Direct binding and activation of STAT transcription factors by the herpesvirus saimiri protein Tip

The Tip protein from Herpesvirus saimiri specifically binds to and activates the protein tyrosine kinase, p56(lck). It has been demonstrated that the expression of Tip in T cells is capable of inducing the DNA binding of members of the signal transducers and activators of transcription (STAT) family of transcription factors. We have examined the mechanism behind which STATs 1 and 3 are activated by Tip expression. Tip becomes tyrosine phosphorylated by p56(lck) at two sites in the amino-terminal tail region. One site of phosphorylation lies within a consensus YXPQ binding motif for the SH2 domains of STATs 1 and 3. We demonstrate that tyrosine phosphorylation of Tip at this site is required for the binding of STATs, and the induction of STAT dependent transcription. Furthermore, we demonstrate that, similar to STAT activation by v-Src, the optimum induction of STAT-dependent transcription by Tip requires Ras/ Rac mediated signaling events.