Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor.

Gutch, Michael J.; Daly, Christopher; Reich, Nancy C.

doi:10.1073/pnas.89.23.11411

Cited by 78 publications

(31 citation statements)

References 35 publications

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“…Biochemical analysis has shown that tyrosine phosphorylation is crucial for the activity of STATs (10,14,20,35,39). It has been found that Stat1 is phosphorylated on a single residue, Tyr-701, in response to stimulation by a number of ligands, including IFNs and epidermal growth factor (40,41).…”

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confidence: 99%

Enhancement of Antiproliferative Activity of Gamma Interferon by the Specific Inhibition of Tyrosine Dephosphorylation of Stat1

Shuai

Liao

Song

1996

Molecular and Cellular Biology

145

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Gamma interferon (IFN-␥) signals to the nucleus through the activation, by tyrosine phosphorylation, of the latent cytoplasmic transcription factor Stat1 (signal transducer and activator of transcription). It has been demonstrated that the activity of Stat1 is dependent on tyrosine phosphorylation which is regulated by Jak tyrosine kinases as well as by the as-yet-unidentified protein tyrosine phosphatase. We report that the N-terminal domain of Stat1, which is highly conserved among all STAT family members, is required for its tyrosine dephosphorylation. A single amino acid substitution (Arg-31 to Ala) in the Stat1 N-terminal domain inhibited Stat1 tyrosine dephosphorylation. The deletion of the Stat1 N-terminal domain resulted in a mutant Stat1 protein which was constitutively phosphorylated on Tyr-701. Upon IFN-␥ stimulation, the tyrosine phosphorylation of this mutant protein was further enhanced but was not down-regulated by protein tyrosine phosphatase in vivo. When expressed in NIH 3T3 cells, this mutant protein greatly enhanced the antiproliferative activity of IFN-␥. We suggest that the N-terminal domains of STATs are crucial for modulating STAT activities through regulating the tyrosine dephosphorylation of STATs.Interferons (IFNs) have antiviral, immunomodulatory, and antiproliferative properties (8). A direct signal transduction pathway from the IFN receptor to the nucleus has been discovered (4,22,36,45). The binding of IFN to its receptor leads to receptor dimerization and the activation of Janus kinase (Jak) tyrosine kinases (30,41,42,46,48). Specific tyrosine residues on the receptor are then phosphorylated by activated Jaks and serve as docking sites for recruiting a family of latent cytoplasmic transcription factors termed signal transducers and activators of transcription (STATs) (12, 13). The STATs are then phosphorylated on tyrosine, most likely by Jaks, and form homo-or heterodimers which subsequently translocate into the nucleus and direct immediate gene activation. It has been shown that gamma IFN (IFN-␥) activates the Stat1 homodimer, which binds to the IFN-␥ response element and activates transcription (6,38,39).STATs belong to a growing family of proteins involved in signal transduction by many cytokines and growth factors. Sequence analysis indicates that members of the STAT family of proteins are highly homologous in several regions. The SH2 domains of STATs have been shown to be crucial for both the activation and dimerization of STAT proteins (10,38). It has been shown that the specificity of STAT activation is largely determined by the SH2 domains of STATs (16) as well as the specific STAT binding motifs present on ligand receptors (13,43).

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Enhancement of Antiproliferative Activity of Gamma Interferon by the Specific Inhibition of Tyrosine Dephosphorylation of Stat1

Shuai

Liao

Song

1996

Molecular and Cellular Biology

145

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“…The signal transducers and activators of transcription (STATs) 1 remain the only characterized DNA binding factors that are regulated directly by tyrosine phosphorylation (1)(2)(3)(4). Tyrosine phosphorylation confers new properties to the STAT factors by inducing dimerization via reciprocal phosphotyrosine and Src homology 2 (SH2) domain interactions.…”

