STAT1

STAT1 is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. STAT1 can be activated by various ligands, including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. It is a signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and growth factors. The phosphorylated STATs dimerize, 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 interferon stimulated genes, 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. STAT1 becomes activated in response to KITLG/SCF and KIT signaling and may mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Defects in STAT1 can cause STAT1 deficiency complete and familial candidiasis type 7.

STAT1 Related Areas

Signal Transduction>>Transcription Factor & Regulator>>STAT1

STAT1 Related Pathways

• EGFR Signaling Pathway

STAT1 Alternative Names

STAT1, DKFZp686B04100, ISGF-3, STAT91 [Homo sapiens] Stat1, 2010005J02Rik, AA408197 [Mus musculus]

Summaries for STAT1

Entrez Gene summary for STAT1:

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. Two alternatively spliced transcript variants encoding distinct isoforms have been described.

OMIM - description for STAT1:

The JAK (see JAK1; 147795)/STAT pathway is an extensive signaling pathway downstream of cytokine receptors (see IL2RG; 308380). STATs are cytosolic proteins of 750 to 800 amino acids with a common structure consisting of an N-terminal oligomerization domain, which favors formation of STAT dimers, followed by a DNA-binding domain and a C-terminal SRC (190090) homology-2 (SH2) domain, which is involved in association between STATs and receptors. STAT1 is critical in signal transduction from both the type I interferons IFNA (see 147660) and IFNB (see 147640) and the type II interferon IFNG (147570). After IFNG stimulation, STAT1 is phosphorylated and homodimerizes. This phosphorylated STAT1 homodimer forms the gamma-activating factor (GAF), which translocates to the nucleus and upregulates transcription of IFNG-regulated genes. In contrast, IFNA or IFNB stimulation produces several products, including GAF and a heterotrimer formed by STAT1, STAT2 (600556), and p48 (ISGF3G; 147574) that is called interferon-stimulated gamma factor-3 (ISGF3)

Wikipedia summary for STAT1:

STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons. In response to IFN-γ stimulation, STAT1 forms homodimers or heterodimers with STAT3 that bind to the GAS (Interferon-Gamma Activated Sequence) promoter element; in response to either IFN-α or IFN-β stimulation, STAT1 forms a heterodimer with STAT2 that can bind the ISRE (Interferon Stimulated Response Element) promoter element.[1] In either case, binding of the promoter element leads to an increased expression of ISG (Interferon Stimulated Genes). Expression of STAT1 can be induced with diallyl disulfide, a compound in garlic.[2]

Human STAT1 Protein General Information

 

• Protein names: Signal transducer and activator of transcription 1-alpha/beta, Short name=STAT1
• Sequence length: 750 AA.
• Sequence similarities: Belongs to the transcription factor STAT family. Contains 1 SH2 domain.
• Post-translational modification: 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. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. 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. 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 PKCdelta 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.
• Subunit structure: Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation. Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation. Interacts with NMI. Interacts with Sendai virus C', C, Y1 and Y2 proteins, Nipah virus P, V and W proteins, and rabies virus phosphoprotein preventing activation of ISRE and GAS promoter By similarity. Interacts with HCV core protein; the interaction results in STAT1 degradation. Interacts with PIAS1; the interaction requires phosphorylation on Ser-727 and inhibits STAT1 activation. Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr-466'. Interacts with IFNAR2. Interacts with PIAS1 (dimethylated on arginine); the interaction results in release of STAT1 from its target gene. Interacts with SRC By similarity. Interacts with ERBB4 (phosphorylated). Interacts with PTK2/FAK1.
• Subcellular location: Cytoplasm. Nucleus. Note: Translocated into the nucleus upon tyrosine phosphorylation and dimerization, in response to IFN-gamma and signaling by activated FGFR1, FGFR2, FGFR3 or FGFR4.
• Involvement in disease: Defects in STAT1 are the cause of STAT1 deficiency complete (STAT1D) [MIM:613796]. STAT1D is a disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness.

General information above from UniProt

Function for STAT1 Protein

UniProtKB:

Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and 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, 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 interferon stimulated genes, 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.

Genatlas:

• STAT1 is activated during monocyte to macrophage differentiation as an early transcription factor initially activated by adherence and then able to modulate the expression of functional genes such as ICAM1 and FCGR1
• STAT1 playing a dual role with JAK1 and STAT3 in myogenic differentiation, participating in myoblast proliferation and actively repressing differentiation
• in response to type II IFN, STAT1 is phosphorylated and forms homodimer that migrates to the nucleus and drives the expression of target genes, inducing a cellular antiviral state
• STAT1 is involved in maintaining the latency III viral program observed in transformed B cells and regulating immunorecognition by EBV-specific T cells
• unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes
• STAT1 is associated with an apoptosis pathway and required to promote the tumor killing effect of STAT3 inhibtion in head and neck squamous cell carcinoma
• STAT1 may be a novel risk genes for the differentiation of peak bone mass at the monocyte stage
• early cellular responses to human interferons are critically dependent on the amount of STAT1 and are essential for the appropriate control of mycobacterial and viral infections
• STAT1 is required for the cell death induced by IFNA1

Homology for human STAT1

• homolog to rattus Stat1 (93.7pc)
• homolog to murine Stat1 (93.6pc)

Phenotype Information for STAT1

• Gene/Locus: STAT1, CANDF7
• Phenotype: Candidiasis, familial, 7 Mycobacterial and viral
  infections, susceptibility to, autosomal recessive
  Mycobacterial infection, atypical, familial disseminated

Phenotype Information for STAT1 from OMIM (Online Mendelian Inheritance in Man)

Drugs for STAT1

Target	Drug Name	Disease	Drug Status
STAT1	Peginterferon alfa-2a	Hairy cell leukemia	Approved
STAT1	Peginterferon alfa-2b	Hepatitis C	Approved
STAT1	Interferon alfa-n1	Hairy cell leukemia	Approved
STAT1	Interferon alfa-n3	Venereal or genital warts	Approved
STAT1	Interferon beta-1a	Multiple sclerosis	Approved
STAT1	Interferon beta-1b	Multiple sclerosis	Approved

Drugs for STAT1 from TTD (Therapeutic Targets Database)