Costimulation by the CD28 family (Homo sapiens)

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7, 25, 421034, 3914, 20488, 211216, 463, 3827, 28, 32, 336, 1127, 32, 415, 182416, 40, 46923, 29184, 3129, 4916, 40, 44, 465, 1830, 35, 5019, 431317, 224151, 374, 314517, 2226, 3647PAK B7-1 homodimer/ B7-2 CD80 CD28B7-2 AKTPIP3 CD80 Phospho CD28 homodimer ICOSICOSL CD80 B7-1 homodimer/ B7-2 Lck/Csk SHP-2/SHP-1 CD28B7-1 AKTPIP3THEM4/TRIB3 Phospho CTLA-4 dimer CD3 epsilon CD3 delta with phosphorylated ITAMs CD28Grb2 CD28 homodimer CDC42-GDP LCK, FYN p-S-AKTPIP3 ICOSPI3K AKTPIP3 THEM4/TRIB3 PI3K alpha CD80 CD80 MHC class II alpha/beta dimer Phosphorylated PD-1 bound to B7DC/B7H1 pBTLA-HVEM complex CD28 homodimer CD80 SHP-1/SHP-2pBTLAHVEM Phospho CTLA-4 dimer Phospho CD28 homodimer B7-1 homodimer/ B7-2 T-cell receptor B7-1 homodimer/ B7-2 CD80 LCK, FYN RAC1-GTP PDK1AKTPIP3 RAC1-GDP PP2A CTLA-4 homodimer SHP-1/SHP-2 bound to phospho PD-1 CTLA-4 homodimer TCR chain beta LCK, FYN CTLA-4PP2A PP2A PP2A CD28 homodimer Phosphorylated PD-1 bound to B7DC/B7H1 CD80 Src family tyrosine kinases CD28 homodimer PP2A pBTLA-HVEM complex phospho CD28B7-1/B7-2 TORC2 complex HLA II beta chain phospho CD28B7-1/B7-2 CD3 zeta dimer with phosphorylated ITAMs B7-1 homodimer/ B7-2 CD28Grb2 CTLA-4PP2A TCR chain beta PD-1 ligands PI3K alpha MHC Class II bearing antigen peptide B7-1 homodimer/ B7-2 CD80 p-S-AKTPDPK1PIP3 B7-1 homodimer/ B7-2 LCK, FYN T-cell receptor complex with dephosphorylated CD3 zeta chain B7-1 homodimer/ B7-2 RAC1-GTP PIP3PDK1active AKT TCR chain alpha Phospho CD28 homodimer CD80 CD80 PD-1 ligands LCK, FYN CD80 Phosphorylated CTLA-4 bound to kinases MHC class II alpha/beta dimer CTLA-4 homodimer HLA II alpha chain CD3 epsilon CD3 delta with phosphorylated ITAMs Grb2pBTLAHVEM PI3K alpha PD-1PD-1 ligands B7-1 homodimer/ B7-2 CD80 PAK bound to Rac1 and Cdc42 T-cell receptor CDC42GTP TCR chain alpha BTLA-HVEM complex PDPK1PIP3 PDPK1PIP3 PAK homodimer phospho CTLA4B7-1/B7-2 phospho CD28B7-1/B7-2 Phospho CD28 homodimer Antigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4 pBTLA-HVEM complex Phosphorylated CTLA-4 bound to kinases Vav1 bound to PIP3 and Grb2CD28 Active RAC1/CDC42 CD28Grb2 CD3 epsilon CD3 gamma with phosphorylated ITAM T-cell receptor complex with phosphorylated ITAMs Lck/Csk B7-1 homodimer/ B7-2 CD28Gads Phospho CD28 homodimer pVav1PIP3Grb2CD28 Src family tyrosine kinases phospho CD28B7-1/B7-2 Phospho CD28 homodimer pCTLA-4Src kinasesSHP2 HLA II beta chain CD28 bound to B7 ligands MHC Class II bearing antigen peptide CD3 epsilon CD3 gamma with phosphorylated ITAM LCK, FYN CD28PI3K PD-1 ligands SHP-2/SHP-1 PI3K alpha phospho CTLA4B7-1/B7-2 B7-1 