TCR signaling (Homo sapiens)
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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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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| ADP | Metabolite | CHEBI:16761 (ChEBI)  | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Activated CARMA1 | Complex | REACT_13227 (Reactome) | |
| Activated PLC gamma1 bound to PIP2 | Complex | REACT_13147 (Reactome) | |
| Activated ZAP-70 | Complex | REACT_13133 (Reactome) | |
| Active PKC theta bound to DAG | Complex | REACT_12934 (Reactome) | |
| Antigen-bearing MHC
Class II : TCR complex:CD4:Lck | Complex | REACT_13095 (Reactome) | |
| Antigen-bearing MHC
Class II : TCR complex:CD4:p-Lck(Y505) | Complex | REACT_12773 (Reactome) | |
| Antigen-bearing MHC
Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 | Complex | REACT_12817 (Reactome) | |
| Antigen-bearing MHC
Class II: TCR with phosphorylated ITAMs:CD4 | Complex | REACT_12725 (Reactome) | |
| BCL10 [cytosol] | Protein | O95999 (Uniprot-TrEMBL) | |
| BCL10 | Protein | O95999 (Uniprot-TrEMBL) | |
| Bcl10 bound to CARMA1 | Complex | REACT_13143 (Reactome) | Bcl10 interacts with the oligomerized CARMA1 and this is mediated by the CARD-CARD domainn interaction. |
| Bcl10 trimer bound to CARMA1 trimer | Complex | REACT_12824 (Reactome) | |
| CARD11(1-1147) [cytosol] | Protein | Q9BXL7 (Uniprot-TrEMBL) | |
| CARD11(1-1147) | Protein | Q9BXL7 (Uniprot-TrEMBL) | |
| CARMA1 bound to PDK1 | Complex | REACT_13330 (Reactome) | |
| CARMA1 trimer | Complex | REACT_13044 (Reactome) | |
| CD247-1 [plasma membrane] | Protein | P20963-1 (Uniprot-TrEMBL) | |
| CD3D [plasma membrane] | Protein | P04234 (Uniprot-TrEMBL) | |
| CD3E [plasma membrane] | Protein | P07766 (Uniprot-TrEMBL) | |
| CD3G [plasma membrane] | Protein | P09693 (Uniprot-TrEMBL) | |
| CD4 [plasma membrane] | Protein | P01730 (Uniprot-TrEMBL) | |
| CHUK [cytosol] | Protein | O15111 (Uniprot-TrEMBL) | |
| CSK [cytosol] | Protein | P41240 (Uniprot-TrEMBL) | |
| CSK | Protein | P41240 (Uniprot-TrEMBL) | |
| Csk:p-PAG | Complex | REACT_13273 (Reactome) | |
| DAGs [plasma membrane] | Metabolite | CHEBI:18035 (ChEBI) | |
| DAGs | Metabolite | CHEBI:18035 (ChEBI) | |
| Ena/VASP proteins | Protein | REACT_20983 (Reactome) | |
| FYB(1-783) [cytosol] | Protein | O15117 (Uniprot-TrEMBL) | |
| FYB(1-783) | Protein | O15117 (Uniprot-TrEMBL) | |
| GADS:p-5Y-LAT | Complex | REACT_13309 (Reactome) | |
| GRAP2 [cytosol] | Protein | O75791 (Uniprot-TrEMBL) | |
| GRAP2 | Protein | O75791 (Uniprot-TrEMBL) | |
| H2O | Metabolite | CHEBI:15377 (ChEBI) | |
| HLA class II
histocompatibility antigen, DP [plasma membrane] | Protein | P04440 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DP alpha chain precursor [plasma membrane] | Protein | P20036 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DQ [plasma membrane] | Protein | P01906 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DQ [plasma membrane] | Protein | P01909 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DQ [plasma membrane] | Protein | P01920 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DQ beta 2 chain [plasma membrane] | Protein | P05538 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DQB1*0602 beta chain precursor [plasma membrane] | Protein | P01920 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DR alpha chain precursor [plasma membrane] | Protein | P01903 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DR beta 4 chain [plasma membrane] | Protein | P13762 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DR beta 5 chain [plasma membrane] | Protein | Q30154 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DR-1 beta chain precursor [plasma membrane] | Protein | P01912 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-1 beta chain [plasma membrane] | Protein | P04229 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-10 beta chain [plasma membrane] | Protein | Q30167 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-11 beta chain [plasma membrane] | Protein | P20039 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-12 beta chain [plasma membrane] | Protein | Q95IE3 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-13 beta chain [plasma membrane] | Protein | Q5Y7A7 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-14 beta chain [plasma membrane] | Protein | Q9GIY3 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-15 beta chain [plasma membrane] | Protein | P01911 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-16 beta chain [plasma membrane] | Protein | Q29974 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-4 beta chain [plasma membrane] | Protein | P13760 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-7 beta chain [plasma membrane] | Protein | P13761 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-8 beta chain [plasma membrane] | Protein | Q30134 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB1-9 beta chain precursor [plasma membrane] | Protein | Q9TQE0 (Uniprot-TrEMBL) | |
| HLA class II
histocompatibility antigen, DRB3-1 beta chain precursor [plasma membrane] | Protein | P79483 (Uniprot-TrEMBL) | |
| I(1,4,5)P3 | Metabolite | CHEBI:16595 (ChEBI) | |
| IKBKB [cytosol] | Protein | O14920 (Uniprot-TrEMBL) | |
| IKBKG [cytosol] | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
| IKKA:IKKB:NEMO | Complex | REACT_7693 (Reactome) | |
| INPP5D | Protein | Q92835 (Uniprot-TrEMBL) | |
| ITK [cytosol] | Protein | Q08881 (Uniprot-TrEMBL) | |
| ITK bound to SLP-76:Gads:LAT | Complex | REACT_13016 (Reactome) | |
| ITK | Protein | Q08881 (Uniprot-TrEMBL) | |
| IkB(alpha):NF-kB complex | Complex | REACT_12767 (Reactome) | |
| K63polyUb TRAF6 [cytosol] | Protein | Q9Y4K3 (Uniprot-TrEMBL) | |
| K63polyUb-NEMO [cytosol] | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
