Disease relevance of STAT2

• Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma [1].
• Interestingly, Salmonella or Sendai virus infection also increased the binding of multiple IFN regulatory factors (IRFs), STAT1, and STAT2, to the ISRE element [2].
• The antiviral state generated by regulated IRF9-STAT2 hybrid protein expression is independent of autocrine IFN signaling and inhibits both RNA and DNA viruses [3].
• While type II human parainfluenza virus induces STAT2 degradation, simian virus 5 induces STAT1 degradation [4].
• Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2 [5].

High impact information on STAT2

• We further show that Nmi interacts with all STATs except Stat2 [6].
• The possibility has been explored of using a specific angiotensin ii antagonist, saralasin (P-113, 1-sar-8-ala-angiotensin ii) to recognize patients whose hypertension depends upon excessive angiotensin ii activity [7].
• Moreover, E1A represses Stat2 transactivation and IFN-alpha-activated transcription by inhibiting p300/CBP function [8].
• Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha [8].
• The Jak family substrates STAT1 and STAT2 (for signal transducers and activators of transcription) are rapidly tyrosine-phosphorylated in response to angiotensin II [9].

Chemical compound and disease context of STAT2

• The IFNs were similar in inducing the specific phosphorylation of the type I receptor-associated tyrosine kinase Tyk2, and the transcription factors Stat1 alpha and Stat2, suggesting that phosphorylation of these signal transduction proteins is not involved in the cellular toxicity associated with type I IFNs [10].
• Treatment of freshly isolated acute promyelocytic leukemia (APL) cells and the myelogenous leukemia cell lines, NB4, HL-60, and U937, with all-trans retinoic acid (ATRA) results in a remarkable elevation in the amounts of Stat1 alpha and Stat2 proteins [11].
• Higher P113 doses totally obliterated all three responses to A II infused at 10 ng/kg/min, a dose that provides arterial A II concentrations in the range found in angiotensin-mediated hypertension [12].

Biological context of STAT2

• A mutant STAT2 protein in which the phosphorylated tyrosine at position 690 is changed to phenylalanine does not restore normal phosphorylation of STAT1 in response to IFN-alpha [13].
• Of these components, STAT2 provides a fundamental and essential transcriptional activation function for ISGF3 [14].
• Import-defective STAT1 and STAT2 proteins were readily phosphorylated and dimerized, but they functioned as dominant negative molecules inhibiting the nuclear import of heterologous STAT protein [15].
• A hybrid IRF9-STAT2 protein recapitulates interferon-stimulated gene expression and antiviral response [3].
• Moreover, expression of the IRF9-STAT2 fusion can recapitulate the type I IFN biological response, producing a cellular antiviral state that protects cells from virus-induced cytopathic effects and inhibits virus replication [3].

Anatomical context of STAT2

• We have isolated U6A, a mutant cell line which lacks the STAT2 subunit of the transcription factor interferon (IFN)-stimulated gene factor 3 (ISGF3) [13].
• Furthermore, the murine/human STAT2 protein was expressed in murine CD4(+) T cells and was activated by murine IFN-alpha signaling [16].
• Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages [17].
• In myeloid cells IFNalpha/beta activates signal transducers and activators of transcription STAT1, STAT2, and STAT3 [18].
• However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells, apparently correlating to an enhanced responsiveness of these cells to IFNs [19].

Associations of STAT2 with chemical compounds

• In the present study, we show that ISGF3-mediated transcription is dependent on STAT2 interactions with DRIP150, a subunit of the multimeric Mediator coactivator complex [14].
• Binding of type I interferons (IFNs) to their receptors induces rapid tyrosine phosphorylation of multiple proteins, including the alpha and beta subunits of the receptor, the polypeptides that form the transcriptional activator ISGF3 alpha (Stat113, Stat84, and Stat91), and the p135tyk2 and Jak-1 tyrosine kinases [20].
• In this report we demonstrate that there are functionally redundant phosphotyrosine-dependent and -independent binding sites for Stat2 in the alpha and beta subunits of the type I IFN-R [21].
• STAT2 export could be inhibited with leptomycin B, indicating a nuclear export signal within STAT2 is recognized by the CRM1 exportin carrier [22].
• Induction of ISGF3 gamma but not of ISGF3 alpha needed ongoing protein synthesis and was blocked by 2-aminopurine [23].
• This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP [24].

Physical interactions of STAT2

• We provide evidence that STAT2 specifically interacts with p48 in vivo before and after IFN-alpha stimulation [25].
• Results from the analysis of Stat2 complexes in the electrophoretic mobility shift assay were consistent with genomic DNA affinity chromatography results and identified a Stat2:1 complex that binds with low affinity to the pIRE of the interferon regulatory factor-1 gene [26].
• STAT1 also binds but only when STAT2 is present [27].
• We now find that STAT2 binds to the cytoplasmic domain of the IFNAR2c (also known as IFNAR2-2) subunit of the IFN-alpha receptor in extracts of untreated cells [27].
• Previous work showed that a point mutation in the Src homology 2 (SH2) domain prevents STAT2 from binding to phosphotyrosine 466 of the IFNAR1 subunit of the activated receptor [27].

Enzymatic interactions of STAT2

• Type I interferon (IFN) stimulates transcription through a heteromeric transcription factor that contains tyrosine-phosphorylated STAT2 [28].

Regulatory relationships of STAT2

• Retention by STAT2 may serve to regulate the activity of free p48 and/or guarantee that cytoplasmic pools of preassociated STAT2:p48 are available for rapid activation of the IFN response [29].
• Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction [4].
• Recruitment of Stat4 to the human interferon-alpha/beta receptor requires activated Stat2 [30].
• EGF induces nuclear translocation of STAT2 without tyrosine phosphorylation in intestinal epithelial cells [31].

Other interactions of STAT2

• A complex containing p48 and phosphorylated STAT91 but lacking STAT113 bound the ISRE in vitro [32].
• One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNgamma signaling [33].
• STAT1 and STAT2 mediate the antiviral and inflammatory effects of IFNalpha/beta, but the function of IFNalpha/beta-activated STAT3 is not known [18].
• Members of the Rubulavirus genus of the Paramyxovirus family of RNA viruses have acquired the ability to specifically target either STAT1 or STAT2 for proteolytic degradation as a countermeasure for evading IFN responses [4].
• Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha [34].

Analytical, diagnostic and therapeutic context of STAT2

• These results support STAT2 as an important molecular target for skin cancer chemoprevention [35].
• Application of genomic DNA affinity chromatography identifies multiple interferon-alpha-regulated Stat2 complexes [26].
• Using chromatin immunoprecipitation and DNA microarray analysis (ChIP-chip), we have identified the regions of human chromosome 22 bound by STAT1 and STAT2 in interferon-treated cells [36].
• Here we show by site-directed mutagenesis that the very C-terminal arm repeats 8 and 9 of importin alpha5 form a unique binding site for STAT1 homodimers and STAT1-STAT2 heterodimers [37].
• By RT-PCR, the heat shock 90 Kd protein1 alpha, STAT2 and interferon receptor 1 genes showed increased expression in phytohemagglutinin (PHA)-stimulated or antigen stimulated T cell line [38].

References