Food and Drug Administration,

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 stud-ies demonstrated that a protein-tyrosine phosphatase (PTP) is required for activation of the ISGF3 transcrip-tion complex by IFNa/b, but the specific PTP responsi-ble remained unidentified. We now show that the SH2 domain containing tyrosine phosphatase PTP1D (also designated as SHPTP2, SHPTP3, PTP2C, or Syp) is con-stitutively associated with the IFNa/b receptor and be-comes tyrosine-phosphorylated in response to ligand. Furthermore, transient expression of a phosphatase-in-active mutant or the COOH-terminal SH2 domain of PTP1D causes a dominant negative effect on IFNa/b