Interferon gamma signaling (Homo sapiens)

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14, 18, 22, 3821, 39, 4145, 4620, 311, 11, 32, 37, 40...30, 39, 414, 13, 255, 7, 12, 16, 23...9, 10, 36, 432, 82719, 27-297, 15, 24, 446, 333, 17, 29IFNG-activated factor IFNGR complex with p-JAK HLA II alpha chain IFNGIFNGR1JAK1IFNGR2p-JAK2SOCS-1/-3 IFNG homodimer IFNGR2JAK2 IFNGR complex with p-JAK2 IFNGp-IFNGR1p-JAK1IFNGR2p-JAK2 IFNG-activated factor IFNG homodimer p-STAT1 dimer bound to p-IFNGR1 IFNGIFNGR1JAK1IFNGR2p-JAK2 p-IFNGR1pJAK1IFNGR2p-JAK2 IFNGR1JAK1 p-IFNGR1pJAK1IFNGR2p-JAK2 IFNG homodimer IFNGR1JAK1INFG2JAK2 IFNGR2p-JAK2 p-STAT1IFNG homodimer IFNGR2p-JAK2 IFNGR1JAK1INFG2JAK2 IFNGIFNGR1p-JAK1IFNGR2p-JAK2 MHC class II alpha/beta dimer IFNGR1JAK1 lysosomal lumenIFNGR1p-JAK1 IFNG-activated factor IFNG homodimer IFNGR2p-JAK2 IFNGR2p-JAK2 p-STAT1 dimerPIASSUMO1 p-IFNGR1p-JAK1 GAF bound to GAS promoter element IFNG homodimer IFNGp-IFNGR1p-JAK1IFNGR2p-JAK2 IFNGp-IFNGR1p-JAK1IFNGR2p-JAK2 IFNGIFNGR1JAK1IFNGR2JAK2 IFNG-activated factor IFNGR1JAK1 IFNGR2p-JAK2 IFNGR1JAK1 p-IFNGR1p-JAK1 IFNG homodimer IFNGp-IFNGR1p-JAK1IFNGR2p-JAK2 IFNGR2p-JAK2 IFNGR2p-JAK2 p-IFNGR1p-JAK1 IFNGIFNGR1JAK1IFNGR2p-JAK2 IFNG-activated factor endoplasmic reticulum lumenp-IFNGR1pJAK1IFNGR2p-JAK2 STAT1 bound to p-IFNGR1 nucleoplasmSOCS-1 and SOCS-3 cytosolp-IFNGR1pJAK1IFNGR2p-JAK2 IFNGR2JAK2 IFNG homodimer IFNG homodimer HLA II beta chain IFNGR complex with p-JAK2 p-STAT1 homodimer p-IFNGR1p-JAK1 PTPN6HLA class II histocompatibility antigen, DRB1-11 beta chain HLA class II histocompatibility antigen, DQ STAT1-1STAT1-1 JAK1 IFNGIFNGR1JAK1IFNGR2p-JAK2HLA class II histocompatibility antigen, DP PTPN1IFI30ADPPiIFNGR1 HLA class II histocompatibility antigen, DRB1-16 beta chain IFNGR2 p-Y-JAK1 IFNGR2 p-STAT1 dimer bound to p-IFNGR1p-S727,Y701-STAT1-1 PTPN2-1p-Y1007-JAK2 p-S727,Y701-STAT1-1 p-Y440-IFNGR1 STAT1-1OAS proteinsHLA class II histocompatibility antigen, DQ GAF bound to GAS promoter elementIFNGR2 p-STAT1 dimerPIASSUMO1IFNGR1 IFNGR2 p-Y440-IFNGR1 PTAFRHLA class II histocompatibility antigen, DRB1-7 beta chain SP100IFNGIFNGR1p-JAK1IFNGR2p-JAK2FCGRASUMO1ADPCaMKII and PKC-deltap-Y440-IFNGR1 IRF 1-9Class I MHC heavy chain IFNG IFNGR2 HLA class II histocompatibility antigen, DRB1-1 beta chain IFNG-activated factor PiHLA class II histocompatibility antigen, DR beta 5 chain H2OSOCS3 p-Y1007-JAK2 SOCS1 B2Mp-Y-JAK1 HLA class II histocompatibility antigen, DQ HLA class II histocompatibility antigen, DRB1-15 beta chain IFNGp-IFNGR1p-JAK1IFNGR2p-JAK2IFNG IFNGIFNGR1JAK1IFNGR2JAK2PTPs-SHP1/2/PTP1BHLA class II histocompatibility antigen, DP alpha chain precursor ATPHLA class II histocompatibility antigen, DRB1-14 beta chain IFNGR2 p-S727,Y701-STAT1-1 p-Y701-STAT1-1 IFN-gamma upregulated CAMsIFNG homodimerH2OHLA class II histocompatibility antigen, DRB1-9 beta chain precursor IFNG p-Y1007-JAK2 ADPIFNGR1 PIAS1 p-Y1007-JAK2 GBPATPHLA class II histocompatibility antigen, DQB1*0602 beta chain precursor GAS promoter region in IFNG-regulated genesIFNG SOCS-1 and SOCS-3ADPIFNG p-Y-JAK1 IFNGR1JAK1INFG2JAK2IFNG JAK1 IFNG HLA class II histocompatibility antigen, DRB1-13 beta chain SUMO1 HLA class II histocompatibility antigen, DRB1-10 beta chain p-Y-JAK1 ATPIFNG IFNG JAK2 JAK1 p-Y440-IFNGR1 IFNGR2 HLA class II histocompatibility antigen, DQ beta 2 chain PMLHLA class II histocompatibility antigen, DRB1-4 beta chain IFNGR1 IFNGIFNGR1JAK1IFNGR2p-JAK2SOCS-1/-3p-STAT1ATPp-S727,Y701-STAT1-1 PIAS1HLA class II histocompatibility antigen, DRB3-1 beta chain precursor ATPJAK1 CIITAHLA class II histocompatibility antigen, DRB1-12 beta chain JAK2 p-Y-JAK1 IFNG-activated factor IFNGR2 p-Y1007-JAK2 p-Y1007-JAK2 HLA class II histocompatibility antigen, DR-1 beta chain precursor MHC class II alpha/beta dimerHLA class II histocompatibility antigen, DRB1-8 beta chain p-S727,Y701-STAT1-1 IFNGR2 IFNGR1 MT2AHLA class II histocompatibility antigen, DR alpha chain precursor ADPSTAT1 bound to p-IFNGR1p-Y1007-JAK2 HLA class II histocompatibility antigen, DR beta 4 chain 47, 48265, 12