| K63polyUb | REACT_21645 (Reactome) | ||
| LAT | Protein | O43561 (Uniprot-TrEMBL) | |
| LCK [cytosol] | Protein | P06239 (Uniprot-TrEMBL) | |
| LCP2 [cytosol] | Protein | Q13094 (Uniprot-TrEMBL) | |
| LCP2 | Protein | Q13094 (Uniprot-TrEMBL) | |
| MALT1 [cytosol] | Protein | Q9UDY8 (Uniprot-TrEMBL) | |
| MALT1 trimer bound
to Bcl10 and CARMA1 trimer | Complex | REACT_13172 (Reactome) | |
| MALT1 trimer | Complex | REACT_12682 (Reactome) | |
| Mg2+ [cytosol] | Metabolite | CHEBI:18420 (ChEBI) | |
| NCK1 [cytosol] | Protein | P16333 (Uniprot-TrEMBL) | |
| NCK1 | Protein | P16333 (Uniprot-TrEMBL) | |
| NF-kB complex | Complex | REACT_12832 (Reactome) | |
| NFKB1(1-433) [cytosol] | Protein | P19838 (Uniprot-TrEMBL) | |
| NFKBIA [cytosol] | Protein | P25963 (Uniprot-TrEMBL) | |
| PAK1 [cytosol] | Protein | Q13153 (Uniprot-TrEMBL) | |
| PAK2(1-524) [cytosol] | Protein | Q13177 (Uniprot-TrEMBL) | |
| PAK | Protein | REACT_19640 (Reactome) | |
| PDK1:PIP2,PIP3 | Complex | REACT_12991 (Reactome) | |
| PDPK1 [plasma membrane] | Protein | O15530 (Uniprot-TrEMBL) | |
| PDPK1 | Protein | O15530 (Uniprot-TrEMBL) | |
| PI(3,4)P2 [plasma membrane] | Metabolite | CHEBI:16152 (ChEBI) | |
| PI(3,4)P2 | Metabolite | CHEBI:16152 (ChEBI) | |
| PI(3,4,5)P3 [plasma membrane] | Metabolite | CHEBI:16618 (ChEBI) | |
| PI(3,4,5)P3 | Metabolite | CHEBI:16618 (ChEBI) | |
| PI(4,5)P2 [plasma membrane] | Metabolite | CHEBI:18348 (ChEBI) | |
| PI(4,5)P2 | Metabolite | CHEBI:18348 (ChEBI) | |
| PI3K bound to TRAT | Complex | REACT_13152 (Reactome) | |
| PI3K | Complex | REACT_4240 (Reactome) | |
| PIK3CA [cytosol] | Protein | P42336 (Uniprot-TrEMBL) | |
| PIK3CB [cytosol] | Protein | P42338 (Uniprot-TrEMBL) | |
| PIK3R1 [cytosol] | Protein | P27986 (Uniprot-TrEMBL) | |
| PIK3R2 [cytosol] | Protein | O00459 (Uniprot-TrEMBL) | |
| PIP3, PI(3,4)P2 | Metabolite | REACT_12804 (Reactome) | |
| PKC-theta (open): DAG | Complex | REACT_13197 (Reactome) | |
| PLC-gamma1 bound to LAT or SLP-76 | Complex | REACT_13341 (Reactome) | |
| PLCG1(2-1290) [cytosol] | Protein | P19174 (Uniprot-TrEMBL) | |
| PLCG1(2-1290) | Protein | P19174 (Uniprot-TrEMBL) | |
| PLCG1:p-3Y-SLP-76:Gads:LAT | Complex | REACT_13137 (Reactome) | |
| PLCG1:p-5Y-LAT | Complex | REACT_13281 (Reactome) | |
| PPi | Metabolite | CHEBI:29888 (ChEBI) | |
| PRKCQ [plasma membrane] | Protein | Q04759 (Uniprot-TrEMBL) | |
| PRKQC closed conformation | Protein | Q04759 (Uniprot-TrEMBL) | |
| PTEN [cytosol] | Protein | P60484 (Uniprot-TrEMBL) | |
| PTEN:Mg2+ | Complex | REACT_12877 (Reactome) | |
| PTPRC | Protein | P08575 (Uniprot-TrEMBL) | |
| Phosphorylated
PLC-gamma1 bound to LAT or SLP-76 | Complex | REACT_13004 (Reactome) | |
| Phosphorylated Bcl10
bound to CARMA1 and RIP2 | Complex | REACT_12759 (Reactome) | Bcl10 interacts with the oligomerized CARMA1 and this is mediated by the CARD-CARD domainn interaction. |
| Pi | Metabolite | CHEBI:18367 (ChEBI) | |
