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

The Tip protein from Herpesvirus saimiri specifically binds to and activate s 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 memb ers of the signal transducers and activators of transcription (STAT) family of transcription factors. We have examined the mechanism behind which STAT s 1 and 3 are activated by Tip expression. Tip becomes tyrosine phosphoryla ted 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 dom ains 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 STA T dependent transcription. Furthermore, we demonstrate that, similar to STA T activation by v-Src, the optimum induction of STAT-dependent transcriptio n by Tip requires Ras/ Rac mediated signaling events.