Costimulation by the CD28 family (Homo sapiens)

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1, 13, 2633, 5212, 225, 3429, 31, 5814, 558, 2827, 42, 457, 29, 31, 589, 27, 30, 45351810, 21403168, 4311, 19, 32, 41, 46...12, 4748574417, 3615, 23, 3914, 5512, 476, 372, 5631, 5820, 49525033, 524, 25cytosolcytosolcytosolcytosolcytosolPPP2R1A CD80 LCK LCK p-S474-AKT2 HLA class II histocompatibility antigen, DRB1-13 beta chain CDC42 GDP HLA class II histocompatibility antigen, DRB3-1 beta chain precursor H2OCD247-1 GTP p-Y149,Y160-CD3D CD86 HLA class II histocompatibility antigen, DP CD28 B7-1 homodimer/ B7-2GTPLCK, FYNHLA class II histocompatibility antigen, DR-1 beta chain precursor p-T305,S472-AKT3 HLA class II histocompatibility antigen, DRB1-7 beta chain HLA class II histocompatibility antigen, DRB1-10 beta chain PP2APAK3 CD86HLA class II histocompatibility antigen, DRB1-14 beta chain AKT2 PIK3R1 PAK3 AKTPPP2R5D CD86 T-cell receptor alpha chain V region PY14 precursor ADPCD28:B7-2TCRB YES1 LCK AKT3 PIK3R1 CTLA-4:PP2ACD28 PI(4,5)P2RAC1:GTPPPP2CB PIK3CA RICTOR PP2A:CTLA4:B7-1/B7-2ADPICOS-1ATPPPP2R1B GRAP2AKT:PIP3PAK3 HLA class II histocompatibility antigen, DR-1 beta chain precursor PI3K alphaHLA class II histocompatibility antigen, DP GTP p-Y180-ICOS CD80 LYN RAC1:GDPFYN HLA class II histocompatibility antigen, DRB1-4 beta chain CD86 YES1 PDPK1 PI(3,4,5)P3 AKT1 B7-DC,B7-H1ADPHLA class II histocompatibility antigen, DRB1-8 beta chain CTLA4 PAK2 CD80 p-Y223,Y248-PDCD1 PPP2R5C CDC42:GTPp-Y226,Y257,Y282-BTLA THEM4 CD4 p-MAP3K14PDCD1LG2 PPP2R5A p-Y191-CD28 CTLA-4 homodimerFYN PTPN11 PPP2R5A pCTLA-4:Srckinases:SHP2p-Y188,Y199-CD3E p-T308,S473-AKT1 PI(3,4,5)P3 PP2ATNFRSF14 PIK3R2 AKT2 ADPp-Y160,Y171-CD3G PPP2R5B CD86 VAV1:PIP3:CD28:GRB2MTOR PIK3R3 CD28 homodimerPAK2 TCRB PPP2R5E ATPPIK3R2 GRB2-1HLA class II histocompatibility antigen, DRB1-13 beta chain PPP2R5C CDC42 PPP2R5E MAPKAP1 p-Y160,Y171-CD3G PPP2R1B GDPHLA class II histocompatibility antigen, DRB1-9 beta chain precursor HLA class II histocompatibility antigen, DRB1-8 beta chain PAK1 CD80 Src family tyrosinekinases (SFKs)PTPN6 PTPN11HLA class II histocompatibility antigen, DP alpha chain precursor AKT3 p-Y191-CD28 MAP3K8CD86 FYN CD274 p-Y394-LCK RAC1 p-Y191-CD28 PPP2R5E CD28 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor ATPp-S400-MAP3K8HLA class II histocompatibility antigen, DRB1-12 beta chain p-Y165,Y182-CTLA4 TCRA CD86 PPP2R5C CD28:PI3KLCK LCK HLA class II histocompatibility antigen, DRB1-14 beta chain HLA class II histocompatibility antigen, DRB1-9 beta chain precursor p-Y191-CD28 LCK PAK2 TRBV12-3 FYN HLA class II histocompatibility antigen, DQ TCRA LYN PTPN6,PTPN11FYN FYN Antigen PI(3,4,5)P3 PTPN11 PIK3R3 PI(3,4,5)P3 CTLA4 ICOS:ICOSLAKT3 ATPBTLA PPP2R1B CD4 p-BTLA-HVEM complexPPP2CA PTPN6 Antigen-bearing MHCClass II: TCR withdephosphorylatedCD3 zeta chain:CD4GTP HLA class II histocompatibility antigen, DQ CDC42 ADPCD80 Src family tyrosinekinases (SFKs)PPP2R5D CD86 AKT1 p-Y223,Y248-PDCD1 CD80 AKT:PIP3:THEM4/TRIB3CD86 Antigen-bearing MHCClass II: TCR withphosphorylatedITAMs:CD4LCK RAC1 HLA class II histocompatibility antigen, DQ beta 2 chain PPP2CA HLA class II