homodimer/ B7-2 HLA II alpha chain PAK cytosolAntigen-bearing MHC Class II TCR with dephosphorylated CD3 zeta chainCD4 phospho CD28B7-1/B7-2 cytosolphospho CD28B7-1/B7-2 CDC42GTP PP2ACTLA4B7-1/B7-2 p-S-AKTPIP3 ATPPIGRAP2 p-Y165,Y182-CTLA4 p-Y191-CD28 CD80 GTP LYNCD28B7-2VAV1 PIHLA class II histocompatibility antigen, DRB1-14 beta chain CD86 HLA class II histocompatibility antigen, DP alpha chain precursor CTLA-4 homodimerGTPCD80 PiCTLA-4PP2AActive AKTPTPN6 p-Y188,Y199-CD3E LCK HLA class II histocompatibility antigen, DR alpha chain precursor GDP CD80 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor Lck/CskHLA class II histocompatibility antigen, DRB3-1 beta chain precursor SHP-2/SHP-1Antigen-bearing MHC Class II TCR with dephosphorylated CD3 zeta chainCD4PIP3PDK1active AKTPIK3CA RAC1 GRB2-1PI3K alphaLCK LCK CD274 CD80 ATPFYNp-Y191-CD28 HLA class II histocompatibility antigen, DQ beta 2 chain PICD28GadsHLA class II histocompatibility antigen, DRB1-13 beta chain PIMAPKAP1 PAK bound to Rac1 and Cdc42p-Y180-ICOS-1 HLA class II histocompatibility antigen, DP Vav1 bound to PIP3 and Grb2CD28AKTPIP3THEM4/TRIB3PDPK1 HLA class II histocompatibility antigen, DP alpha chain precursor p-Y191-CD28 HLA class II histocompatibility antigen, DRB3-1 beta chain precursor HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor ATPTRIB3 CD86 AKTPIP3GDP TRACHLA class II histocompatibility antigen, DR-1 beta chain precursor PDCD1LG2 BTLA CD86 LCK HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor CD28 homodimerp-Y149,Y160-CD3D HLA class II histocompatibility antigen, DRB1-1 beta chain CDC42-GDPPhosphorylated PD-1 bound to B7DC/B7H1FYNLCK RAC1-GDPPD-1 ligandsPAK1 PIADPFYNp-Y180-ICOS-1Src family tyrosine kinases CD274 p-S-AKTPIP3CDC42 p-Y223,Y248-PDCD1 HLA class II histocompatibility antigen, DRB1-8 beta chain ADPHLA class II histocompatibility antigen, DQ TRBV12-3 RAC1-GTPATPPTPN11PIK3CA TCRA CSK TRBV12-3 HLA class II histocompatibility antigen, DR beta 4 chain Grb2pBTLAHVEMPDCD1HLA class II histocompatibility antigen, DRB1-12 beta chain HLA class II histocompatibility antigen, DRB1-4 beta chain FYNTNFRSF14 p-Y226,Y257,Y282-BTLA CD86 HLA class II histocompatibility antigen, DRB1-15 beta chain PDK1AKTPIP3BTLAPDPK1PIP3HLA class II histocompatibility antigen, DR beta 5 chain p-Y188,Y199-CD3E ADPCTLA4 PDPK1 p-S-AKTPDPK1PIP3p-Y394-LCK HLA class II histocompatibility antigen, DRB1-15 beta chain PDCD1 FYNPP2AADPT-cell receptor alpha chain V region PY14 precursor TORC2 complexHLA class II histocompatibility antigen, DR-1 beta chain precursor RAC1 HLA class II histocompatibility antigen, DRB1-7 beta chain CD80 PAK2PP2ALCK PICD86 GDPPIPIK3CA p-6Y-CD247-1 PDCD1LG2 HLA class