The SH2 domain-containing tyrosine phosphatase PTP1D is required for interferon alpha/beta-induced gene expression.
Interferons (IFNs) induce early response genes by stimulating Janus family (Jak) tyrosine kinases, leading to tyrosine phosphorylation of Stat (signal transducer and activator of transcription) proteins. Previous studies demonstrated that a protein-tyrosine phosphatase (PTP) is required for activation of the ISGF3 transcription complex by IFNalpha/beta, but the specific PTP responsible remained unidentified. We now show that the SH2 domain containing tyrosine phosphatase PTP1D (also designated as SHPTP2, SHPTP3, PTP2C, or Syp) is constitutively associated with the IFNalpha/beta receptor and becomes tyrosine-phosphorylated in response to ligand. Furthermore, transient expression of a phosphatase-inactive mutant or the COOH-terminal SH2 domain of PTP1D causes a dominant negative effect on IFNalpha/beta-induced early response gene expression. These results provide strong evidence that PTP1D functions as a positive regulator of the IFNalpha/beta-induced Jak/Stat signal transduction pathway.
David
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Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Zhou
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Pine
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Dixon
J E
JE
Larner
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D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000096:biosynthesis; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017471:Receptors, Interferon / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D018909:src Homology Domains
D017931:DNA Primers; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D016899:Interferon-beta; D008156:Luciferases; D005982:Glutathione Transferase; D013937:Thymidine Kinase; D011505:Protein-Tyrosine Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases