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FUNCTION Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors (PubMed:11294897, PubMed:11972023, PubMed:19088846, PubMed:22065572, PubMed:9344858). 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 (By similarity). The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (By similarity). 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 (PubMed:22065572). In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:11972023). 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 (By similarity). Becomes activated in response to KITLG/SCF and KIT signaling (By similarity). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:19088846). Following bacterial lipopolysaccharide (LPS)-induced TLR4 endocytosis, phosphorylated at Thr-748 by IKBKB which promotes binding of STAT1 to the 5'-TTTGAGGC-3' sequence in the ARID5A promoter, resulting in transcriptional activation of ARID5A and subsequent ARID5A-mediated stabilization of IL6 (By similarity). Phosphorylation at Thr-748 also promotes binding of STAT1 to the 5'-TTTGAGTC-3' sequence in the IL12B promoter and activation of IL12B transcription (By similarity). Involved in food tolerance in small intestine: associates with the Gasdermin-D, p13 cleavage product (13 kDa GSDMD) and promotes transcription of CIITA, inducing type 1 regulatory T (Tr1) cells in upper small intestine (PubMed:37327784).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). Independently of its phosphorylation status, interacts with OTOP1 (PubMed:24379350). Interacts with IFNGR1 (By similarity). Interacts with STAT4 (By similarity).INTERACTION Translocated into the nucleus upon tyrosine phosphorylation and dimerization, in response to IFN-gamma and signaling by activated FGFR1, FGFR2, FGFR3 or FGFR4. Monomethylation at Lys-525 is required for phosphorylation at Tyr-701 and translocation into the nucleus. Translocates into the nucleus in response to interferon-beta stimulation.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 (PubMed:11294897, PubMed:22065572, PubMed:9344858). Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus (PubMed:21135090). Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus (PubMed:22065572). Growth hormone (GH) activates STAT1 signaling only via JAK2 (By similarity). Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:19088846). Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2 and CAMK2/CAMKII in response to IFN-gamma stimulation, is required for maximal transcriptional activity (PubMed:11972023, PubMed:22065572). Phosphorylated on Ser-727 by CAMK2/CAMKII in response to IFN-gamma stimulation and calcium mobilization, promoting activity (PubMed:11972023). Phosphorylated by CAMK2/CAMKII in response to IFN-beta stimulation and calcium mobilization in epithelial cells, promoting activity (By similarity). Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS (By similarity). Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents (By similarity). Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase (PubMed:12138178). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling (By similarity). 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 (PubMed:17332413). Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701 (PubMed:17332413). Phosphorylation at Thr-748 by IKBKB/IKKB promotes transcriptional activation of ARID5A and IL12B by STAT1 (By similarity). Phosphorylation at Thr-748 restricts interferon signaling and anti-inflammatory responses and promotes innate inflammatory responses (PubMed:38621137).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. 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.PTM Deubiquitinated by USP13; leading to STAT1 stabilization and positive regulation of type I and type II IFN signalings.DISRUPTION PHENOTYPE Resistance to bacterial lipopolysaccharide (LPS)-induced lethality.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).
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