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STAT2 Nuclear Trafficking

Banninger¹,

Reich

2004

Journal of Biological Chemistry

121

131

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STAT2 is a transcription factor critical to the signal transduction pathway of type I interferons (e.g. IFN␣). STAT2 resides primarily in the cytoplasm and is tyrosine-phosphorylated after IFN␣ binds to cell surface receptors. In response to tyrosine phosphorylation STAT2 rapidly localizes to the nucleus and acquires the ability to bind specific DNA targets in association with two other proteins, STAT1 and IFN regulatory factor-9 (IRF-9). To elucidate the mechanisms that regulate cellular localization of STAT2, we investigated STAT2 nuclear trafficking both prior to tyrosine phosphorylation and after phosphorylation. Prior to phosphorylation, STAT2 is primarily resident in the cytoplasm, however, we found that it dynamically shuttles between nuclear and cytoplasmic compartments. The nuclear translocation of latent unphosphorylated STAT2 was found to be dependent on its constitutive association with IRF-9, and the export of STAT2 from the nucleus was contingent upon the function of an intrinsic nuclear export signal within the carboxyl terminus of STAT2. STAT2 export could be inhibited with leptomycin B, indicating a nuclear export signal within STAT2 is recognized by the CRM1 exportin carrier. In contrast, following tyrosine phosphorylation, STAT2 dimerizes with phosphorylated STAT1 and accumulates in the nucleus. In the absence of STAT1, STAT2 does not accumulate in the nucleus. In addition, subsequent to nuclear import of phosphorylated STAT2, it redistributes to the cytoplasm within an hour coordinate with its dephosphorylation in the nucleus. The regulation of STAT2 nuclear trafficking is distinct from the previously characterized STAT1 factor.The signal transducers and activators of transcription (STATs) 1 remain the only characterized DNA binding factors that are regulated directly by tyrosine phosphorylation (1-4). Tyrosine phosphorylation confers new properties to the STAT factors by inducing dimerization via reciprocal phosphotyrosine and Src homology 2 (SH2) domain interactions. This conformational change can contribute to nuclear translocation and is essential for binding to specific DNA targets. The STAT1 and STAT2 factors are tyrosine-phosphorylated in the cytoplasm by Janus kinases (JAKs) activated in response to type I interferon (IFN) (5, 38). The phosphorylated STATs subsequently dimerize and localize to the nucleus. The STAT2 factor is unique among the STATs in that it is associated constitutively with a distinct transcription factor, interferon regulatory factor-9 (IRF-9) (7-9). After phosphorylation, a trimeric complex forms of STAT1⅐STAT2⅐IRF-9, known as IFN-stimulated gene factor 3 (ISGF3), that binds to a specific IFN-stimulated response element in the promoters of responsive genes (reviewed in Refs. 10 -12). A successful innate immune response to viral infection requires the induced expression of genes by ISGF3. Targeted gene disruptions of STAT1, STAT2, or IRF-9 clearly demonstrate that animals lacking one of these factors succumb to infection (13-15).STATs serve as a link between the ...

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“…ISGF3 contains tyrosine-phosphorylated dimers of STAT1 and STAT2, and the STAT2-associated factor IFN regulatory factor 9 (IRF-9) (9,16,17). ISGF3 is responsible for the transcriptional induction of a set of ISGs, one of which is ISG54 (18 -21).…”

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The Interferon Stimulated Gene 54 Promotes Apoptosis

Stawowczyk

Scoy

Kumar

et al. 2011

Journal of Biological Chemistry

148

153

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The ability of interferons (IFNs) to inhibit viral replication and cellular proliferation is well established, but the specific contribution of each IFN-stimulated gene (ISG) to these biological responses remains to be completely understood. In this report we demonstrate that ISG54, also known as IFN-induced protein with tetratricopeptide repeats 2 (IFIT2), is a mediator of apoptosis. Expression of ISG54, independent of IFN stimulation, elicits apoptotic cell death. Cell death and apoptosis were quantified by propidium iodide uptake and annexin-V staining, respectively. The activation of caspase-3, a key mediator of the execution phase of apoptosis, was clearly apparent in cells expressing ISG54.

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Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor.

Cited by 78 publications

References 35 publications

Enhancement of Antiproliferative Activity of Gamma Interferon by the Specific Inhibition of Tyrosine Dephosphorylation of Stat1

Enhancement of Antiproliferative Activity of Gamma Interferon by the Specific Inhibition of Tyrosine Dephosphorylation of Stat1

STAT2 Nuclear Trafficking

The Interferon Stimulated Gene 54 Promotes Apoptosis

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