histocompatibility antigen, DRB1-16 beta chain Antigen p-S474-AKT2 LCK CDC42:GDPPI3K alphaPDPK1LCK HLA class II histocompatibility antigen, DQ TORC2 complexFYN TRBC1 SHP-1/SHP-2:pBTLA:HVEMPDCD1LG2 HLA class II histocompatibility antigen, DP alpha chain precursor p-S-AKT:PIP3AKT1 CD80 PPP2R5C PI(3,4,5)P3 PDPK1 GRAP2 ATPTRIB3 PIK3R1 p-Y180-ICOSp-Y165,Y182-CTLA-4dimer:SFKsPAK1,2,3 dimerPPP2R1A HLA class II histocompatibility antigen, DRB1-15 beta chain p-S-AKT:PDPK1:PIP3AKT2 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor PRR5 HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor T-cell receptor alpha chain V region HPB-MLT precursor CD28 p-Y142,Y160,Y174-VAV1 p-6Y-CD247-1 FYNPPP2CB HLA class II histocompatibility antigen, DRB1-10 beta chain HLA class II histocompatibility antigen, DQ beta 2 chain PAK1,2,3:CDC42:GTP,RAC1:GTPHLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DRB1-4 beta chain ADPPDCD1 PPP2R5B FYNPI(3,4,5)P3 PPP2CB CD86 PDPK1:PIP3CD80 PIK3CA MAP3K14TRBC1 CDC42 p-Y188,Y199-CD3E p-Y223,248-PDCD1:B7-DC,B7-H1LCK PTPN6 SRC-1 PPP2R5D PIK3R3 YES1 TRAC CD80 ATPPTPN6,PTPN11GRB2-1 p-Y142,160,174-VAV1:PIP3:CD28:GRB2Active AKTTNFRSF14 HLA class II histocompatibility antigen, DR beta 5 chain p-Y191-CD28 ICOS:PI3KPPP2R5E CD274 CD86 PPP2R5A HLA class II histocompatibility antigen, DRB1-11 beta chain PiHLA class II histocompatibility antigen, DR beta 5 chain PPP2CB PIK3CA HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DR alpha chain precursor PIK3CA unknown kinaseGTPPPP2R1A p-S473-AKT1 CD274 CD86 ATPHLA class II histocompatibility antigen, DRB1-1 beta chain p-Y191-CD28 TRBV12-3 CD28:B7-1,B7-2HLA class II histocompatibility antigen, DR beta 4 chain PPP2R5A PTPN11 CD80 (B7-1)homodimerCTLA4 LCK GRB2-1 LYN phosphoCD28:B7-1/B7-2FYN CSK PAK1 VAV1 CD80 CD80 p-S472-AKT3 VAV1PPP2R5D PPiSRC-1 PPP2R1A PIK3R2 PAK1 FYN CD80 GRB2-1 FYN PIK3R3 CD28:Grb2PAK1,2,3ATPCD28:B7-1PI(3,4,5)P3 SRC-1 MLST8 HLA class II histocompatibility antigen, DRB1-15 beta chain PTPN6 p-Y226,Y257,Y282-BTLA p-Y165,Y182-CTLA4 GTP PIK3R1 PDCD1LG2 RAC1 ATPTNFRSF14 BTLA-HVEM complexLYN HLA class II histocompatibility antigen, DRB1-1 beta chain HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DQ T-cell receptor alpha chain V region HPB-MLT precursor PTPN11 YES1 PPP2R1B CD80 RAC1 ICOSLG PPP2R5B PPP2CA CSK GDPSRC-1 PDCD1CD274 ICOSLGADPCD86 CSK BTLAHLA class II histocompatibility antigen, DR alpha chain precursor ICOS-1 LCK p-Y394-LCK PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1p-S473-AKT1 HLA class II histocompatibility antigen, DRB1-7 beta chain T-cell receptor alpha chain V region PY14 precursor LCK, CSKCD28:GRAP2HLA class II histocompatibility antigen, DR beta 4 chain ATPp-S472-AKT3 ADPGRB2:pBTLA:HVEMGRB2-1 PDCD1:B7-DC,B7-H1PPP2CA FYN TNFRSF14 TRAC PDCD1LG2 ADPHLA class II histocompatibility antigen, DQ PPP2R5B HLA class II histocompatibility antigen, DRB1-11 beta chain GRB2-1PTPN11 p-T309,S474-AKT2 PI(3,4,5)P3TNFRSF14PIK3R2 GDP CDC42:GTP, RAC1:GTPp-Y149,Y160-CD3D LCK LCK p-Y226,Y257,Y282-BTLA ADP5138, 59242451


Description

Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation.
The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity.
