Herpesvirus saimiri Tip-484 membrane protein upregulates p56^lck activity in human T cells

Herpesvirus saimiri (HVS) is a lymphotropic oncogenic primate virus. In vitro, HVS has the ability to transform human T cells to an interleukin-2 independent phenotype and immortalize them. A protein encoded by HVS known as Tip-484 (for Tyrosine kinase Interacting Protein from HVS strain-484) is required for this transformation. Tip-484 binds specifically to the non-receptor protein tyrosine kinase p56^lck. P56^lck is a required element in the transduction of activation signals from the T cell receptor to the nucleus. By transfecting Tip-484 into T cells, we now show that the Tip-484/p56^lck interaction leads to a dramatic increase in the kinase activity of p56^lck. Tip-484 is part of a protein complex which is dependent upon the presence of p56^lck and is phosphorylated. We also show that two of the completed proteins represent two phosphorylated forms of Tip-484. Furthermore, the p56^lck kinase activity in HVS infected human peripheral blood lymphocytes was at least nine-fold higher than in non-infected control cells, and significantly decreased in cells infected with a Tip-484 deletion mutant virus. The data 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 growth, and ultimately, lymphocytic tumor formation.