| RELA [cytosol] | Protein | Q04206 (Uniprot-TrEMBL) | |
| RIPK2 | Protein | O43353 (Uniprot-TrEMBL) | |
| SLP-76 bound to Gads:LAT | Complex | REACT_13131 (Reactome) | |
| T-cell receptor
alpha chain V region HPB-MLT precursor [plasma membrane] | Protein | P04436 (Uniprot-TrEMBL) | |
| T-cell receptor
alpha chain V region PY14 precursor [plasma membrane] | Protein | P01737 (Uniprot-TrEMBL) | |
| TAB2 [plasma membrane] | Protein | Q9NYJ8 (Uniprot-TrEMBL) | |
| TAB2/TAK1 complex | Complex | REACT_13271 (Reactome) | |
| TAK1/TAB2 complex
bound to TRAF6/CBM complex | Complex | REACT_12884 (Reactome) | |
| TCRA [plasma membrane] | Protein | P04437 (Uniprot-TrEMBL) | |
| TCRB [plasma membrane] | Protein | P04435 (Uniprot-TrEMBL) | |
| TRAC(?-142) [plasma membrane] | Protein | P01848 (Uniprot-TrEMBL) | |
| TRAF6 [cytosol] | Protein | Q9Y4K3 (Uniprot-TrEMBL) | |
| TRAF6 trimer bound to CBM complex | Complex | REACT_12970 (Reactome) | |
| TRAF6 | Protein | Q9Y4K3 (Uniprot-TrEMBL) | |
| TRBC1(?-177) [plasma membrane] | Protein | P01850 (Uniprot-TrEMBL) | |
| TRBV12-3 [plasma membrane] | Protein | P01733 (Uniprot-TrEMBL) | |
| UBE2N [cytosol] | Protein | P61088 (Uniprot-TrEMBL) | |
| UBE2V1 [cytosol] | Protein | Q13404 (Uniprot-TrEMBL) | |
| Ub-TRAF6 trimer bound to CBM complex | Complex | REACT_12752 (Reactome) | |
| Ubc13:UBE2V1 | Complex | REACT_12995 (Reactome) | |
| WAS [cytosol] | Protein | P42768 (Uniprot-TrEMBL) | |
| WAS | Protein | P42768 (Uniprot-TrEMBL) | |
| ZAP-70 and ITK tyrosine kinases | REACT_12862 (Reactome) | ||
| ZAP-70 bound to
phosphorylated ITAM motifs | Complex | REACT_13388 (Reactome) | |
| ZAP70 [cytosol] | Protein | P43403 (Uniprot-TrEMBL) | |
| ZAP70 | Protein | P43403 (Uniprot-TrEMBL) | |
| p-4Y-PLCG1 [plasma membrane] | Protein | P19174 (Uniprot-TrEMBL) | |
| p-5Y-LAT [plasma membrane] | Protein | O43561 (Uniprot-TrEMBL) | |
| p-5Y-LAT | Protein | O43561 (Uniprot-TrEMBL) | |
| p-6Y-CD247-1 [plasma membrane] | Protein | P20963-1 (Uniprot-TrEMBL) | |
| p-BCL10 [cytosol] | Protein | O95999 (Uniprot-TrEMBL) | |
| p-BCL10 | Protein | O95999 (Uniprot-TrEMBL) | |
| p-MAP3K7 [cytosol] | Protein | O43318 (Uniprot-TrEMBL) | |
| p-S177,S181-IKBKB [cytosol] | Protein | O14920 (Uniprot-TrEMBL) | |
| p-S177,S181-IKKB:IKKA:NEMO | Complex | REACT_13373 (Reactome) | |
| p-S177,S181-IKKB:IKKA:pUb-NEMO | Complex | REACT_12853 (Reactome) | |
| p-S32,S36-NFKBIA | Protein | P25963 (Uniprot-TrEMBL) | |
| p-S552-CARD11(1-1147) [cytosol] | Protein | Q9BXL7 (Uniprot-TrEMBL) | |
| p-S552-CARD11(1-1147) | Protein | Q9BXL7 (Uniprot-TrEMBL) | |
| p-SLP-76:ADAP:Ena/VASP | Complex | REACT_20995 (Reactome) | |
| p-SLP-76:ADAP | Complex | REACT_20709 (Reactome) | |
| p-SLP-76:NCK1:WASP | Complex | REACT_21025 (Reactome) | |
| p-SLP-76:NCK1 | Complex | REACT_20974 (Reactome) | |
| p-SLP-76:NCK:PAK | Complex | REACT_21232 (Reactome) | |