The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 388841
Reactome-version 
Reactome version: 64
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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History

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CompareRevisionActionTimeUserComment
115025view16:56, 25 January 2021ReactomeTeamReactome version 75
113470view11:54, 2 November 2020ReactomeTeamReactome version 74
112668view16:05, 9 October 2020ReactomeTeamReactome version 73
101585view11:45, 1 November 2018ReactomeTeamreactome version 66
101121view21:29, 31 October 2018ReactomeTeamreactome version 65
100649view20:03, 31 October 2018ReactomeTeamreactome version 64
100199view16:47, 31 October 2018ReactomeTeamreactome version 63
99750view15:14, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99314view12:46, 31 October 2018ReactomeTeamreactome version 62
93892view13:43, 16 August 2017ReactomeTeamreactome version 61
93463view11:24, 9 August 2017ReactomeTeamreactome version 61
87163view19:18, 18 July 2016MkutmonOntology Term : 'adaptive immune response pathway' added !
86558view09:20, 11 July 2016ReactomeTeamreactome version 56
83406view11:08, 18 November 2015ReactomeTeamVersion54
81606view13:08, 21 August 2015ReactomeTeamVersion53
77064view08:36, 17 July 2014ReactomeTeamFixed remaining interactions
76769view12:13, 16 July 2014ReactomeTeamFixed remaining interactions
76092view10:15, 11 June 2014ReactomeTeamRe-fixing comment source
75803view11:34, 10 June 2014ReactomeTeamReactome 48 Update
75154view14:10, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74801view08:53, 30 April 2014ReactomeTeamReactome46
42022view21:51, 4 March 2011MaintBotAutomatic update
39825view05:51, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT2 ProteinP31751 (Uniprot-TrEMBL)
AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
AKT:PIP3:THEM4/TRIB3ComplexR-HSA-199453 (Reactome)
AKT:PIP3ComplexR-HSA-2317329 (Reactome)
AKTComplexR-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTComplexR-HSA-202074 (Reactome)
Antigen R-ALL-173548 (Reactome)
Antigen-bearing MHC

Class II: TCR with dephosphorylated

CD3 zeta chain:CD4
ComplexR-HSA-390339 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated

ITAMs:CD4
ComplexR-HSA-203494 (Reactome)
B7-1 homodimer/ B7-2ComplexR-HSA-388762 (Reactome)
B7-DC,B7-H1ComplexR-HSA-388774 (Reactome)
BTLA ProteinQ7Z6A9 (Uniprot-TrEMBL)
BTLA-HVEM complexComplexR-HSA-389525 (Reactome)
BTLAProteinQ7Z6A9 (Uniprot-TrEMBL)
CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
CD274 ProteinQ9NZQ7 (Uniprot-TrEMBL)
CD28 ProteinP10747 (Uniprot-TrEMBL)
CD28 homodimerComplexR-HSA-179780 (Reactome)
CD28:B7-1,B7-2ComplexR-HSA-388765 (Reactome)
CD28:B7-1ComplexR-HSA-388767 (Reactome)
CD28:B7-2ComplexR-HSA-388768 (Reactome)
CD28:GRAP2ComplexR-HSA-389384 (Reactome)
CD28:Grb2ComplexR-HSA-388786 (Reactome)
CD28:PI3KComplexR-HSA-388783 (Reactome)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CD80 (B7-1) homodimerComplexR-HSA-179787 (Reactome)
CD80 ProteinP33681 (Uniprot-TrEMBL)
CD86 ProteinP42081 (Uniprot-TrEMBL)
CD86ProteinP42081 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GDPComplexR-HSA-418830 (Reactome)
CDC42:GTP, RAC1:GTPComplexR-HSA-389778 (Reactome)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CSK ProteinP41240 (Uniprot-TrEMBL)
CTLA-4 homodimerComplexR-HSA-179766 (Reactome)
CTLA-4:PP2AComplexR-HSA-389533 (Reactome)
CTLA4 ProteinP16410 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRAP2ProteinO75791 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:pBTLA:HVEMComplexR-HSA-389921 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
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)
ICOS-1 ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
ICOS-1ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
ICOS:ICOSLComplexR-HSA-388788 (Reactome)
