Protein tyrosine phosphorylation is an early and requisite event in lymphocyte receptor-mediated signaling. We have demonstrated that induction of protein tyrosine phosphorylation by pharmacologic and genetic approaches can be sufficient to reproduce some aspects of lymphocyte activation including induction of key transcription factors and cytokine secretion. We have previously demonstrated that T-cell receptor (TCR) and FcR- mediated signaling in natural killer (NK) cells share many similarities both in their utilization of signaling subunits and the use of protein tyrosine kinases. However, we also demonstrated that NK cells have high basal protei tyrosine phosphorylation relative to T cells. This was not explained by expression of known protein tyrosine kinases (PTK) or protein tyrosine phosphatases. We therefore set out to clone novel PTK from NK cells. We succeeded in cloning two PTK, one of which is a new member of the Janus family of kinases (JAK) that is termed JAK-3 (or L-JAK for leukocyte JAK). JAK-3 has limited tissue distribution, unlike other JAKs, it is highly regulated by activation of lymphocyte and monocytes. Functionally, we demonstrated that JAK-3 is linked to IL-2, IL-4, IL-7, IL-9, and IL-15 signaling. Thus JAK-3 is likely to be of critical importance in lymphocyte activation and in particular in cytokine-mediated signal transduction. It will likely provide an excellent target for the design of new immunomodulatory agents.