| p-T184,T187-MAP3K7 [cytosol] | Protein | O43318 (Uniprot-TrEMBL) | |
| p-Y113,Y128,Y145-LCP2 [cytosol] | Protein | Q13094 (Uniprot-TrEMBL) | |
| p-Y113,Y128,Y145-LCP2 | Protein | Q13094 (Uniprot-TrEMBL) | |
| p-Y113,Y128,Y145-SLP-76:Gads: LAT | Complex | REACT_13181 (Reactome) | |
| p-Y149,Y160-CD3D [plasma membrane] | Protein | P04234 (Uniprot-TrEMBL) | |
| p-Y160,Y171-CD3G [plasma membrane] | Protein | P09693 (Uniprot-TrEMBL) | |
| p-Y188,Y199-CD3E [plasma membrane] | Protein | P07766 (Uniprot-TrEMBL) | |
| p-Y315,Y493-ZAP70 [cytosol] | Protein | P43403 (Uniprot-TrEMBL) | |
| p-Y317-PAG1 [plasma membrane] | Protein | Q9NWQ8 (Uniprot-TrEMBL) | |
| p-Y317-PAG1 | Protein | Q9NWQ8 (Uniprot-TrEMBL) | |
| p-Y394-LCK [cytosol] | Protein | P06239 (Uniprot-TrEMBL) | |
| p-Y493-ZAP70 [cytosol] | Protein | P43403 (Uniprot-TrEMBL) | |
| p-Y505-LCK [plasma membrane] | Protein | P06239 (Uniprot-TrEMBL) | |
| p-Y63,Y79,Y110-TRAT1 [plasma membrane] | Protein | Q6PIZ9 (Uniprot-TrEMBL) | |
| p-Y63,Y79,Y110-TRAT1 | Protein | Q6PIZ9 (Uniprot-TrEMBL) | |
| p-Y771,Y783,Y1254-PLCG1 [cytosol] | Protein | P19174 (Uniprot-TrEMBL) | |
| p-Y771,Y783,Y1254-PLCG1 | Protein | P19174 (Uniprot-TrEMBL) | |
| p-Y90,T538,S676,S695-PRKCQ [plasma membrane] | Protein | Q04759 (Uniprot-TrEMBL) | |
| p-Y90-PKC-theta:DAG | Complex | REACT_12758 (Reactome) | |
| p-Y90-PRKCQ [plasma membrane] | Protein | Q04759 (Uniprot-TrEMBL) | |
| phopshorylated
PLC-gamma1 bound to SLP-76 | Complex | REACT_13258 (Reactome) | |
| phospho tyrosine ZAP-70 | Complex | REACT_13031 (Reactome) | |
| phosphorylated
PLC-gamma1 bound to LAT | Complex | REACT_13372 (Reactome) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_12394 (Reactome) | ||
| ADP | Arrow | REACT_12399 (Reactome) | ||
| ADP | Arrow | REACT_12421 (Reactome) | ||
| ADP | Arrow | REACT_12467 (Reactome) | ||
| ADP | Arrow | REACT_12498 (Reactome) | ||
| ADP | Arrow | REACT_12518 (Reactome) | ||
| ADP | Arrow | REACT_12538 (Reactome) | ||
| ADP | Arrow | REACT_12557 (Reactome) | ||
| ADP | Arrow | REACT_12561 (Reactome) | ||
| ADP | Arrow | REACT_12566 (Reactome) | ||
| ADP | Arrow | REACT_12573 (Reactome) | ||
| ADP | Arrow | REACT_12581 (Reactome) | ||
| ADP | Arrow | REACT_12615 (Reactome) | ||
| ADP | Arrow | REACT_12619 (Reactome) | ||
| ADP | Arrow | REACT_12633 (Reactome) | ||
| ADP | Arrow | REACT_12640 (Reactome) | ||
| ATP | REACT_12394 (Reactome) | |||
| ATP | REACT_12399 (Reactome) | |||
| ATP | REACT_12421 (Reactome) | |||
| ATP | REACT_12467 (Reactome) | |||
| ATP | REACT_12498 (Reactome) | |||
| ATP | REACT_12518 (Reactome) | |||
| ATP | REACT_12538 (Reactome) | |||
| ATP | REACT_12557 (Reactome) | |||
| ATP | REACT_12561 (Reactome) | |||
| ATP | REACT_12566 (Reactome) | |||
| ATP | REACT_12573 (Reactome) | |||
| ATP | REACT_12581 (Reactome) | |||
| ATP | REACT_12615 (Reactome) | |||
| ATP | REACT_12619 (Reactome) | |||
| ATP | REACT_12633 (Reactome) | |||
| ATP | REACT_12640 (Reactome) | |||