ICOS:PI3KComplexR-HSA-388785 (Reactome)
ICOSLG ProteinO75144 (Uniprot-TrEMBL)
ICOSLGProteinO75144 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCK, CSKComplexR-HSA-389743 (Reactome)
LCK, FYNComplexR-HSA-389329 (Reactome)
LYN ProteinP07948 (Uniprot-TrEMBL)
MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
MAP3K8ProteinP41279 (Uniprot-TrEMBL)
MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK1,2,3 dimerComplexR-HSA-399856 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPComplexR-HSA-389782 (Reactome)
PAK1,2,3ComplexR-HSA-390765 (Reactome)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PAK3 ProteinO75914 (Uniprot-TrEMBL)
PDCD1 ProteinQ15116 (Uniprot-TrEMBL)
PDCD1:B7-DC,B7-H1ComplexR-HSA-388800 (Reactome)
PDCD1LG2 ProteinQ9BQ51 (Uniprot-TrEMBL)
PDCD1ProteinQ15116 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alphaComplexR-HSA-198379 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PP2A:CTLA4:B7-1/B7-2ComplexR-HSA-388784 (Reactome)
PP2AComplexR-HSA-196206 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5A ProteinQ15172 (Uniprot-TrEMBL)
PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP2R5E ProteinQ16537 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRR5 ProteinP85299 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1ComplexR-HSA-389749 (Reactome)
PTPN6,PTPN11ComplexR-HSA-389744 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
SHP-1/SHP-2:pBTLA:HVEMComplexR-HSA-389935 (Reactome)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
Src family tyrosine kinases (SFKs)ComplexR-HSA-211064 (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)
TCRA ProteinP04437 (Uniprot-TrEMBL)
TCRB ProteinP04435 (Uniprot-TrEMBL)
THEM4 ProteinQ5T1C6 (Uniprot-TrEMBL)
TNFRSF14 ProteinQ92956 (Uniprot-TrEMBL)
TNFRSF14ProteinQ92956 (Uniprot-TrEMBL)
TORC2 complexComplexR-HSA-198626 (Reactome)
TRAC ProteinP01848 (Uniprot-TrEMBL)
TRBC1 ProteinP01850 (Uniprot-TrEMBL)
TRBV12-3 ProteinP01733 (Uniprot-TrEMBL)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1:PIP3:CD28:GRB2ComplexR-HSA-389334 (Reactome)
VAV1ProteinP15498 (Uniprot-TrEMBL)
YES1 ProteinP07947 (Uniprot-TrEMBL)
p-6Y-CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
p-BTLA-HVEM complexComplexR-HSA-389920 (Reactome)
p-MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
p-S-AKT:PDPK1:PIP3ComplexR-HSA-2317313 (Reactome)
p-S-AKT:PIP3ComplexR-HSA-2317310 (Reactome)
p-S400-MAP3K8ProteinP41279 (Uniprot-TrEMBL)
p-S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-Y142,160,174-VAV1:PIP3:CD28:GRB2ComplexR-HSA-389332 (Reactome)
p-Y142,Y160,Y174-VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-Y149,Y160-CD3D ProteinP04234 (Uniprot-TrEMBL)
p-Y160,Y171-CD3G ProteinP09693 (Uniprot-TrEMBL)
p-Y165,Y182-CTLA-4 dimer:SFKsComplexR-HSA-388795 (Reactome)
p-Y165,Y182-CTLA4 ProteinP16410 (Uniprot-TrEMBL)
p-Y180-ICOS ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
p-Y180-ICOSProteinQ9Y6W8-1 (Uniprot-TrEMBL)
p-Y188,Y199-CD3E ProteinP07766 (Uniprot-TrEMBL)
p-Y191-CD28 ProteinP10747 (Uniprot-TrEMBL)
p-Y223,248-PDCD1:B7-DC,B7-H1ComplexR-HSA-389746 (Reactome)
p-Y223,Y248-PDCD1 ProteinQ15116 (Uniprot-TrEMBL)
p-Y226,Y257,Y282-BTLA ProteinQ7Z6A9 (Uniprot-TrEMBL)
p-Y394-LCK ProteinP06239 (Uniprot-TrEMBL)
pCTLA-4:Src kinases:SHP2ComplexR-HSA-388793 (Reactome)
phospho CD28:B7-1/B7-2ComplexR-HSA-388777 (Reactome)
unknown kinaseR-HSA-451336 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-198270 (Reactome)
ADPArrowR-HSA-198640 (Reactome)
ADPArrowR-HSA-388831 (Reactome)
ADPArrowR-HSA-388833 (Reactome)
ADPArrowR-HSA-389158 (Reactome)
ADPArrowR-HSA-389354 (Reactome)
ADPArrowR-HSA-389756 (Reactome)
ADPArrowR-HSA-389762 (Reactome)
ADPArrowR-HSA-392530 (Reactome)
ADPArrowR-HSA-6790087 (Reactome)
AKT:PIP3:THEM4/TRIB3TBarR-HSA-198640 (Reactome)
AKT:PIP3ArrowR-HSA-2317332 (Reactome)
