ENHANCEMENT OF ANTIPROLIFERATIVE ACTIVITY OF GAMMA-INTERFERON BY THE SPECIFIC-INHIBITION OF TYROSINE DEPHOSPHORYLATION OF STAT1

Gamma interferon (IFN-gamma) signals to the nucleus through the activa tion, by tyrosine phosphorylation, of the latent cytoplasmic transcrip tion factor Stat1 (Signal transducer and activator of transcription), It has been demonstrated that the activity of Stat1 is dependent on ty rosine phosphorylation which is regulated by Jak tyrosine kinases as w ell as by the as-yet-unidentified protein tyrosine phosphatase. We rep ort that the N-terminal domain of Stat1, which is highly conserved amo ng all STAT family members, is required for its tyrosine dephosphoryla tion, A single amino acid substitution (Arg-31 to Ala) in the Stat1 N- terminal domain inhibited Stat1 tyrosine dephosphorylation, The deleti on of the Stat1 N-terminal domain resulted in a mutant Stat1 protein w hich was constitutively phosphorylated on Tyr-701, Upon IFN-gamma stim ulation, the tyrosine phosphorylation of this mutant protein was furth er 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-gamma, We suggest that the N-terminal domains of STATs are crucial for modulating STAT activ ities through regulating the tyrosine dephosphorylation of STATs.