INTERLEUKIN-2 SIGNAL TRANSDUCTION IN HUMAN NK CELLS - MULTISITE PHOSPHORYLATION AND ACTIVATION OF THE TYROSINE KINASE P56LCK

Interleukin-2 (IL-2) potently stimulates natural killer (NK) cell proliferation and cytotoxic function. However, the molecular mechanisms by which IL-2 delivers activation signals from the IL-2 receptor to the NK cell interior are incompletely understood. Previous studies demonstrated that IL-2 stimulation induced the tyrosine phosphorylation of multiple proteins in NK cells, together with a prominent reduction in the electrophoretic mobility of p56(lck). The present studies indicate that IL-2 induces a rapid (less-than-or-equal-to 1 min) increase in the catalytic activity of p56(lck), as measured by increases in protein tyrosine kinase activity in vitro. Furthermore, in response to IL-2, p56(lck) itself undergoes complex alterations in serine and tyrosine phosphorylation. Cyanogen bromide cleavage maps indicate that IL-2 stimulates a pronounced increase in the phosphorylation of the NH2-terminal region of p56(1ck) containing multiple known sites of serine phosphorylation. In addition, IL-2 induced a marked increase in the phosphorylation of a COOH-terminal peptide containing the regulatory Tyr-505 residue of p56(lck). These results suggest that p55(lck) serves as a substrate for both protein serine and tyrosine kinases activated during stimulation of this cell type with IL-2. Furthermore, these results indicate that the pleiotropic effects of IL-2 on NK cell physiology are initiated and regulated by a complex and multitiered interaction of different protein kinases including p56(lck).