AKT:PIP3R-HSA-198640 (Reactome)
AKTArrowR-HSA-390329 (Reactome)
AKTR-HSA-2317332 (Reactome)
ATPR-HSA-198270 (Reactome)
ATPR-HSA-198640 (Reactome)
ATPR-HSA-388831 (Reactome)
ATPR-HSA-388833 (Reactome)
ATPR-HSA-389158 (Reactome)
ATPR-HSA-389354 (Reactome)
ATPR-HSA-389756 (Reactome)
ATPR-HSA-389762 (Reactome)
ATPR-HSA-392530 (Reactome)
ATPR-HSA-6790087 (Reactome)
Active AKTArrowR-HSA-198270 (Reactome)
Active AKTR-HSA-390329 (Reactome)
Active AKTmim-catalysisR-HSA-389756 (Reactome)
Antigen-bearing MHC

Class II: TCR with dephosphorylated

CD3 zeta chain:CD4
ArrowR-HSA-389758 (Reactome)
Antigen-bearing MHC

Class II: TCR with phosphorylated

ITAMs:CD4
R-HSA-389758 (Reactome)
B7-1 homodimer/ B7-2R-HSA-388809 (Reactome)
B7-DC,B7-H1R-HSA-388828 (Reactome)
BTLA-HVEM complexArrowR-HSA-389523 (Reactome)
BTLA-HVEM complexR-HSA-6790087 (Reactome)
BTLAR-HSA-389523 (Reactome)
CD28 homodimerR-HSA-388808 (Reactome)
CD28 homodimerR-HSA-388811 (Reactome)
CD28:B7-1,B7-2R-HSA-388831 (Reactome)
CD28:B7-1ArrowR-HSA-388811 (Reactome)
CD28:B7-2ArrowR-HSA-388808 (Reactome)
CD28:GRAP2ArrowR-HSA-389381 (Reactome)
CD28:Grb2ArrowR-HSA-388814 (Reactome)
CD28:Grb2R-HSA-389352 (Reactome)
CD28:PI3KArrowR-HSA-388832 (Reactome)
CD28:PI3Kmim-catalysisR-HSA-389158 (Reactome)
CD80 (B7-1) homodimerR-HSA-388811 (Reactome)
CD86R-HSA-388808 (Reactome)
CDC42:GDPR-HSA-389350 (Reactome)
CDC42:GTP, RAC1:GTPR-HSA-389788 (Reactome)
CDC42:GTPArrowR-HSA-389350 (Reactome)
CTLA-4 homodimerR-HSA-389532 (Reactome)
CTLA-4:PP2AArrowR-HSA-389532 (Reactome)
CTLA-4:PP2AR-HSA-388809 (Reactome)
FYNmim-catalysisR-HSA-389354 (Reactome)
GDPArrowR-HSA-389348 (Reactome)
GDPArrowR-HSA-389350 (Reactome)
GRAP2R-HSA-389381 (Reactome)
GRB2-1R-HSA-388814 (Reactome)
GRB2-1R-HSA-389919 (Reactome)
GRB2:pBTLA:HVEMArrowR-HSA-389919 (Reactome)
GTPR-HSA-389348 (Reactome)
GTPR-HSA-389350 (Reactome)
H2OR-HSA-390329 (Reactome)
ICOS-1R-HSA-388817 (Reactome)
ICOS:ICOSLArrowR-HSA-388817 (Reactome)
ICOS:ICOSLArrowR-HSA-388830 (Reactome)
ICOS:PI3KArrowR-HSA-388830 (Reactome)
ICOSLGR-HSA-388817 (Reactome)
LCK, CSKR-HSA-389762 (Reactome)
LCK, CSKmim-catalysisR-HSA-389762 (Reactome)
LCK, FYNR-HSA-388831 (Reactome)
MAP3K14R-HSA-392530 (Reactome)
MAP3K8R-HSA-389756 (Reactome)
PAK1,2,3 dimerR-HSA-389788 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPArrowR-HSA-389788 (Reactome)
PAK1,2,3ArrowR-HSA-389788 (Reactome)
PDCD1:B7-DC,B7-H1ArrowR-HSA-388828 (Reactome)
PDCD1:B7-DC,B7-H1R-HSA-389762 (Reactome)
PDCD1R-HSA-388828 (Reactome)
PDPK1:PIP3ArrowR-HSA-198270 (Reactome)
PDPK1:PIP3ArrowR-HSA-2316429 (Reactome)
PDPK1:PIP3R-HSA-2317314 (Reactome)
PDPK1R-HSA-2316429 (Reactome)
PI(3,4,5)P3ArrowR-HSA-389158 (Reactome)
PI(3,4,5)P3R-HSA-2316429 (Reactome)
PI(3,4,5)P3R-HSA-2317332 (Reactome)
PI(3,4,5)P3R-HSA-389352 (Reactome)
PI(4,5)P2R-HSA-389158 (Reactome)
PI3K alphaR-HSA-388830 (Reactome)
PI3K alphaR-HSA-388832 (Reactome)
PP2A:CTLA4:B7-1/B7-2ArrowR-HSA-388809 (Reactome)
PP2A:CTLA4:B7-1/B7-2R-HSA-388833 (Reactome)
PP2AArrowR-HSA-388833 (Reactome)
PP2AR-HSA-389532 (Reactome)
PP2Amim-catalysisR-HSA-390329 (Reactome)
PPiArrowR-HSA-389758 (Reactome)
PTPN11R-HSA-388829 (Reactome)
PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1ArrowR-HSA-389759 (Reactome)
PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1mim-catalysisR-HSA-389758 (Reactome)
PTPN6,PTPN11R-HSA-389759 (Reactome)
PTPN6,PTPN11R-HSA-389941 (Reactome)
PiArrowR-HSA-390329 (Reactome)
R-HSA-198270 (Reactome) Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-198640 (Reactome) Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.
Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-2316429 (Reactome) PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
R-HSA-2317314 (Reactome) Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005)
R-HSA-2317332 (Reactome) PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied.
