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 fa mily (Jak) tyrosine kinases, leading to tyrosine phosphorylation of St at (signal transducer and activator of transcription) proteins. Previo us studies demonstrated that a protein-tyrosine phosphatase (PTP) is r equired for activation of the ISGF3 transcription complex by IFN alpha /beta, but the specific PTP responsible remained unidentified. We now show that the SH2 domain containing tyrosine phosphatase PTP1D (also d esignated as SHPTP2, SHPTP3, PTP2C, or Syp) is constitutively associat ed with the IFN alpha/beta receptor and becomes tyrosine-phosphorylate d in response to ligand. Furthermore, transient expression of a phosph atase-inactive mutant or the COOH-terminal SH2 domain of PTP1D causes a dominant negative effect on IFN alpha/beta-induced early response ge ne expression. These results provide strong evidence that PTP1D functi ons as a positive regulator of the IFN alpha/beta-induced Jak/Stat sig nal transduction pathway.