (Reactome)
p-SLP-76 NCK1ComplexREACT_20974 (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

LAT		ComplexREACT_13181 (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 DAGComplexREACT_12758 (Reactome)
p-Y90-PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
phopshorylated PLC-gamma1 bound to SLP-76ComplexREACT_13258 (Reactome)
phospho tyrosine ZAP-70ComplexREACT_13031 (Reactome)
phosphorylated PLC-gamma1 bound to LATComplexREACT_13372 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_12394 (Reactome)
ADPArrowREACT_12399 (Reactome)
ADPArrowREACT_12467 (Reactome)
ADPArrowREACT_12498 (Reactome)
ADPArrowREACT_12518 (Reactome)
ADPArrowREACT_12538 (Reactome)
ADPArrowREACT_12557 (Reactome)
ADPArrowREACT_12561 (Reactome)
ADPArrowREACT_12566 (Reactome)
ADPArrowREACT_12573 (Reactome)
ADPArrowREACT_12581 (Reactome)
ADPArrowREACT_12615 (Reactome)
ADPArrowREACT_12619 (Reactome)
ADPArrowREACT_12633 (Reactome)
ADPArrowREACT_12640 (Reactome)
ATPREACT_12394 (Reactome)
ATPREACT_12399 (Reactome)
ATPREACT_12421 (Reactome)
ATPREACT_12467 (Reactome)
ATPREACT_12498 (Reactome)
ATPREACT_12518 (Reactome)
ATPREACT_12538 (Reactome)
ATPREACT_12557 (Reactome)
ATPREACT_12561 (Reactome)
ATPREACT_12566 (Reactome)
ATPREACT_12573 (Reactome)
ATPREACT_12581 (Reactome)
ATPREACT_12615 (Reactome)
ATPREACT_12619 (Reactome)
ATPREACT_12633 (Reactome)
ATPREACT_12640 (Reactome)
Activated CARMA1ArrowREACT_12573 (Reactome)
Activated CARMA1REACT_12571 (Reactome)
Activated PLC gamma1 bound to PIP2mim-catalysisREACT_12585 (Reactome)
Activated ZAP-70ArrowREACT_12394 (Reactome)
Activated ZAP-70mim-catalysisREACT_12421 (Reactome)
Activated ZAP-70mim-catalysisREACT_12615 (Reactome)
Active PKC theta bound to DAGArrowREACT_12557 (Reactome)
Active PKC theta bound to DAGmim-catalysisREACT_12573 (Reactome)
Antigen-bearing MHC Class II 
TCR with phosphorylated ITAMs
CD4		ArrowREACT_12633 (Reactome)
Antigen-bearing MHC Class II 
TCR with phosphorylated ITAMs
CD4		REACT_12642 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

p-Lck		ArrowREACT_12640 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

p-Lck		REACT_12446 (Reactome)
Antigen-bearing MHC Class II

TCR complex CD4

Lck phosphorylated at Tyr394		ArrowREACT_12467 (Reactome)
Antigen-bearing MHC Class II

TCR complex CD4

Lck phosphorylated at Tyr394		REACT_12633 (Reactome)
Antigen-bearing MHC Class II

TCR complex CD4

Lck phosphorylated at Tyr394		mim-catalysisREACT_12538 (Reactome)
Antigen-bearing MHC Class II

TCR complex CD4

Lck phosphorylated at Tyr394		mim-catalysisREACT_12566 (Reactome)
Antigen-bearing MHC Class II

TCR complex CD4

Lck phosphorylated at Tyr394		mim-catalysisREACT_12633 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

Lck		ArrowREACT_12446 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

Lck		REACT_12467 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

Lck		REACT_12640 (Reactome)
Antigen-bearing MHC Class II 
TCR complex

CD4

Lck		mim-catalysisREACT_12467 (Reactome)
BCL10REACT_12574 (Reactome)
Bcl10 bound to CARMA1REACT_12619 (Reactome)
Bcl10 trimer bound to CARMA1 trimerREACT_12563 (Reactome)
CARD11REACT_12609 (Reactome)
CARMA1 bound to PDK1REACT_12573 (Reactome)
CARMA1 trimerREACT_12574 (Reactome)
CSKREACT_12603 (Reactome)
Csk p-PAGmim-catalysisREACT_12640 (Reactome)
DAGsArrowREACT_12585 (Reactome)
DAGsREACT_12493 (Reactome)
Ena/VASP proteinsREACT_20624 (Reactome)
FYBREACT_20591 (Reactome)
GADS p-5Y-LATREACT_12489 (Reactome)
GRAP2REACT_12570 (Reactome)
H2OREACT_12446 (Reactome)
H2OREACT_12585 (Reactome)
IArrowREACT_12585 (Reactome)
IKKA

