title: Roles of protein-tyrosine phosphatases in Stat1 alpha-mediated cell signaling.
abstract: Different Stat proteins are activated through phosphorylation of unique tyrosine residues in response to different cytokines and growth factors. Interferon-gamma activates Stat1 molecules that form homodimers and bind cognate DNA elements. Here we show that treatment of permeabilized cells with 200-500 microM peroxo-derivatives of vanadium, molybdenum, and tungsten results in the accumulation of constitutively phosphorylated Stat1 alpha molecules. In contrast, treatment of permeabilized cells with orthovanadate, vanadyl sulfate, molybdate, and tungstate at the same range of concentrations does not result in the accumulation of activated Stat1 alpha molecules in the absence of ligand. However, these compounds inhibit the inactivation of interferon-gamma-induced DNA-binding activity of Stat1 alpha. A 4-6-h exposure of the permeabilized cells to orthovanadate, molybdate, and tungstate, but not vanadyl sulfate, results in a ligand-independent activation of Stat1 alpha, which is blocked by the inhibition or depletion of NADPH oxidase activity in the cells, indicating that NADPH oxidase-catalyzed superoxide formation is required for the bioconversion of these metal oxides to the corresponding peroxo-compounds. Interestingly, ligand-independent Stat1 alpha activation by peroxo-derivatives of these transition metals does not require Jak1, Jak2, or Tyk2 kinase activity, suggesting that other kinases can phosphorylate Stat1 alpha on tyrosine 701.
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Foundation, Ohio 44195, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Haque
authors.forename: V
authors.initials: V
authors.lastname: Flati
authors.forename: A
authors.initials: A
authors.lastname: Deb
authors.forename: B R
authors.initials: BR
authors.lastname: Williams
mesh_terms: D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008954:Models, Biological; D008969:Molecular Sequence Data; D008982:Molybdenum / Q000494:pharmacology; D010545:Peroxides / Q000494:pharmacology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D017973:Tungsten Compounds / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D010545:Peroxides; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D017973:Tungsten Compounds; C079868:gamma interferon activation factor; D014638:Vanadates; C025399:sodium tungstate(VI); D008982:Molybdenum; D007371:Interferon-gamma; C024687:sodium molybdate(VI); D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D017027:Protein Tyrosine Phosphatases