| Activated CARMA1 | Arrow | REACT_12573 (Reactome) | ||
| Activated CARMA1 | REACT_12571 (Reactome) | |||
| Activated PLC gamma1 bound to PIP2 | Arrow | REACT_12460 (Reactome) | ||
| Activated PLC gamma1 bound to PIP2 | mim-catalysis | REACT_12585 (Reactome) | ||
| Activated ZAP-70 | Arrow | REACT_12394 (Reactome) | ||
| Activated ZAP-70 | mim-catalysis | REACT_12421 (Reactome) | ||
| Activated ZAP-70 | mim-catalysis | REACT_12615 (Reactome) | ||
| Active PKC theta bound to DAG | Arrow | REACT_12557 (Reactome) | ||
| Active PKC theta bound to DAG | mim-catalysis | REACT_12573 (Reactome) | ||
| Antigen-bearing MHC
Class II : TCR complex:CD4:Lck | Arrow | REACT_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-catalysis | REACT_12467 (Reactome) | ||
| Antigen-bearing MHC
Class II : TCR complex:CD4:p-Lck(Y505) | Arrow | REACT_12640 (Reactome) | ||
| Antigen-bearing MHC
Class II : TCR complex:CD4:p-Lck(Y505) | REACT_12446 (Reactome) | |||
| Antigen-bearing MHC
Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 | Arrow | REACT_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-catalysis | REACT_12538 (Reactome) | ||
| Antigen-bearing MHC
Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 | mim-catalysis | REACT_12566 (Reactome) | ||
| Antigen-bearing MHC
Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 | mim-catalysis | REACT_12633 (Reactome) | ||
| Antigen-bearing MHC
Class II: TCR with phosphorylated ITAMs:CD4 | Arrow | REACT_12633 (Reactome) | ||
| Antigen-bearing MHC
Class II: TCR with phosphorylated ITAMs:CD4 | REACT_12642 (Reactome) | |||
| BCL10 | REACT_12574 (Reactome) | |||
| Bcl10 bound to CARMA1 | Arrow | REACT_12574 (Reactome) | ||
| Bcl10 bound to CARMA1 | REACT_12619 (Reactome) | |||
| Bcl10 trimer bound to CARMA1 trimer | Arrow | REACT_12639 (Reactome) | ||
| Bcl10 trimer bound to CARMA1 trimer | REACT_12563 (Reactome) | |||
| CARD11(1-1147) | REACT_12609 (Reactome) | |||
| CARMA1 bound to PDK1 | Arrow | REACT_12609 (Reactome) | ||
| CARMA1 bound to PDK1 | REACT_12573 (Reactome) | |||
| CARMA1 trimer | Arrow | REACT_12571 (Reactome) | ||
| CARMA1 trimer | REACT_12574 (Reactome) | |||
| CSK | REACT_12603 (Reactome) | |||
| Csk:p-PAG | Arrow | REACT_12603 (Reactome) | ||
| Csk:p-PAG | mim-catalysis | REACT_12640 (Reactome) | ||
| DAGs | Arrow | REACT_12585 (Reactome) | ||
| DAGs | REACT_12493 (Reactome) | |||
| Ena/VASP proteins | REACT_20624 (Reactome) | |||
| FYB(1-783) | REACT_20591 (Reactome) | |||
| GADS:p-5Y-LAT | Arrow | REACT_12570 (Reactome) | ||
| GADS:p-5Y-LAT | REACT_12489 (Reactome) | |||
| GRAP2 | REACT_12570 (Reactome) | |||
| H2O | REACT_12446 (Reactome) | |||
| H2O | REACT_12585 (Reactome) | |||
| I(1,4,5)P3 | Arrow | REACT_12585 (Reactome) | ||
| IKKA:IKKB:NEMO | REACT_12581 (Reactome) | |||
| INPP5D | mim-catalysis | REACT_12405 (Reactome) | ||
| ITK bound to SLP-76:Gads:LAT | Arrow | REACT_12604 (Reactome) | ||