II histocompatibility antigen, DRB1-1 beta chain ICOS-1CD80 CD86 SHP-2/SHP-1HLA class II histocompatibility antigen, DRB1-10 beta chain T-cell receptor alpha chain V region HPB-MLT precursor GTP CD86 HLA class II histocompatibility antigen, DRB1-16 beta chain CD86 PIK3CA TRACTNFRSF14 HLA class II histocompatibility antigen, DRB1-7 beta chain T-cell receptor alpha chain V region PY14 precursor Phosphorylated CTLA-4 bound to kinasesTNFRSF14 CD28PI3KHLA class II histocompatibility antigen, DRB1-8 beta chain HLA class II histocompatibility antigen, DQ PTPN6 CD80 CD86 TCRB MAP3K14PICD80 PAKT-cell receptor alpha chain V region HPB-MLT precursor p-Y226,Y257,Y282-BTLA PIHLA class II histocompatibility antigen, DRB1-12 beta chain FYNGRAP2CD28 CD86 CD28 PPiADPCD28Grb2RICTOR CDC42 HLA class II histocompatibility antigen, DRB1-11 beta chain GRB2-1 PD-1PD-1 ligandsYES1CD86 LCK CD86 p-Y149,Y160-CD3D PP2ACTLA4B7-1/B7-2ADPHLA class II histocompatibility antigen, DQ ADPLCK, FYNp-Y394-LCK GTPLYNp-Y226,Y257,Y282-BTLA ICOS-1 HLA class II histocompatibility antigen, DRB1-14 beta chain CD80 PICD80 Active RAC1/CDC42THEM4 phospho CD28B7-1/B7-2FYNTCRA pVav1PIP3Grb2CD28CD86HLA class II histocompatibility antigen, DRB1-10 beta chain CD28 bound to B7 ligandsPI3K alphaTCRB p-Y191-CD28 CDC42GTPCTLA4 PAK2Antigen-bearing MHC Class II TCR with phosphorylated ITAMsCD4GRB2-1pCTLA-4Src kinasesSHP2ADPBTLA-HVEM complexB7-1 homodimer/ B7-2p-MAP3K14ATPSRC-1 p-Y191-CD28 HLA class II histocompatibility antigen, DRB1-9 beta chain precursor ICOSLG CDC42 AKTCTLA4 HLA class II histocompatibility antigen, DR beta 4 chain GRB2-1 HLA class II histocompatibility antigen, DRB1-13 beta chain HLA class II histocompatibility antigen, DQ MLST8 p-S400-MAP3K8PAK1 Src family tyrosine kinases SHP-1/SHP-2pBTLAHVEMHLA class II histocompatibility antigen, DQ GDPHLA class II histocompatibility antigen, DRB1-4 beta chain HLA class II histocompatibility antigen, DQ beta 2 chain HLA class II histocompatibility antigen, DR beta 5 chain CD80 LCK PTPN11 HLA class II histocompatibility antigen, DR alpha chain precursor MTOR TNFRSF14CD274 p-Y191-CD28 ICOSLGGTP SRC-1 PIVAV1FYNICOSPI3KHLA class II histocompatibility antigen, DRB1-16 beta chain HLA class II histocompatibility antigen, DQ CD80 PDPK1 CD247-1 p-Y160,Y171-CD3G pBTLA-HVEM complexp-Y160,Y171-CD3G ATPLCK PTPN11 HLA class II histocompatibility antigen, DP ATPPILCK CD28B7-1GRB2-1 p-Y165,Y182-CTLA4 PDCD1LG2 p-Y142,Y160,Y174-VAV1 CD4 SHP-1/SHP-2 bound to phospho PD-1CD80 ATPICOSICOSLPDPK1 CD28 HLA class II histocompatibility antigen, DRB1-11 beta chain TRBC1YES1CD28 p-Y223,Y248-PDCD1 MAP3K8FYNPTPN11 RAC1 CD80 TNFRSF14 ADPTRBC1CD4 PAK homodimerATPPDPK1CSK GRB2-1 22