Description

Interferon-gamma (IFN-gamma) belongs to the type II interferon family and is secreted by activated immune cells-primarily T and NK cells, but also B-cells and APC. INFG exerts its effect on cells by interacting with the specific IFN-gamma receptor (IFNGR). IFNGR consists of two chains, namely IFNGR1 (also known as the IFNGR alpha chain) and IFNGR2 (also known as the IFNGR beta chain). IFNGR1 is the ligand binding receptor and is required but not sufficient for signal transduction, whereas IFNGR2 do not bind IFNG independently but mainly plays a role in IFNG signaling and is generally the limiting factor in IFNG responsiveness. Both IFNGR chains lack intrinsic kinase/phosphatase activity and thus rely on other signaling proteins like Janus-activated kinase 1 (JAK1), JAK2 and Signal transducer and activator of transcription 1 (STAT-1) for signal transduction. IFNGR complex in its resting state is a preformed tetramer and upon IFNG association undergoes a conformational change. This conformational change induces the phosphorylation and activation of JAK1, JAK2, and STAT1 which in turn induces genes containing the gamma-interferon activation sequence (GAS) in the promoter. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=877300

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Bibliography

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History

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CompareRevisionActionTimeUserComment
115093view17:04, 25 January 2021ReactomeTeamReactome version 75
113535view12:01, 2 November 2020ReactomeTeamReactome version 74
112733view16:13, 9 October 2020ReactomeTeamReactome version 73
101649view11:51, 1 November 2018ReactomeTeamreactome version 66
101185view21:39, 31 October 2018ReactomeTeamreactome version 65
100711view20:11, 31 October 2018ReactomeTeamreactome version 64
100261view16:56, 31 October 2018ReactomeTeamreactome version 63
99814view15:20, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99357view12:48, 31 October 2018ReactomeTeamreactome version 62
93905view13:44, 16 August 2017ReactomeTeamreactome version 61
93478view11:24, 9 August 2017ReactomeTeamreactome version 61
86576view09:21, 11 July 2016ReactomeTeamreactome version 56
83234view10:27, 18 November 2015ReactomeTeamVersion54
81633view13:10, 21 August 2015ReactomeTeamVersion53
77096view08:39, 17 July 2014ReactomeTeamFixed remaining interactions
76802view12:18, 16 July 2014ReactomeTeamFixed remaining interactions
76125view10:19, 11 June 2014ReactomeTeamRe-fixing comment source
75837view11:40, 10 June 2014ReactomeTeamReactome 48 Update
75198view09:43, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74845view10:07, 30 April 2014ReactomeTeamReactome46
44865view09:58, 6 October 2011MartijnVanIerselOntology Term : 'immune response pathway' added !
42056view21:53, 4 March 2011MaintBotAutomatic update
39862view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
B2MProteinP61769 (Uniprot-TrEMBL)
CIITAProteinP33076 (Uniprot-TrEMBL)
CaMKII and PKC-deltaProteinREACT_26704 (Reactome)
Class I MHC heavy chain ProteinREACT_26784 (Reactome)
FCGRAProteinREACT_26475 (Reactome)
GAF bound to GAS promoter elementComplexREACT_25470 (Reactome)
GAS promoter region in IFNG-regulated genesREACT_26763 (Reactome)
GBPProteinREACT_26189 (Reactome)
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)
IFI30ProteinP13284 (Uniprot-TrEMBL)
IFN-gamma upregulated CAMsProteinREACT_26072 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

