BioPAX pathway converted from "Interaction of IRF9 with p-STAT2:p-STAT1" in the Reactome database.LEFT-TO-RIGHTInteraction of IRF9 with p-STAT2:p-STAT1The phosphorylated STAT2:STAT1 heterodimer associates with interferon-regulating factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex.Authored: Garapati, P V, 2010-07-07Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17Edited: Garapati, P V, 2010-07-07p-STAT2:p-STAT1STAT2:1 hetero dimerReactome DB_ID: 909702cytosolGENE ONTOLOGYGO:0005829p-STAT2p-Y690-STAT2phospho STAT2 (Y690)Reactome DB_ID: 909683UniProt:P52630 STAT2STAT2FUNCTION Signal transducer and activator of transcription that mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with IRF9/ISGF3G to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state (PubMed:9020188, PubMed:23391734). Acts as a regulator of mitochondrial fission by modulating the phosphorylation of DNM1L at 'Ser-616' and 'Ser-637' which activate and inactivate the GTPase activity of DNM1L respectively (PubMed:26122121).SUBUNIT Heterodimer with STAT1 upon IFN-alpha/beta induced phosphorylation (By similarity). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9; interacts with IRF9 in the cytoplasm (By similarity). Interacts with CRSP2 and CRSP6 (PubMed:12509459). Can form a homodimer upon IFN-alpha induced phosphorylation (PubMed:9020188). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr-466' (PubMed:9121453). Interacts with IFNAR2 (PubMed:9121453). Interacts with ARL2BP (By similarity). Interacts with E3 ubiquitin ligase DCST1; the interaction results in STAT2 ubiquitin-mediated proteasomal degradation (PubMed:27782195).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C6.SUBUNIT (Microbial infection) Interacts with Simian virus 5 protein V.SUBUNIT (Microbial infection) Interacts with Rabies virus phosphoprotein.SUBUNIT (Microbial infection) Interacts with Human cytomegalovirus/HHV-5 protein UL123; this interaction promotes viral growth.SUBUNIT (Microbial infection) Interacts with Dengue virus NS5; this interaction inhibits the phosphorylation of STAT2, and, when all viral proteins are present (polyprotein), targets STAT2 for degradation.SUBUNIT (Microbial infection) Interacts with Zika virus NS5; this interaction targets STAT2 for degradation.PTM Tyrosine phosphorylated in response to IFN-alpha. Phosphorylation at Ser-287 negatively regulates the transcriptional response.PTM 'Lys-48'-linked ubiquitination by DCST1 leads to STAT2 proteasomal degradation.SIMILARITY Belongs to the transcription factor STAT family.Homo sapiensNCBI Taxonomy9606UniProtP52630690EQUALO4'-phospho-L-tyrosineMODMOD:000481EQUAL851EQUALReactome Database ID Release 75909683Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=909683ReactomeR-HSA-9096831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-909683.1Reactomehttp://www.reactome.org1Converted from EntitySet in Reactomep-STAT1Reactome DB_ID: 909689p-STAT1-alphap-Y701-STAT1-1p-Y701-STAT1 isoform 1Phospho-STAT1Reactome DB_ID: 873791UniProt:P42224-1 STAT1STAT1FUNCTION Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426). ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788). It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.SUBUNIT Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation (PubMed:8605877, PubMed:28753426). Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation (PubMed:8605877). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (By similarity). Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene (PubMed:9724754, PubMed:17897103). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr-466' (PubMed:9121453). Interacts with IFNAR2 (PubMed:9121453). Found in a complex with NMI and CREBBP/CBP (PubMed:9989503). Interacts with NMI which is required for CREBBP/CBP recruitment to the complex (PubMed:9989503). Interacts with PTK2/FAK1 (PubMed:11278462). Interacts with SRC (By similarity). Interacts with ERBB4 (phosphorylated) (PubMed:18721752). Interacts with PARP9 and DTX3L independently of IFN-beta or IFN-gamma-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation (PubMed:26479788). Interacts with OTOP1 (By similarity).SUBUNIT (Microbial infection) Interacts with Sendai virus C', C, Y1 and Y2 proteins, preventing activation of ISRE and GAS promoter.SUBUNIT (Microbial infection) Interacts with Nipah virus P, V and W proteins preventing activation of ISRE and GAS promoter.SUBUNIT (Microbial infection) Interacts with Rabies virus phosphoprotein preventing activation of ISRE and GAS promoter.SUBUNIT (Microbial infection) Interacts with HCV core protein; the interaction results in STAT1 degradation.SUBUNIT (Microbial infection) Interacts with ebolavirus protein VP24.PTM Phosphorylated on tyrosine and serine residues in response to a variety of cytokines/growth hormones including IFN-alpha, IFN-gamma, PDGF and EGF. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus. Growth hormone (GH) activates STAT1 signaling only via JAK2. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2 and CAMKII on IFN-gamma stimulation, regulates STAT1 transcriptional activity. Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS. Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents. Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling. Upon viral infection or IFN induction, phosphorylation on Ser-708 occurs much later than phosphorylation on Tyr-701 and is required for the binding of ISGF3 on the ISREs of a subset of IFN-stimulated genes IKBKE-dependent. Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701.PTM Sumoylated with SUMO1, SUMO2 and SUMO3. Sumoylation is enhanced by IFN-gamma-induced phosphorylation on Ser-727, and by interaction with PIAS proteins. Enhances the transactivation activity.PTM ISGylated.PTM Mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14; ADP-ribosylation prevents phosphorylation at Tyr-701 (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question and the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).PTM Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense.SIMILARITY Belongs to the transcription factor STAT family.CAUTION Has been shown to be mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14 which prevents phosphorylation at Tyr-701 (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question (PubMed:29858569). It has been suggested that the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).UniProt IsoformP42224-1701EQUAL1EQUAL750EQUALReactome Database ID Release 75873791Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=873791ReactomeR-HSA-8737911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-873791.1p-STAT1-betap-Y701-STAT1-2Reactome DB_ID: 909686UniProt:P42224-2 STAT1STAT1FUNCTION Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426). ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788). It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.SUBUNIT Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation (PubMed:8605877, PubMed:28753426). Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation (PubMed:8605877). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (By similarity). Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene (PubMed:9724754, PubMed:17897103). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr-466' (PubMed:9121453). Interacts with IFNAR2 (PubMed:9121453). Found in a complex with NMI and CREBBP/CBP (PubMed:9989503). Interacts with NMI which is required for CREBBP/CBP recruitment to the complex (PubMed:9989503). Interacts with PTK2/FAK1 (PubMed:11278462). Interacts with SRC (By similarity). Interacts with ERBB4 (phosphorylated) (PubMed:18721752). Interacts with PARP9 and DTX3L independently of IFN-beta or IFN-gamma-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation (PubMed:26479788). Interacts with OTOP1 (By similarity).SUBUNIT (Microbial infection) Interacts with Sendai virus C', C, Y1 and Y2 proteins, preventing activation of ISRE and GAS promoter.SUBUNIT (Microbial infection) Interacts with Nipah virus P, V and W proteins preventing activation of ISRE and GAS promoter.SUBUNIT (Microbial infection) Interacts with Rabies virus phosphoprotein preventing activation of ISRE and GAS promoter.SUBUNIT (Microbial infection) Interacts with HCV core protein; the interaction results in STAT1 degradation.SUBUNIT (Microbial infection) Interacts with ebolavirus protein VP24.PTM Phosphorylated on tyrosine and serine residues in response to a variety of cytokines/growth hormones including IFN-alpha, IFN-gamma, PDGF and EGF. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus. Growth hormone (GH) activates STAT1 signaling only via JAK2. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2 and CAMKII on IFN-gamma stimulation, regulates STAT1 transcriptional activity. Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS. Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents. Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling. Upon viral infection or IFN induction, phosphorylation on Ser-708 occurs much later than phosphorylation on Tyr-701 and is required for the binding of ISGF3 on the ISREs of a subset of IFN-stimulated genes IKBKE-dependent. Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701.PTM Sumoylated with SUMO1, SUMO2 and SUMO3. Sumoylation is enhanced by IFN-gamma-induced phosphorylation on Ser-727, and by interaction with PIAS proteins. Enhances the transactivation activity.PTM ISGylated.PTM Mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14; ADP-ribosylation prevents phosphorylation at Tyr-701 (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question and the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).PTM Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense.SIMILARITY Belongs to the transcription factor STAT family.CAUTION Has been shown to be mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14 which prevents phosphorylation at Tyr-701 (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question (PubMed:29858569). It has been suggested that the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).UniProt IsoformP42224-2701EQUAL1EQUAL712EQUALReactome Database ID Release 75909686Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=909686ReactomeR-HSA-9096861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-909686.1Reactome Database ID Release 75909689Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=909689ReactomeR-HSA-9096891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-909689.11Reactome Database ID Release 75909702Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=909702ReactomeR-HSA-9097021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-909702.1IRF9Interferon regulatory factor 9IRF9_HUMANReactome DB_ID: 879183UniProt:Q00978 IRF9IRF9ISGF3GFUNCTION Transcription factor that plays an essential role in anti-viral immunity. It mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. IRF9/ISGF3G associates with the phosphorylated STAT1:STAT2 dimer to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state.SUBUNIT Interacts with STAT2 in the cytoplasm. Forms the interferon-stimulated gene factor 3 complex (ISGF3) with the heterodimer STAT1:STAT2; upon stimulation.INDUCTION By IFN-alpha and IFNB1/IFN-beta.SIMILARITY Belongs to the IRF family.UniProtQ009781EQUAL393EQUALReactome Database ID Release 75879183Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879183ReactomeR-HSA-8791831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-879183.1ISGF3Interferon-stimulated gene factor 3p-STAT2:p-STAT1:IRF9Reactome DB_ID: 90969811Reactome Database ID Release 75909698Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=909698ReactomeR-HSA-9096985Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-909698.5ComplexPortalCPX-6016additional informationMIMI:0361Reactome Database ID Release 75909725Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=909725ReactomeR-HSA-9097251Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-909725.19242679Pubmed1997Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3Martinez-Moczygemba, MGutch, MJFrench, DLReich, NCJ Biol Chem 272:20070-68621447Pubmed1996Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alphaLi, XLeung, SQureshi, SDarnell JE, JrStark, GRJ Biol Chem 271:5790-47537377Pubmed1995Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3Qureshi, SASalditt-Georgieff, MDarnell JE, JrProc Natl Acad Sci U S A 92:3829-33