| ITK | REACT_12604 (Reactome) | |||
| IkB(alpha):NF-kB complex | REACT_12399 (Reactome) | |||
| K63polyUb | REACT_12553 (Reactome) | |||
| K63polyUb | REACT_12595 (Reactome) | |||
| LAT | REACT_12421 (Reactome) | |||
| LCP2 | REACT_12489 (Reactome) | |||
| MALT1 trimer bound
to Bcl10 and CARMA1 trimer | Arrow | REACT_12563 (Reactome) | ||
| MALT1 trimer bound
to Bcl10 and CARMA1 trimer | REACT_12448 (Reactome) | |||
| MALT1 trimer | REACT_12563 (Reactome) | |||
| NCK1 | REACT_20599 (Reactome) | |||
| NF-kB complex | Arrow | REACT_12399 (Reactome) | ||
| PAK | REACT_20657 (Reactome) | |||
| PDK1:PIP2,PIP3 | Arrow | REACT_12641 (Reactome) | ||
| PDK1:PIP2,PIP3 | REACT_12609 (Reactome) | |||
| PDK1:PIP2,PIP3 | mim-catalysis | REACT_12557 (Reactome) | ||
| PDPK1 | REACT_12641 (Reactome) | |||
| PI(3,4)P2 | Arrow | REACT_12405 (Reactome) | ||
| PI(3,4,5)P3 | Arrow | REACT_12561 (Reactome) | ||
| PI(3,4,5)P3 | REACT_12405 (Reactome) | |||
| PI(3,4,5)P3 | REACT_12545 (Reactome) | |||
| PI(4,5)P2 | Arrow | REACT_12545 (Reactome) | ||
| PI(4,5)P2 | REACT_12460 (Reactome) | |||
| PI(4,5)P2 | REACT_12561 (Reactome) | |||
| PI(4,5)P2 | REACT_12585 (Reactome) | |||
| PI3K bound to TRAT | Arrow | REACT_12486 (Reactome) | ||
| PI3K bound to TRAT | mim-catalysis | REACT_12561 (Reactome) | ||
| PI3K | REACT_12486 (Reactome) | |||
| PIP3, PI(3,4)P2 | REACT_12641 (Reactome) | |||
| PKC-theta (open): DAG | Arrow | REACT_12493 (Reactome) | ||
| PKC-theta (open): DAG | REACT_12566 (Reactome) | |||
| PLC-gamma1 bound to LAT or SLP-76 | REACT_12498 (Reactome) | |||
| PLCG1(2-1290) | REACT_12398 (Reactome) | |||
| PLCG1(2-1290) | REACT_12506 (Reactome) | |||
| PLCG1:p-3Y-SLP-76:Gads:LAT | Arrow | REACT_12506 (Reactome) | ||
| PLCG1:p-5Y-LAT | Arrow | REACT_12398 (Reactome) | ||
| PPi | Arrow | REACT_12405 (Reactome) | ||
| PPi | Arrow | REACT_12545 (Reactome) | ||
| PRKQC closed conformation | REACT_12493 (Reactome) | |||
| PTEN:Mg2+ | mim-catalysis | REACT_12545 (Reactome) | ||
| PTPRC | mim-catalysis | REACT_12446 (Reactome) | ||
| Phosphorylated
PLC-gamma1 bound to LAT or SLP-76 | Arrow | REACT_12498 (Reactome) | ||
| Phosphorylated Bcl10
bound to CARMA1 and RIP2 | Arrow | REACT_12619 (Reactome) | ||
| Phosphorylated Bcl10
bound to CARMA1 and RIP2 | REACT_12639 (Reactome) | |||
| Pi | Arrow | REACT_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. | |||
| RIPK2 | mim-catalysis | REACT_12619 (Reactome) | ||
| SLP-76 bound to Gads:LAT | Arrow | REACT_12489 (Reactome) | ||
| SLP-76 bound to Gads:LAT | REACT_12615 (Reactome) | |||
| TAB2/TAK1 complex | REACT_12518 (Reactome) | |||
| TAB2/TAK1 complex | mim-catalysis | REACT_12518 (Reactome) | ||
| TAK1/TAB2 complex
bound to TRAF6/CBM complex | Arrow | REACT_12518 (Reactome) | ||
| TAK1/TAB2 complex
bound to TRAF6/CBM complex | mim-catalysis | REACT_12581 (Reactome) | ||
| TRAF6 trimer bound to CBM complex | Arrow | REACT_12448 (Reactome) | ||
