Roles of Protein-tyrosine Phosphatases in Stat1α-mediated Cell Signaling

Haque, S. Jaharul; Flati, Vincenzo; Deb, Amitabha; Williams, Bryan R.G.

doi:10.1074/jbc.270.43.25709

Cited by 91 publications

(78 citation statements)

References 58 publications

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“…Activities of PTPase and phosphoserine phosphatase counterparts represent an essential regulatory mechanism that can be exploited for therapeutic bene®ts. With respect to STATs, studies with inhibitors of protein phosphatases reveal the importance of protein dephosphorylation in modulating STAT functions (David et al, 1993;Haque et al, 1995;Woetmann et al, 1999). Two PTPases, SHP-1 and SHP-2, as well as a protein serine/threonine phosphatase, PP2A, are strongly implicated in STAT signaling, including Stat1, Stat3 and Stat5 (Ram and Waxman, 1997;Schaper et al, 1998;Shuai et al, 1996b;Stofega et al, 1998;Strehlow and Schindler, 1998;Woetmann et al, 1999;Yu et al, 2000).…”

Section: (4) Modulation Of Phosphatasesmentioning

confidence: 99%

STAT proteins: novel molecular targets for cancer drug discovery

2000

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Section: (4) Modulation Of Phosphatasesmentioning

confidence: 99%

STAT proteins: novel molecular targets for cancer drug discovery

2000

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“…Tyrosine phosphorylation of STAT1 is regulated both by Jak1/Jak2 protein-tyrosine kinases and by protein-tyrosine phosphatase. Significantly, treatment with sodium vanadate, a protein-tyrosine phosphatase inhibitor, can sustain the phosphorylation of Tyr-701, preventing down-regulation of STAT1 transcriptional activity (18,19). Biochemical analysis has demonstrated that dephosphorylated STAT1 is rapidly exported back into the cytoplasm and takes part in subsequent activation-inactivation cycles and that loss of dephosphorylation leads to prolonged STAT1 activation in the nucleus (20 -27).…”

mentioning

confidence: 99%

STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7

Sironi

Ouchi

2004

Journal of Biological Chemistry

107

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STAT1(signal transducer and activator of transcription 1) has been implicated as a mediator of a variety of biological responses in response to stimulation by specific growth factors and cytokines. To understand better the role of STAT1 in the interferon-␥ (IFN-␥)-induced phenotype, we generated an active form of STAT1 (STAT1C) by substituting Cys residues for both Arg-656 and Asn-658 within the C-terminal loop of the STAT1 SH2 domain. The IFN-␥ activation site element was stimulated and bound efficiently by STAT1C without IFN-␥ treatment. STAT1C was found to be tyrosine-phosphorylated in the nucleus for more than 30 h after IFN-␥ stimulation. STAT1-negative U3A cells reexpressing STAT1C showed retarded cell growth and underwent apoptosis when treated with IFN-␥. Further analysis demonstrated that apoptosis was preceded by proteolytic cleavage of caspases 2, 3, and 7, and wild type STAT1 also induced cleavage of caspase 7 when expressed in STAT1-negative U3A cells, indicating that STAT1C augments potential activity of wild type STAT1. Studies with cycloheximide treatment showed that protein synthesis induced in the first 24 h after IFN-␥ treatment was required for apoptosis under these conditions. Finally, we found that STAT1C-induced apoptosis was, in part, mediated by caspase 2, 3, and 7 because benzyloxycarbonyl-valyl-aspartyl-valyl-alanyl-aspartic acid fluoromethyl ketone (Z-VDVAD-FMK) treatment partially blocked apoptosis. These results suggest that prolonged nuclear localization of activated STAT1 results in apoptosis involving specific regulation of caspase pathway.Signal transducer and activator of transcription (STAT) 1 1 plays an important role in such IFN-␥-induced biological responses as tumor surveillance (1-4), the immune response (5, 6), and cell growth control (7,8). It has been suggested that it serves as a tumor suppressor by activating proapoptotic pathways (3, 9 -14).In response to IFN-␥ stimulation, STAT1 becomes phosphorylated on Tyr-701 and forms a homodimer through reciprocal SH2-phosphotyrosine interactions. Phosphorylation on Tyr-701 is required for subsequent nuclear translocation, DNA binding, and gene activation (15)(16)(17). Tyrosine phosphorylation of STAT1 is regulated both by Jak1/Jak2 protein-tyrosine kinases and by protein-tyrosine phosphatase. Significantly, treatment with sodium vanadate, a protein-tyrosine phosphatase inhibitor, can sustain the phosphorylation of Tyr-701, preventing down-regulation of STAT1 transcriptional activity (18,19). Biochemical analysis has demonstrated that dephosphorylated STAT1 is rapidly exported back into the cytoplasm and takes part in subsequent activation-inactivation cycles and that loss of dephosphorylation leads to prolonged STAT1 activation in the nucleus (20 -27).STAT1 has been implicated in apoptosis in response to IFN-␥ stimulation. Mutant forms of STAT1 lacking the N-terminal 62 amino acid residues or carrying a single amino acid substitution of Ala-31 for Arg-31 inhibited STAT1 tyrosine dephosphorylation and greatly enhanced the anti...

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“…The tyrosine phosphorylation of STATs is regulated by Jak protein tyrosine kinases as well as the as-yet-unidentified protein tyrosine phosphatase (PTPase). It has been shown that a tyrosine phosphatase activity is involved in the down-regulation of IFN-induced gene expression (5,15,20,21). Treatment with sodium vanadate, a PTPase inhibitor, can maintain the tyrosine phosphorylation of Stat1 and prevent the transcriptional down-regulation of IFN-induced genes (5,21).…”

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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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Roles of Protein-tyrosine Phosphatases in Stat1α-mediated Cell Signaling

Cited by 91 publications

References 58 publications

STAT proteins: novel molecular targets for cancer drug discovery

STAT proteins: novel molecular targets for cancer drug discovery

STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7

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

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