ACTIVATION OF STAT TRANSCRIPTION FACTORS BY HERPESVIRUS SAIMIRI TIP-484 REQUIRES P56(LCK)

Signal transducers and activators of transcription (STATs) relay signa ls from activated cell surface receptors directly to the nucleus. Prev iously, a protein required for T-cell transformation by the DNA tumor virus herpesvirus saimiri (HVS) and designated tyrosine kinase interac ting protein (Tip-484) was shown to interact with and dramatically upr egulate the activity of p56(lck). p56(lck) is a nonreceptor tyrosine k inase that is essential for signaling by the T-cell receptor and also interacts with the CD4, CD8, and interleukin-2 receptors. The present data show activation of STAT1 and -3 by Tip-484, STAT1 and -3 were als o found to complex with glutathione S-transferase-Tip-484 only in the presence of p56(lck), and STAT3 aas shown to be phosphorylated by the Tip-484-p56(lck) multiprotein complex in vitro, Infection of T cells w ith HVS or expression of recombinant Tip-484 significantly increased t he DNA-binding activity of the STAT1 and STAT3 transcription factors i n nuclear extracts and also increased the phosphorylation of STAT3 in vivo, This is the first report of STAT activation by a DNA tumor virus protein. Moreover, these studies demonstrate that p56(lck) is require d for STAT activation by Tip-484.