JAK2		ComplexREACT_25865 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2 p-JAK2

SOCS-1/-3		ComplexREACT_26775 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

p-JAK2		ComplexREACT_26738 (Reactome)
IFNG

IFNGR1 p-JAK1 IFNGR2

p-JAK2		ComplexREACT_26286 (Reactome)
IFNG

p-IFNGR1 p-JAK1 IFNGR2

p-JAK2		ComplexREACT_25650 (Reactome)
IFNG ProteinP01579 (Uniprot-TrEMBL)
IFNG homodimerComplexREACT_26955 (Reactome)
IFNG-activated factor ComplexREACT_26144 (Reactome)
IFNG-activated factor ComplexREACT_26637 (Reactome)
IFNGR1

JAK1 INFG2

JAK2		ComplexREACT_25803 (Reactome)
IFNGR1 ProteinP15260 (Uniprot-TrEMBL)
IFNGR2 ProteinP38484 (Uniprot-TrEMBL)
IRF 1-9ProteinREACT_26465 (Reactome)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
MHC class II alpha/beta dimerComplexREACT_121884 (Reactome)
MT2AProteinP02795 (Uniprot-TrEMBL)
OAS proteinsProteinREACT_26755 (Reactome)
PIAS1 ProteinO75925 (Uniprot-TrEMBL)
PIAS1ProteinO75925 (Uniprot-TrEMBL)
PMLProteinP29590 (Uniprot-TrEMBL)
PTAFRProteinP25105 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PTPN2-1ProteinP17706-2 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
PTPs-SHP1/2/PTP1BProteinREACT_26675 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
SOCS-1 and SOCS-3ProteinREACT_25587 (Reactome)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS3 ProteinO14543 (Uniprot-TrEMBL)
SP100ProteinP23497 (Uniprot-TrEMBL)
STAT1 bound to p-IFNGR1ComplexREACT_26587 (Reactome)
STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
STAT1-1ProteinP42224-1 (Uniprot-TrEMBL)
SUMO1 ProteinP63165 (Uniprot-TrEMBL)
SUMO1ProteinP63165 (Uniprot-TrEMBL)
p-S727,Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
p-STAT1 dimer

PIAS

SUMO1		ComplexREACT_25840 (Reactome)
p-STAT1 dimer bound to p-IFNGR1ComplexREACT_25936 (Reactome)
p-STAT1ComplexREACT_26108 (Reactome)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y440-IFNGR1 ProteinP15260 (Uniprot-TrEMBL)
p-Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_24928 (Reactome)
ADPArrowREACT_24933 (Reactome)
ADPArrowREACT_24993 (Reactome)
ADPArrowREACT_25139 (Reactome)
ADPArrowREACT_25369 (Reactome)
ATPREACT_24928 (Reactome)
ATPREACT_24933 (Reactome)
ATPREACT_24993 (Reactome)
ATPREACT_25139 (Reactome)
ATPREACT_25369 (Reactome)
B2MArrowREACT_25082 (Reactome)
CIITAArrowREACT_25082 (Reactome)
CaMKII and PKC-deltamim-catalysisREACT_25369 (Reactome)
Class I MHC heavy chain ArrowREACT_25082 (Reactome)
FCGRAArrowREACT_25082 (Reactome)
GAF bound to GAS promoter elementArrowREACT_25082 (Reactome)
GAS promoter region in IFNG-regulated genesREACT_25118 (Reactome)
GBPArrowREACT_25082 (Reactome)
H2OREACT_25185 (Reactome)
H2OREACT_25190 (Reactome)
IFI30ArrowREACT_25082 (Reactome)
IFN-gamma upregulated CAMsArrowREACT_25082 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