R-HSA-388808 (Reactome) CD28 delivers the costimulatory signal by interacting with its ligand B7-2 on the antigen-presenting cell and modulates T cell antigen recognition. The V-like domains of CD28 contains a strictly conserved MYPPPY sequence motif that maps to the CDR3-analogous loop and is critical for recognition of its ligand B7-2. Engagement of CD28 with B7-1 and with B7-2 have different bilogical functions in-vivo. Rapid dissociation of B7-2 from CD28 may not permit the robust tyrosine phosphorylation that the prolonged binding of B7-1 induces.
R-HSA-388809 (Reactome) CTLA4 binds with high affinity to the ligands B71 and B72. The interaction of B7 molecules with CTLA4 provides inhibitory signals required for downregulation of the TCR response. The interaction is mediated by the CDR3 analogous loop of CTLA4, composed of an MYPPY motif, with a concave surface on the B7 formed predominately by the G, F, C, C' and C" strands. Its also been demonstrated that B7 binding is not totally essential for CTLA-4 activity.
R-HSA-388811 (Reactome) A costimulatory signal involved in T cell activation is transmitted by CD28. This signal is delivered by the interaction of the CD28 receptor on T cells with its ligand B7-1 on the antigen-presenting cell and modulates T cell antigen recognition. Despite the homodimeric structure of CD28, it interacts with B7-1 as though it has a single binding site. The V-like domains of CD28 contains a strictly conserved MYPPPY sequence motif that maps to the CDR3-analogous loop and is critical for recognition of its ligands. B7-1 and B7-2 bind to overlapping but not identical sites on CD28
R-HSA-388814 (Reactome) CD28 is capable of binding the Src homology 3 (SH3) domains of several proteins, including Grb2. The phospho-YMNM motif in CD28's cytoplasmic domain facilitates tandem SH2–SH3 domain binding. Grb-2 has been shown to bind to the CD28 YMNM motif with additional SH3 domain binding to the diproline motif in the C-terminal portion of the cytoplasmic domain of CD28.
R-HSA-388817 (Reactome) Inducible T cell co-stimulatory (ICOS) protein is the third member of the CD28 family that regulates T-cell activation and function. ICOS interacts with B7H2 (ICOSL, B7RP-1), a member of the B7 family expressed on the antigen-presenting cell.
R-HSA-388828 (Reactome) The Programmed cell death protein 1 (PD-1) is functionally similar to CTLA4 and exerts an inhibitory signal on T cell activation. PD-1 binds the ligands B7H1 and B7DC but with different affinities. Interaction of PD-1/B7DC exhibited a 2-6-fold higher affinity and had different association/dissociation kinetics compared with the interaction of PD-1/B7H1.
R-HSA-388829 (Reactome) CTLA4 associates with the SH2 domain containing tyrosine phosphatase SHP2 and this interaction is mediated through the YVKM motif of CTLA-4. Phosphorylation of tyrosine in the YVKM motif recruits SHP-2.
Still the association of SHP-2 with CTLA-4 is unclear and remains controversial. Several other studies have reported that CTLA-4 does not directly associate with SHP-2. The interaction between the phosphatase and CTLA-4 may be an indirect event, possibly mediated by PI3-kinase/SHP-2 binding.
R-HSA-388830 (Reactome) The p85 unit of PI3K is the only signaling molecule identified so far that interacts with ICOS. ICOS contains several conserved motifs also found in CD28, including the YxxM motif in the cytoplasmic tail, which binds the lipid kinase phosphatidylinositol 3-kinase (PI3K) upon tyrosine phosphorylation after complex formation with ICOS. However, ICOS costimulation shows greater PI3K activity than CD28 in T cells.
R-HSA-388831 (Reactome) The interaction of CD28 with its ligands, B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells enhances a number of TCR-mediated responses like production of interleukins. CD28 mediated costimulation is dependent upon phosphorylation of tyrosine residue 191 of the CD28 cytoplasmic tail, present in a 'YMNM' motif. p56Lck and p59Fyn phosphorylate CD28 and the phosphorylated residue allows the recruitment of PI3K, growth factor receptor-bound protein 2 (GRB2) and Grb2-related adaptor downstream of SHC (GADS) via their src-homology region 2 (SH2) domains.
R-HSA-388832 (Reactome) PI3K inducibly associates with CD28: the SH2 domains of the PI3K p85 adaptor subunit interact with a cytoplasmic YMNM consensus motif at residues 173-176 of CD28.
R-HSA-388833 (Reactome) Upon TCR-CTLA-4 complex formation, CTLA4 is tyrosine phosphorylated. Src family tyrosine kinases Fyn, Lyn, and Lck associate with CTLA-4 and phosphorylate both Y-165 and Y-182 that are mainly responsible for interaction with Fyn through its SH2 domain. Once tyrosine 165 is phosphorylated, PP2A is activated and disassociates from CTLA4; this correlates with T cell inactivation.