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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=388841

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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)
AKT

PIP3

THEM4/TRIB3		ComplexREACT_12823 (Reactome)
AKT PIP3ComplexREACT_147984 (Reactome)
AKTProteinREACT_12946 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTProteinREACT_13319 (Reactome)
Active RAC1/CDC42ComplexREACT_20094 (Reactome)
Antigen-bearing MHC Class II 
TCR with dephosphorylated CD3 zeta chain
CD4		ComplexREACT_19788 (Reactome)
Antigen-bearing MHC Class II 
TCR with phosphorylated ITAMs
CD4		ComplexREACT_12725 (Reactome)
B7-1 homodimer/ B7-2ComplexREACT_20199 (Reactome)
BTLA ProteinQ7Z6A9 (Uniprot-TrEMBL)
BTLA-HVEM complexComplexREACT_20471 (Reactome)
BTLAProteinQ7Z6A9 (Uniprot-TrEMBL)
CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
CD274 ProteinQ9NZQ7 (Uniprot-TrEMBL)
CD28 B7-1ComplexREACT_19811 (Reactome)
CD28 B7-2ComplexREACT_20140 (Reactome)
CD28 GadsComplexREACT_20416 (Reactome)
CD28 Grb2ComplexREACT_20227 (Reactome)
CD28 PI3KComplexREACT_19529 (Reactome)
CD28 ProteinP10747 (Uniprot-TrEMBL)
CD28 bound to B7 ligandsComplexREACT_19594 (Reactome)
CD28 homodimerComplexREACT_19916 (Reactome)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CD80 ProteinP33681 (Uniprot-TrEMBL)
CD80 ComplexREACT_19742 (Reactome)
CD86 ProteinP42081 (Uniprot-TrEMBL)
CD86ProteinP42081 (Uniprot-TrEMBL)
CDC42 GTPComplexREACT_12889 (Reactome)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42-GDPComplexREACT_20401 (Reactome)
CSK ProteinP41240 (Uniprot-TrEMBL)
CTLA-4 PP2AComplexREACT_19731 (Reactome)
CTLA-4 homodimerComplexREACT_19654 (Reactome)
CTLA4 ProteinP16410 (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)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Grb2

pBTLA

HVEM		ComplexREACT_20022 (Reactome)
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 ICOSLComplexREACT_20114 (Reactome)
ICOS PI3KComplexREACT_19686 (Reactome)
ICOS-1 ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
ICOS-1ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
ICOSLG ProteinO75144 (Uniprot-TrEMBL)
ICOSLGProteinO75144 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCK, FYNProteinREACT_20035 (Reactome)
LYNProteinP07948 (Uniprot-TrEMBL)
Lck/CskProteinREACT_20288 (Reactome)
MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
MAP3K8ProteinP41279 (Uniprot-TrEMBL)
MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
PAK bound to Rac1 and Cdc42ComplexREACT_19943 (Reactome)
PAK homodimerComplexREACT_19479 (Reactome)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK2ProteinQ13177 (Uniprot-TrEMBL)
PAKProteinREACT_19640 (Reactome)
PD-1 PD-1 ligandsComplexREACT_20041 (Reactome)
PD-1 ligandsProteinREACT_20259 (Reactome)
PDCD1 ProteinQ15116 (Uniprot-TrEMBL)
PDCD1LG2 ProteinQ9BQ51 (Uniprot-TrEMBL)
PDCD1ProteinQ15116 (Uniprot-TrEMBL)
PDK1

AKT

PIP3		ComplexREACT_13226 (Reactome)
PDPK1 PIP3ComplexREACT_148385 (Reactome)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI3K alphaComplexREACT_12697 (Reactome)
PIMetaboliteCHEBI:16618 (ChEBI)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIP3

PDK1

active AKT		ComplexREACT_13230 (Reactome)
PP2A

CTLA4

B7-1/B7-2		ComplexREACT_19452 (Reactome)
PP2AComplexREACT_10628 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
Phosphorylated CTLA-4 bound to kinasesComplexREACT_19872 (Reactome)
Phosphorylated PD-1 bound to B7DC/B7H1ComplexREACT_19810 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1-GDPComplexREACT_22018 (Reactome)
RAC1-GTPComplexREACT_21594 (Reactome)
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
SHP-1/SHP-2

pBTLA

HVEM		ComplexREACT_19540 (Reactome)
SHP-1/SHP-2 bound to phospho PD-1ComplexREACT_19972 (Reactome)
SHP-2/SHP-1ProteinREACT_20250 (Reactome)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
Src family tyrosine kinases ProteinREACT_13328 (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 complexComplexREACT_13222 (Reactome)
TRACProteinP01848 (Uniprot-TrEMBL)
TRBC1ProteinP01850 (Uniprot-TrEMBL)
TRBV12-3 ProteinP01733 (Uniprot-TrEMBL)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1ProteinP15498 (Uniprot-TrEMBL)
Vav1 bound to PIP3 and Grb2 CD28ComplexREACT_19524 (Reactome)
YES1ProteinP07947 (Uniprot-TrEMBL)
p-6Y-CD247-1 ProteinP20963-1 (Uniprot-TrEMBL)
p-MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
p-S-AKT