JAK2		ArrowREACT_25190 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

JAK2		REACT_25139 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

JAK2		mim-catalysisREACT_25139 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2 p-JAK2

SOCS-1/-3		TBarREACT_24928 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

p-JAK2		ArrowREACT_25139 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

p-JAK2		REACT_24928 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

p-JAK2		REACT_25158 (Reactome)
IFNG

IFNGR1 JAK1 IFNGR2

p-JAK2		mim-catalysisREACT_24928 (Reactome)
IFNG

IFNGR1 p-JAK1 IFNGR2

p-JAK2		ArrowREACT_24928 (Reactome)
IFNG

IFNGR1 p-JAK1 IFNGR2

p-JAK2		REACT_24933 (Reactome)
IFNG

IFNGR1 p-JAK1 IFNGR2

p-JAK2		REACT_25190 (Reactome)
IFNG

IFNGR1 p-JAK1 IFNGR2

p-JAK2		mim-catalysisREACT_24933 (Reactome)
IFNG

p-IFNGR1 p-JAK1 IFNGR2

p-JAK2		ArrowREACT_24933 (Reactome)
IFNG

p-IFNGR1 p-JAK1 IFNGR2

p-JAK2		ArrowREACT_24944 (Reactome)
IFNG

p-IFNGR1 p-JAK1 IFNGR2

p-JAK2		REACT_25056 (Reactome)
IFNG homodimerREACT_25347 (Reactome)
IFNG-activated factor ArrowREACT_24944 (Reactome)
IFNG-activated factor REACT_25118 (Reactome)
IFNG-activated factor REACT_25185 (Reactome)
IFNG-activated factor REACT_25331 (Reactome)
IFNGR1