R-HSA-389158 (Reactome) PI3K enzyme bound to co-stimulatory protein CD28 catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and PKB.
R-HSA-389348 (Reactome) Vav1, once activated by PIP3 binding and phosphorylation by Fyn, stimulates the GDP/GTP exchange activity of Rac. Vav1 is selective for Rac and catalyses exchange of bound GDP for GTP.
R-HSA-389350 (Reactome) Vav1 serves as a GEF for Cdc42-GTPase. It interacts with and activates Cdc42. The activated Cdc42 in turn transmits its signals through the downstream target, the PAK1 kinase.
R-HSA-389352 (Reactome) Vav1 protein is a cytoplasmic guanine nucleotide exchange factor (GEF) for Rho-family GTPases. CD28 co-stimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. Vav1 contains a unique arrangement of signaling motifs a calponin homology domain, an acidic domain, a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain (CR), and a SH2 domain flanked by two proline-binding SH3 domains. Vav-1 may be recruited to the membrane through its PH domain by binding PI(3,4,5)P3 produced by CD28-bound PI3K and also by binding to CD28:Grb2 complexes by the dimerized SH3 domains in both the molecules.
R-HSA-389354 (Reactome) Vav1 exists in an auto-inhibitory state folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the CH domain to the C1 region. Activation of Vav may involve at least three different events to relieve this auto-inhibition. Phosphorylation of the tyrosines causes them to be displaced from the DH domain, binding of a ligand to the CH domain may cause it to release the C1 domain and PIP3 may bind to the PH domain, altering its conformation. Vav1 is phosphorylated on at least three tyrosines (Y142, Y160 and Y174) in the acidic domain, and this phosphorylation results in an increase in GEF activity. Fyn tyrosine kinase phosphorylates Vav1 after CD28 ligation.
R-HSA-389381 (Reactome) Gads (Grb2-related adaptor protein 2) is essential for CD28 mediated NF-kB activation. This signal is mediated by the binding of Gads to the CD28 YMNM motif. The CD28 cytoplasmic PxxP motif is also required for this association.
R-HSA-389523 (Reactome) The B and T lymphocyte attenuator, BTLA, is one of the co-inhibitory receptors of CD28 superfamily along with CTLA-4 and PD-1. BTLA differs from other CD28 members by having an extracellular Ig C-like domain, instead of a V-like one. Herpesvirus entry mediator (HVEM) is the external ligand for BTLA, providing the first example of a functional interaction between a TNFR and an Ig superfamily member. Binding of HVEM to BTLA delivers an inhibitory signal to T cells.
R-HSA-389532 (Reactome) Newly synthesized CTLA4 expressed on the transmembrane associates with PP2A, and under these conditions the inhibitory function of CTLA4 is inactive. CTLA4 homodimer has a PP2A trimer bound to each tail. The A subunit of PP2A binds the lysine-rich motif located at lysine residues 152, 155, and 156 of the juxtamembrane region of the CTLA-4 tail, and the C subunit binds the Y165 residue.
R-HSA-389756 (Reactome) Cot/Tpl 2 is a serine/threonine kinase of the mitogen activated protein kinase kinase kinase (MAP3K) family. Cot is observed as one of the downstream effectors of Akt. Based on in-vitro kinase assays and following overexpression in cell lines its been showed that AKT can phosphorylate Cot under non-physiological conditions. Akt and Cot physically interact through the amino terminus of Cot, and this interaction results in the phosphorylation of Cot on serine 400. Cot was shown to activate the IkB kinase (IKK) complex, possibly acting through NF kB inducing kinase (NIK).
R-HSA-389758 (Reactome) PD-1 delivers inhibitory signals and downregulates antigen receptor signaling through direct dephosphorylation of signaling intermediates. The phosphatases SHP-1 and SHP-2 dephosphorylate CD3 zeta and inhibit the phosphorylation of ZAP-70 and PKC theta.
R-HSA-389759 (Reactome) Once phosphorylated, SH2-domain containing tyrosine phosphatases SHP-1 and SHP-2 bind to the ITIM and ITSM motifs of PD-1. The association between SHP-1 and PD-1 appears to be weaker than the interaction of PD-1 with SHP-2.
R-HSA-389762 (Reactome) The cytoplasmic domain of PD-1 has two tyrosine motifs, ITIM and ITSM. On engagement with B7 ligands B7DC and B7H1, PD-1 is phosphorylated on tyrosine residues 223 and 248 within these motifs. Kinases Lck and Csk also bind to these motifs and these kinases may be involved in the phosphorylation of PD-1.
R-HSA-389788 (Reactome) Inactive p21-associated kinases (PAKs), PAK1, PAK2 and PAK3, form homodimers that are autoinhibited through in trans interaction between the inhibitory N-terminus of one PAK molecule and the catalytic domain of the other PAK molecule. All PAK isoforms are direct effectors of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to a highly conserved motif in the amino terminus of PAK known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. This binding induces a conformational change that disrupts PAK homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain, thereby inducing autophosphorylation at several sites and enabling the phosphorylation of exogenous substrates (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009).