PDPK1

PIP3		ComplexREACT_148335 (Reactome)
p-S-AKT PIP3ComplexREACT_148552 (Reactome)
p-S400-MAP3K8ProteinP41279 (Uniprot-TrEMBL)
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-CTLA4 ProteinP16410 (Uniprot-TrEMBL)
p-Y180-ICOS-1 ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
p-Y180-ICOS-1ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
p-Y188,Y199-CD3E ProteinP07766 (Uniprot-TrEMBL)
p-Y191-CD28 ProteinP10747 (Uniprot-TrEMBL)
p-Y223,Y248-PDCD1 ProteinQ15116 (Uniprot-TrEMBL)
p-Y226,Y257,Y282-BTLA ProteinQ7Z6A9 (Uniprot-TrEMBL)
p-Y394-LCK ProteinP06239 (Uniprot-TrEMBL)
pBTLA-HVEM complexComplexREACT_19709 (Reactome)
pCTLA-4

Src kinases

SHP2		ComplexREACT_19498 (Reactome)
pVav1

PIP3 Grb2

CD28		ComplexREACT_20129 (Reactome)
phospho CD28 B7-1/B7-2ComplexREACT_19582 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_12391 (Reactome)
ADPArrowREACT_12584 (Reactome)
ADPArrowREACT_19141 (Reactome)
ADPArrowREACT_19232 (Reactome)
ADPArrowREACT_19264 (Reactome)
ADPArrowREACT_19274 (Reactome)
ADPArrowREACT_19312 (Reactome)
ADPArrowREACT_19316 (Reactome)
ADPArrowREACT_19380 (Reactome)
AKT

PIP3

THEM4/TRIB3		TBarREACT_12391 (Reactome)
AKT PIP3REACT_12391 (Reactome)
AKTREACT_147886 (Reactome)
ATPREACT_12391 (Reactome)
ATPREACT_12584 (Reactome)
ATPREACT_19141 (Reactome)
ATPREACT_19232 (Reactome)
ATPREACT_19264 (Reactome)
ATPREACT_19274 (Reactome)
ATPREACT_19312 (Reactome)
ATPREACT_19316 (Reactome)
ATPREACT_19380 (Reactome)
Active AKTArrowREACT_12584 (Reactome)
Active AKTREACT_19232 (Reactome)
Active RAC1/CDC42REACT_19246 (Reactome)
Antigen-bearing MHC Class II 
TCR with dephosphorylated CD3 zeta chain
CD4		ArrowREACT_19146 (Reactome)
B7-1 homodimer/ B7-2REACT_19129 (Reactome)
BTLAREACT_19395 (Reactome)
CD28 Grb2REACT_19244 (Reactome)
CD28 PI3KREACT_19274 (Reactome)
CD28 bound to B7 ligandsREACT_19264 (Reactome)
CD28 homodimerREACT_19148 (Reactome)
CD28 homodimerREACT_19240 (Reactome)
CD80 REACT_19148 (Reactome)
CD86REACT_19240 (Reactome)
CDC42 GTPArrowREACT_19286 (Reactome)
CDC42-GDPREACT_19286 (Reactome)
CTLA-4 PP2AREACT_19129 (Reactome)
CTLA-4 homodimerREACT_19404 (Reactome)
FYNREACT_19316 (Reactome)
GDPArrowREACT_19243 (Reactome)
GDPArrowREACT_19286 (Reactome)
GRAP2REACT_19159 (Reactome)
GRB2-1REACT_19254 (Reactome)
GRB2-1REACT_19406 (Reactome)
GTPREACT_19243 (Reactome)
GTPREACT_19286 (Reactome)
ICOS-1REACT_19418 (Reactome)
ICOSLGREACT_19418 (Reactome)
LCK, FYNREACT_19264 (Reactome)
Lck/CskREACT_19312 (Reactome)
MAP3K14REACT_19141 (Reactome)
MAP3K8REACT_19232 (Reactome)
PAK bound to Rac1 and Cdc42ArrowREACT_19246 (Reactome)
PAK homodimerREACT_19246 (Reactome)
PAKArrowREACT_19246 (Reactome)
PD-1 PD-1 ligandsREACT_19312 (Reactome)
PD-1 ligandsREACT_19196 (Reactome)
PDCD1REACT_19196 (Reactome)
PDK1