JAK1 INFG2

JAK2		REACT_25347 (Reactome)
IRF 1-9ArrowREACT_25082 (Reactome)
MHC class II alpha/beta dimerArrowREACT_25082 (Reactome)
MT2AArrowREACT_25082 (Reactome)
OAS proteinsArrowREACT_25082 (Reactome)
PIAS1REACT_25331 (Reactome)
PMLArrowREACT_25082 (Reactome)
PTAFRArrowREACT_25082 (Reactome)
PTPN2-1mim-catalysisREACT_25185 (Reactome)
PTPN6TBarREACT_24928 (Reactome)
PTPs-SHP1/2/PTP1Bmim-catalysisREACT_25190 (Reactome)
PiArrowREACT_25185 (Reactome)
PiArrowREACT_25190 (Reactome)
REACT_24928 (Reactome) The initial phosphorylation of JAK1 and JAK2 is mediated by JAK2. Autophosphorylated JAK2 may transphopshorylate JAK1 bound to IFNGR1 chain. Tyrosine 1033 in the activation loop of the JAK1 kinase domain may be the target for transphosphorylation (phosphorylation site mentioned here is based on sequence similarity with all the other JAK kinases).
REACT_24933 (Reactome) The phosphorylated active JAK1 kinase inturn phosphorylates tyrosine residue 440 on each of the IFNGR1 chains to form two adjacent docking sites for the latent STAT1 SH2 domains.
REACT_24944 (Reactome) The phosphorylated STAT1 on IFNGR1 chains homodimerize through reciprocal SH2-phosphotyrosine interactions to form p-STAT1 homodimer called gamma-activated-factor (GAF). This phosphorylated STAT1 homodimer disassociates from the receptor complex and translocates to the nucleus.
REACT_24993 (Reactome) STAT1 pair recruited to the receptor complex is phosphorylated near the C-terminus at residue Y701, probably by JAK2. This phosphorylation enables the STAT1 homodimer formation which is further phosphorylated on residue S727.
REACT_25056 (Reactome) The phosphorylated tyrosine residue 440 in the 440YDKPH444 motif on IFNGR1 chain serves as a docking site and recruits STAT1, an SH2 domain-containing transcription factor to the functional receptor unit.
REACT_25082 (Reactome) IFN-gamma stimulates gene expression of about 200 genes which include the primary response genes like IRFs, Fc-gamma receptor (FCGR), GBPs (guanylate-binding proteins) and also major histocompatibility complex (MHC) class I and class II molecules, proteins involved in antigen presentation, antiviral proteins like PKR, OAS proteins etc. A wonderful list of most of the IFN-gamma inducible proteins with corresponding literature are mentioned in the review article and the supplementary document by Boehm et al 1997.
REACT_25118 (Reactome) GAF transcription factor translocated into nucleus binds to defined DNA sequence called GAS (gamma activated sequence) elements in the promoters of IFN-gamma responsive elements and initiate transcription.
REACT_25139 (Reactome) IFN-gamma binding to the receptor complex, induces JAK2 autophosphorylation and activation. Like all protein tyrosine kinases (PTKs) JAK2 activity also depends on the phosphorylation of tandem tyrosine residues within the activation loop that results in the removal of the activation loop from the active site. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity. Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only tyrosine 1007 is represented in the reaction.
REACT_25158 (Reactome) SOCS-1 and SOCS-3 coprecipitates with JAK kinases upon IFNG stimulation and are able to inhibit the JAK-STAT pathway, although with different affinity and kinetics. SOCS1 and SOCS3 binds to phosphorylated JAK1/2 and prevent the tyrosine kinase activity of JAKs through their kinase inhibitory region (KIR), thereby inhibiting downstream IFNG signaling. SOCS1 may also prevent IFNG signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway.
REACT_25185 (Reactome) The nuclear isoform of T cell protein tyrosine phosphatase (TC-PTP) referred as TC45 (or TC-PTPa) dephosphorylates p-STAT1 dimer in the nucleus. It can also dephosphorylate p-JAK1/3 in IFNG stimulated cells.
REACT_25190 (Reactome) Protein tyrosine phosphatases (PTPs) SHP1 and SHP2 down regulate the IFNG signaling by dephosphorylating the tyrosine residues critical to the activation of JAK kinases. PTP1B interacts directly with JAK2 but not JAK1 and dephosphorylate the tyrosine Y1007 on JAK2.
REACT_25331 (Reactome) PIAS1 protein interacts directly with phoshorylated STAT1 dimers and inhibit the transcriptional activity of STAT1 by blocking the DNA-binding domain of STAT1. It has also been suggested that PIAS proteins might regulate transcription by promoting small ubiquitin-related modifier (SUMO1) conjugation of STAT1. The significance of STAT1 sumoylation in regulating STAT1 activity is controversial and needs to be clarified.
REACT_25347 (Reactome) The IFNG receptor complex is a pre-assembled entity, as constitutive interactions are seen between IFNGR1 and IFNGR2, and between two IFNGR2 chains in the absence of ligand IFNG. JAK1 and JAK2 constitutively associate with the intracellular domains of the subunits of the IFNG receptor complex, providing it with tyrosine kinase activity. In unstimulated cells JAK1 preferentially associates with IFNGR1 and while JAK2 associates with IFNGR2 chains. JAK1 enhances the interaction between IFNGR1 and IFNGR2 chains, and thus has a major role in the pre-assembly of the IFNGR complex, in contrast the kinase activity of JAK2 is required to observe any signaling by IFNG.
IFNG binds directly to both the receptor chains IFNGR1 and IFNGR2. IFNGR1 is a high affinity receptor and binds directly to IFNG whereas IFNGR2 binds to IFNG in presence of IFNGR1. According to Krause et al. model IFNG binds to IFNGR1 chains first and then IFNGR2 chains interact with the IFNGR1:IFNG:IFNGR1 complex.
REACT_25369 (Reactome) Kinases like Protein kinase C delta (PKC-delta) and Calcium/calmodulin-dependent protein kinase II (CaMK II ) can phosphorylate STAT1 at serine 727 (S727). This phosphorylation is not required for STAT1 homodimer formation, nuclear translocation and DNA binding. However, it is essential for the full transcriptional activation of STAT1.
REACT_25379 (Reactome) Released GAF complex translocates to the nucleus and binds to the gamma-activated sequence (GAS) element present in the promoters of IFNG-regulated genes and induces the transcription of IFNG-responsive genes.
SOCS-1 and SOCS-3REACT_25158 (Reactome)
SP100ArrowREACT_25082 (Reactome)
STAT1 bound to p-IFNGR1REACT_24993 (Reactome)
STAT1 bound to p-IFNGR1mim-catalysisREACT_24993 (Reactome)
STAT1-1ArrowREACT_25185 (Reactome)
STAT1-1REACT_25056 (Reactome)
SUMO1REACT_25331 (Reactome)
p-STAT1 dimer bound to p-IFNGR1ArrowREACT_25369 (Reactome)
p-STAT1ArrowREACT_24993 (Reactome)
p-STAT1REACT_25369 (Reactome)
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