BioPAX pathway converted from "Translocation of ISGF3 complex to nucleus" in the Reactome database.LEFT-TO-RIGHTTranslocation of ISGF3 complex to nucleusThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>ISGF3Reactome DB_ID: 9746787cytosolGENE ONTOLOGYGO:0005829Irf9IRF9Q61179Reactome DB_ID: 9746781UniProt:Q61179Irf9Mus musculusNCBI Taxonomy10090UniProtQ611791EQUAL393EQUALReactome Database ID Release 759746781Database 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=9746781ReactomeR-MMU-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-MMU-879183.1Reactomehttp://www.reactome.org1p-STAT2:p-STAT1Reactome DB_ID: 9746785Q9WVL2phospho-Stat2p-Y690-STAT2Reactome DB_ID: 9746738UniProt:Q9WVL2Stat2UniProtQ9WVL2690EQUALO4'-phospho-L-tyrosineMODMOD:000481EQUAL851EQUALReactome Database ID Release 759746738Database 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=9746738ReactomeR-MMU-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-MMU-909683.11P42225phospho-Stat1p-Y701-STAT1-1Reactome DB_ID: 9746161UniProt:P42225 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. 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. 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 Homodimerizes upon IFN-gamma induced phosphorylation (By similarity). Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation (By similarity). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (PubMed:17332413). Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene (By similarity). Interacts with IFNAR1 (By similarity). Interacts with IFNAR2 (By similarity). Found in a complex with NMI and CREBBP/CBP (By similarity). Interacts with NMI which is required for CREBBP/CBP recruitment to the complex (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with SRC (PubMed:9344858). Interacts with ERBB4 (phosphorylated) (By similarity). Interacts with PARP9 and DTX3L independently of IFN-beta or IFN-gamma-mediated STAT1 'Tyr-701' phosphorylation (By similarity). Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation (By similarity). Interacts with OTOP1 (PubMed:24379350).INDUCTION By IFN and EGF.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-riboslyation prevents phosphorylation at Tyr-701. 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.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 (By similarity). However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question (By similarity). It has been suggested that the lack of phosphorylation may be due to sumoylation of Lys-703 (By similarity).UniProtP42225701EQUAL1EQUAL750EQUALReactome Database ID Release 759746161Database 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=9746161ReactomeR-MMU-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-MMU-873791.11Reactome Database ID Release 759746785Database 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=9746785ReactomeR-MMU-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-MMU-909702.11Reactome Database ID Release 759746787Database 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=9746787ReactomeR-MMU-9096981Reactome 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-MMU-909698.1ISGF3Reactome DB_ID: 9746799nucleoplasmGENE ONTOLOGYGO:0005654p-STAT2:p-STAT1Reactome DB_ID: 9746795Q9WVL2phospho-Stat2p-Y690-STAT2Reactome DB_ID: 97467931EQUAL851EQUALReactome Database ID Release 759746793Database 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=9746793ReactomeR-MMU-9096731Reactome 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-MMU-909673.11P42225phospho-Stat1p-Y701-STAT1-2Reactome DB_ID: 97467891EQUAL712EQUALReactome Database ID Release 759746789Database 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=9746789ReactomeR-MMU-9096761Reactome 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-MMU-909676.11Reactome Database ID Release 759746795Database 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=9746795ReactomeR-MMU-9096931Reactome 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-MMU-909693.11Irf9IRF9Q61179Reactome DB_ID: 97467971EQUAL393EQUALReactome Database ID Release 759746797Database 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=9746797ReactomeR-MMU-9135221Reactome 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-MMU-913522.11Reactome Database ID Release 759746799Database 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=9746799ReactomeR-MMU-9135271Reactome 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-MMU-913527.1Reactome Database ID Release 759746801Database 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=9746801ReactomeR-MMU-9097211Reactome 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-MMU-909721.1The resultant ISGF3 trimeric complex then migrates to the nucleus and binds to interferon-stimulated response elements (ISREs). IRF9 is the DNA binding part of this ISGF3 complex. These ISREs are present in the promoters of a subset of ISGs (interferon stimulated genes), such as promyelocytic leukemia (PML), ISG15 ubiquitin-like modifier (ISG15), interferon-induced protein with tetratricopeptide repeats 2 (ISG54) and interferon alpha-inducible protein 6 (IFI6) to elicit an antiviral response.17351669Pubmed2007STAT activation and differential complex formation dictate selectivity of interferon responsesWesoly, JSzweykowska-Kulinska, ZBluyssen, HAActa Biochim Pol 54:27-38inferred from electronic annotationEVIDENCE CODEECO:0000203