IKKB

NEMO		REACT_12581 (Reactome)
INPP5Dmim-catalysisREACT_12405 (Reactome)
ITKREACT_12604 (Reactome)
IkBREACT_12399 (Reactome)
K63polyUbREACT_12553 (Reactome)
K63polyUbREACT_12595 (Reactome)
LATREACT_12421 (Reactome)
LCP2REACT_12489 (Reactome)
MALT1 trimer bound to Bcl10 and CARMA1 trimerREACT_12448 (Reactome)
MALT1 trimerREACT_12563 (Reactome)
NCK1REACT_20599 (Reactome)
NF-kB complexArrowREACT_12399 (Reactome)
PAKREACT_20657 (Reactome)
PDK1 PIP2,PIP3REACT_12609 (Reactome)
PDK1 PIP2,PIP3mim-catalysisREACT_12557 (Reactome)
PDPK1REACT_12641 (Reactome)
PI3K bound to TRATmim-catalysisREACT_12561 (Reactome)
PI3KREACT_12486 (Reactome)
PIArrowREACT_12405 (Reactome)
PIArrowREACT_12545 (Reactome)
PIArrowREACT_12561 (Reactome)
PIP3, PIREACT_12641 (Reactome)
PIREACT_12460 (Reactome)
PIREACT_12561 (Reactome)
PIREACT_12585 (Reactome)
PKC-theta REACT_12566 (Reactome)
PLC-gamma1 bound to LAT or SLP-76REACT_12498 (Reactome)
PLCG1REACT_12398 (Reactome)
PLCG1REACT_12506 (Reactome)
PPiArrowREACT_12405 (Reactome)
PPiArrowREACT_12545 (Reactome)
PRKQC closed conformationREACT_12493 (Reactome)
PTEN Mg2+mim-catalysisREACT_12545 (Reactome)
PTPRCmim-catalysisREACT_12446 (Reactome)
Phosphorylated Bcl10 bound to CARMA1 and RIP2ArrowREACT_12619 (Reactome)
Phosphorylated Bcl10 bound to CARMA1 and RIP2REACT_12639 (Reactome)
Phosphorylated PLC-gamma1 bound to LAT or SLP-76ArrowREACT_12498 (Reactome)
PiArrowREACT_12446 (Reactome)
REACT_12394 (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.
REACT_12398 (Reactome) PLC-gamma1 interacts with its SH2 domain to the pY132 residue of LAT.
REACT_12399 (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)
REACT_12405 (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.
REACT_12421 (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).
REACT_12446 (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. The inactive Lck is dephosphorylated by CD45 phosphatase. CD45 specifically dephosphorylates the Y505 residue of Lck and induce the active open conformation.
REACT_12448 (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.
REACT_12460 (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.
REACT_12467 (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.
REACT_12486 (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.
REACT_12489 (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.
REACT_12493 (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.
REACT_12498 (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.
REACT_12506 (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.
REACT_12518 (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.
REACT_12525 (Reactome) The activated PLC-gamma1 detaches from its substrate SLP-76 and translocates to the membrane.
REACT_12538 (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.
REACT_12545 (Reactome) PTEN dephosphorylates 3' position of PIP3 to generate PIP2 and negatively regulates the PI3K pathway and PKB activation.
REACT_12553 (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).
REACT_12557 (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.
REACT_12561 (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.
REACT_12563 (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.
REACT_12566 (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.
REACT_12570 (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.
REACT_12571 (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.
REACT_12573 (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.
REACT_12574 (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.
REACT_12581 (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.
REACT_12585 (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.
REACT_12595 (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.
REACT_12603 (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.
REACT_12604 (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.
REACT_12609 (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.
REACT_12615 (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.
REACT_12618 (Reactome) The activated PLC-gamma1 detaches from its substrate LAT and translocates to the membrane.
REACT_12619 (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.
REACT_12633 (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.
REACT_12639 (Reactome) Association with RIP2 and its phosphorylation allows subsequent trimerization of Bcl10.
REACT_12640 (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.
REACT_12641 (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).
REACT_12642 (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.
REACT_20591 (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).
REACT_20599 (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.
REACT_20623 (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.
REACT_20624 (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.
REACT_20657 (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.
RIPK2mim-catalysisREACT_12619 (Reactome)
SLP-76 bound to Gads LATREACT_12615 (Reactome)
TAB2/TAK1 complexREACT_12518 (Reactome)
TAB2/TAK1 complexmim-catalysisREACT_12518 (Reactome)
TAK1/TAB2 complex bound to TRAF6/CBM complexArrowREACT_12518 (Reactome)
TAK1/TAB2 complex bound to TRAF6/CBM complexmim-catalysisREACT_12581 (Reactome)
TRAF6 trimer bound to CBM complexREACT_12595 (Reactome)
TRAF6 trimer bound to CBM complexmim-catalysisREACT_12595 (Reactome)
TRAF6REACT_12448 (Reactome)
Ub-TRAF6 trimer bound to CBM complexArrowREACT_12595 (Reactome)
Ub-TRAF6 trimer bound to CBM complexREACT_12518 (Reactome)
Ub-TRAF6 trimer bound to CBM complexmim-catalysisREACT_12553 (Reactome)
Ubc13 UBE2V1ArrowREACT_12553 (Reactome)
Ubc13 UBE2V1ArrowREACT_12595 (Reactome)
Ubc13 UBE2V1REACT_12553 (Reactome)
Ubc13 UBE2V1REACT_12595 (Reactome)
WASREACT_20623 (Reactome)
ZAP-70 and ITK tyrosine kinasesmim-catalysisREACT_12498 (Reactome)
ZAP-70 bound to phosphorylated ITAM motifsREACT_12538 (Reactome)
ZAP70REACT_12642 (Reactome)
p-5Y-LATArrowREACT_12618 (Reactome)
p-5Y-LATREACT_12398 (Reactome)
p-5Y-LATREACT_12570 (Reactome)
p-BCL10REACT_12639 (Reactome)
p-S177,S181-IKKB