AKT

PIP3		ArrowREACT_19209 (Reactome)
PDPK1 PIP3ArrowREACT_12584 (Reactome)
PDPK1 PIP3REACT_147711 (Reactome)
PDPK1REACT_147873 (Reactome)
PI3K alphaREACT_19171 (Reactome)
PI3K alphaREACT_19212 (Reactome)
PIArrowREACT_19274 (Reactome)
PIREACT_147873 (Reactome)
PIREACT_147886 (Reactome)
PIREACT_19244 (Reactome)
PIREACT_19274 (Reactome)
PP2A

CTLA4

B7-1/B7-2		REACT_19380 (Reactome)
PP2AArrowREACT_19380 (Reactome)
PP2AREACT_19209 (Reactome)
PP2AREACT_19404 (Reactome)
PPiArrowREACT_19146 (Reactome)
PTPN11REACT_19203 (Reactome)
Phosphorylated CTLA-4 bound to kinasesArrowREACT_19380 (Reactome)
Phosphorylated CTLA-4 bound to kinasesREACT_19203 (Reactome)
Phosphorylated PD-1 bound to B7DC/B7H1ArrowREACT_19312 (Reactome)
Phosphorylated PD-1 bound to B7DC/B7H1REACT_19198 (Reactome)
PiArrowREACT_19209 (Reactome)
RAC1-GDPREACT_19243 (Reactome)
RAC1-GTPArrowREACT_19243 (Reactome)
REACT_12391 (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).
REACT_12584 (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).
REACT_147711 (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)
REACT_147873 (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).
REACT_147886 (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.
REACT_19129 (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.
REACT_19141 (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.
REACT_19146 (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.
REACT_19148 (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
REACT_19159 (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.
REACT_19171 (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.
REACT_19196 (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.
REACT_19198 (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.
REACT_19203 (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.
REACT_19209 (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.
REACT_19212 (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.
REACT_19232 (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).
REACT_19240 (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.
REACT_19243 (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.
REACT_19244 (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.
REACT_19246 (Reactome) In its unbound state PAK is maintained in an inactive conformation through intra domain interactions. On stimulation PAK is translocated to the plasma membrane where it specifically interacts with Rho family GTP-binding proteins Rac1-GTP and Cdc42-GTP. All PAK isoforms are direct effectors of the Rac and Cdc42. Rac 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 is thought to induce a conformational change in PAK that relieves autoinhibition of the catalytic carboxy terminal domain, thereby inducing autophosphorylation at several sites and enabling the phosphorylation of exogenous substrates.
REACT_19254 (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.
REACT_19264 (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.
REACT_19274 (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.
REACT_19286 (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.
REACT_19312 (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.
REACT_19316 (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.
REACT_19365 (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.
REACT_19380 (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.
REACT_19395 (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.
REACT_19404 (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.
REACT_19406 (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.
REACT_19418 (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.
SHP-1/SHP-2 bound to phospho PD-1REACT_19146 (Reactome)
SHP-2/SHP-1REACT_19198 (Reactome)
SHP-2/SHP-1REACT_19365 (Reactome)
Src family tyrosine kinases REACT_19264 (Reactome)
Src family tyrosine kinases REACT_19380 (Reactome)
TNFRSF14REACT_19395 (Reactome)
TORC2 complexREACT_12391 (Reactome)
VAV1REACT_19244 (Reactome)
Vav1 bound to PIP3 and Grb2 CD28REACT_19316 (Reactome)
p-MAP3K14ArrowREACT_19141 (Reactome)
p-S-AKT

PDPK1

PIP3		REACT_12584 (Reactome)
p-S-AKT PIP3ArrowREACT_12391 (Reactome)
p-S-AKT PIP3REACT_147711 (Reactome)
p-S400-MAP3K8ArrowREACT_19232 (Reactome)
p-S400-MAP3K8REACT_19141 (Reactome)
p-Y180-ICOS-1REACT_19171 (Reactome)
pBTLA-HVEM complexREACT_19365 (Reactome)
pBTLA-HVEM complexREACT_19406 (Reactome)
pVav1

PIP3 Grb2

CD28		ArrowREACT_19316 (Reactome)
pVav1

PIP3 Grb2

CD28		REACT_19243 (Reactome)
pVav1

PIP3 Grb2

CD28		REACT_19286 (Reactome)
phospho CD28 B7-1/B7-2ArrowREACT_19264 (Reactome)
phospho CD28 B7-1/B7-2REACT_19159 (Reactome)
phospho CD28 B7-1/B7-2REACT_19212 (Reactome)
phospho CD28 B7-1/B7-2REACT_19254 (Reactome)
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