R-HSA-389919 (Reactome) The sequence around Y226 in the BTLA cytoplasmic domain is a predicted recruitment site for Grb2. Despite the prediction there is no direct evidence of protein recruitment to this tyrosine motif.
R-HSA-389941 (Reactome) The cytoplasmic tail of BTLA contains three tyrosine residues that are conserved in most organisms. The tyrosine residues Y257 and Y282 are both present in ITIM motif sequences. These tyrosine residues are phosphorylated after BTLA cross-linking, and both ITIM motifs recruit the tyrosine phosphatases SHP1 and SHP2. The targets of SHP1 and SHP2 recruited to BTLA are not known, although it is possible that they also have a role in dephosphorylating signaling intermediates downstream of antigen receptors in lymphocytes or in specifically targeting the PI3K-AKT pathway.
R-HSA-390329 (Reactome) When CTLA4 is engaged by B7 molecules, PP2A disassociates from CTLA4 in a phosphorylation dependent manner. Released PP2A acts downstream of early TCR and CD28 signaling, by inhibition of the PKB/Akt pathway.
R-HSA-392530 (Reactome) Cot functions upstream of NIK in the CD28-costimulation signaling pathway leading to activation of NF-kB. Cot binds avidly to NIK and induces NIK phosphorylation in vivo.
R-HSA-6790087 (Reactome) Binding of HVEM to BTLA induces tyrosine phosphorylation of BTLA on three cytoplasmic tyrosines. The phosphorylated tyrosine Y274 and 299 ( Y257 and 282 in human BTLA) associate with tyrosine phosphatase SHP2 and down regulate proximal TCR signalling. Phosphorylated Y245 (Y226 in human BTLA) in BTLA associates with growth receptor bound 2 (GRB2) (Murphy et al. 2006).
RAC1:GDPR-HSA-389348 (Reactome)
RAC1:GTPArrowR-HSA-389348 (Reactome)
SHP-1/SHP-2:pBTLA:HVEMArrowR-HSA-389941 (Reactome)
Src family tyrosine kinases (SFKs)R-HSA-388833 (Reactome)
Src family tyrosine kinases (SFKs)mim-catalysisR-HSA-388831 (Reactome)
Src family tyrosine kinases (SFKs)mim-catalysisR-HSA-388833 (Reactome)
TNFRSF14R-HSA-389523 (Reactome)
TORC2 complexmim-catalysisR-HSA-198640 (Reactome)
VAV1:PIP3:CD28:GRB2ArrowR-HSA-389352 (Reactome)
VAV1:PIP3:CD28:GRB2R-HSA-389354 (Reactome)
VAV1R-HSA-389352 (Reactome)
p-BTLA-HVEM complexArrowR-HSA-6790087 (Reactome)
p-BTLA-HVEM complexR-HSA-389919 (Reactome)
p-BTLA-HVEM complexR-HSA-389941 (Reactome)
p-MAP3K14ArrowR-HSA-392530 (Reactome)
p-S-AKT:PDPK1:PIP3ArrowR-HSA-2317314 (Reactome)
p-S-AKT:PDPK1:PIP3R-HSA-198270 (Reactome)
p-S-AKT:PDPK1:PIP3mim-catalysisR-HSA-198270 (Reactome)
p-S-AKT:PIP3ArrowR-HSA-198640 (Reactome)
p-S-AKT:PIP3R-HSA-2317314 (Reactome)
p-S400-MAP3K8ArrowR-HSA-389756 (Reactome)
p-S400-MAP3K8mim-catalysisR-HSA-392530 (Reactome)
p-Y142,160,174-VAV1:PIP3:CD28:GRB2ArrowR-HSA-389354 (Reactome)
p-Y142,160,174-VAV1:PIP3:CD28:GRB2mim-catalysisR-HSA-389348 (Reactome)
p-Y142,160,174-VAV1:PIP3:CD28:GRB2mim-catalysisR-HSA-389350 (Reactome)
p-Y165,Y182-CTLA-4 dimer:SFKsArrowR-HSA-388833 (Reactome)
p-Y165,Y182-CTLA-4 dimer:SFKsR-HSA-388829 (Reactome)
p-Y180-ICOSR-HSA-388830 (Reactome)
p-Y223,248-PDCD1:B7-DC,B7-H1ArrowR-HSA-389762 (Reactome)
p-Y223,248-PDCD1:B7-DC,B7-H1R-HSA-389759 (Reactome)
pCTLA-4:Src kinases:SHP2ArrowR-HSA-388829 (Reactome)
phospho CD28:B7-1/B7-2ArrowR-HSA-388831 (Reactome)
phospho CD28:B7-1/B7-2R-HSA-388814 (Reactome)
phospho CD28:B7-1/B7-2R-HSA-388832 (Reactome)
phospho CD28:B7-1/B7-2R-HSA-389381 (Reactome)
unknown kinasemim-catalysisR-HSA-6790087 (Reactome)
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