IKKA

NEMO		ArrowREACT_12581 (Reactome)
p-S177,S181-IKKB

IKKA

NEMO		REACT_12553 (Reactome)
p-S177,S181-IKKB

IKKA

pUb-NEMO		ArrowREACT_12553 (Reactome)
p-S177,S181-IKKB

IKKA

pUb-NEMO		mim-catalysisREACT_12399 (Reactome)
p-S32,S36-NFKBIAArrowREACT_12399 (Reactome)
p-S552-CARD11REACT_12571 (Reactome)
p-SLP-76 ADAPREACT_20624 (Reactome)
p-SLP-76 NCK1REACT_20623 (Reactome)
p-SLP-76 NCK1REACT_20657 (Reactome)
p-Y113,Y128,Y145-LCP2REACT_20591 (Reactome)
p-Y113,Y128,Y145-LCP2REACT_20599 (Reactome)
p-Y113,Y128,Y145-SLP-76

Gads

LAT		ArrowREACT_12525 (Reactome)
p-Y113,Y128,Y145-SLP-76

Gads

LAT		ArrowREACT_12615 (Reactome)
p-Y113,Y128,Y145-SLP-76

Gads

LAT		REACT_12506 (Reactome)
p-Y113,Y128,Y145-SLP-76

Gads

LAT		REACT_12604 (Reactome)
p-Y317-PAG1REACT_12603 (Reactome)
p-Y63,Y79,Y110-TRAT1REACT_12486 (Reactome)
p-Y771,Y783,Y1254-PLCG1ArrowREACT_12525 (Reactome)
p-Y771,Y783,Y1254-PLCG1ArrowREACT_12618 (Reactome)
p-Y771,Y783,Y1254-PLCG1REACT_12460 (Reactome)
p-Y90-PKC-theta DAGArrowREACT_12566 (Reactome)
p-Y90-PKC-theta DAGREACT_12557 (Reactome)
phospho tyrosine ZAP-70ArrowREACT_12538 (Reactome)
phospho tyrosine ZAP-70REACT_12394 (Reactome)
phospho tyrosine ZAP-70mim-catalysisREACT_12394 (Reactome)
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