HERPESVIRUS SAIMIRI TIP-484 MEMBRANE-PROTEIN MARKEDLY INCREASES P56(LCK) ACTIVITY IN T-CELLS

Herpesvirus saimiri (HVS) is a T-cell-specific transforming and oncoge nic virus, A protein encoded by RVS known as Tip-484 (for tyrosine kin ase interacting protein from HVS strain 484) is required for this tran sformation. Tip-484 binds specifically to the nonreceptor protein tyro sine kinase p56(lck). By transfecting Tip-484 into T cells, we now sho w that this interaction leads to a several hundred-fold increase in th e kinase activity of p56(lck). Tip-484 is part of a protein complex wh ich is dependent on the presence of p56(lck) and is phosphorylated. We also show that two of the complexed proteins represent two phosphoryl ated forms of Tip-484. Furthermore, the p56(lck) kinase activity in HV S-infected human peripheral blood T lymphocytes was at least ninefold higher than that in noninfected control cells and significantly decrea sed in cells infected with a Tip-484 deletion mutant virus. Finally, w e report that Tip-484 is required for oncogenesis in rabbits by the su rvival of rabbits inoculated with Tip-484 deletion mutant HVS. The dat a demonstrate dramatic stimulation of the signaling pathway of p56(lck ). This effect can contribute to the molecular mechanisms that lead to sustained autocrine secretion of growth factors, permanent T-cell gro wth, and ultimately lymphocytic tumor formation.