| TRAF6 trimer bound to CBM complex | REACT_12595 (Reactome) | |||
| TRAF6 trimer bound to CBM complex | mim-catalysis | REACT_12595 (Reactome) | ||
| TRAF6 | REACT_12448 (Reactome) | |||
| Ub-TRAF6 trimer bound to CBM complex | Arrow | REACT_12595 (Reactome) | ||
| Ub-TRAF6 trimer bound to CBM complex | REACT_12518 (Reactome) | |||
| Ub-TRAF6 trimer bound to CBM complex | mim-catalysis | REACT_12553 (Reactome) | ||
| Ubc13:UBE2V1 | Arrow | REACT_12553 (Reactome) | ||
| Ubc13:UBE2V1 | Arrow | REACT_12595 (Reactome) | ||
| Ubc13:UBE2V1 | REACT_12553 (Reactome) | |||
| Ubc13:UBE2V1 | REACT_12595 (Reactome) | |||
| WAS | REACT_20623 (Reactome) | |||
| ZAP-70 and ITK tyrosine kinases | mim-catalysis | REACT_12498 (Reactome) | ||
| ZAP-70 bound to
phosphorylated ITAM motifs | Arrow | REACT_12642 (Reactome) | ||
| ZAP-70 bound to
phosphorylated ITAM motifs | REACT_12538 (Reactome) | |||
| ZAP70 | REACT_12642 (Reactome) | |||
| p-5Y-LAT | Arrow | REACT_12618 (Reactome) | ||
| p-5Y-LAT | REACT_12398 (Reactome) | |||
| p-5Y-LAT | REACT_12570 (Reactome) | |||
| p-BCL10 | REACT_12639 (Reactome) | |||
| p-S177,S181-IKKB:IKKA:NEMO | Arrow | REACT_12581 (Reactome) | ||
| p-S177,S181-IKKB:IKKA:NEMO | REACT_12553 (Reactome) | |||
| p-S177,S181-IKKB:IKKA:pUb-NEMO | Arrow | REACT_12553 (Reactome) | ||
| p-S177,S181-IKKB:IKKA:pUb-NEMO | mim-catalysis | REACT_12399 (Reactome) | ||
| p-S32,S36-NFKBIA | Arrow | REACT_12399 (Reactome) | ||
| p-S552-CARD11(1-1147) | REACT_12571 (Reactome) | |||
| p-SLP-76:ADAP:Ena/VASP | Arrow | REACT_20624 (Reactome) | ||
| p-SLP-76:ADAP | Arrow | REACT_20591 (Reactome) | ||
| p-SLP-76:ADAP | REACT_20624 (Reactome) | |||
| p-SLP-76:NCK1:WASP | Arrow | REACT_20623 (Reactome) | ||
| p-SLP-76:NCK1 | Arrow | REACT_20599 (Reactome) | ||
| p-SLP-76:NCK1 | REACT_20623 (Reactome) | |||
| p-SLP-76:NCK1 | REACT_20657 (Reactome) | |||
| p-SLP-76:NCK:PAK | Arrow | REACT_20657 (Reactome) | ||
| p-Y113,Y128,Y145-LCP2 | REACT_20591 (Reactome) | |||
| p-Y113,Y128,Y145-LCP2 | REACT_20599 (Reactome) | |||
| p-Y113,Y128,Y145-SLP-76:Gads: LAT | Arrow | REACT_12525 (Reactome) | ||
| p-Y113,Y128,Y145-SLP-76:Gads: LAT | Arrow | REACT_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-PAG1 | REACT_12603 (Reactome) | |||
| p-Y63,Y79,Y110-TRAT1 | REACT_12486 (Reactome) | |||
| p-Y771,Y783,Y1254-PLCG1 | Arrow | REACT_12525 (Reactome) | ||
| p-Y771,Y783,Y1254-PLCG1 | Arrow | REACT_12618 (Reactome) | ||
| p-Y771,Y783,Y1254-PLCG1 | REACT_12460 (Reactome) | |||
| p-Y90-PKC-theta:DAG | Arrow | REACT_12566 (Reactome) | ||
| p-Y90-PKC-theta:DAG | REACT_12557 (Reactome) | |||
| phopshorylated
PLC-gamma1 bound to SLP-76 | REACT_12525 (Reactome) | |||
| phospho tyrosine ZAP-70 | Arrow | REACT_12538 (Reactome) | ||
| phospho tyrosine ZAP-70 | REACT_12394 (Reactome) | |||
| phospho tyrosine ZAP-70 | mim-catalysis | REACT_12394 (Reactome) | ||
| phosphorylated
PLC-gamma1 bound to LAT | REACT_12618 (Reactome) |
