INTERACTION BETWEEN LCK AND SYK FAMILY TYROSINE KINASES IN FC-GAMMA RECEPTOR-INITIATED ACTIVATION OF NATURAL-KILLER-CELLS

Ligation of the Fc gamma R on natural killer (NK) cells results in the tyrosine phosphorylation of multiple substrates critical for intracel lular signaling and activation of NK cell effector functions. However, it remains unclear which nonreceptor protein-tyrosine kinases (PTK) p articipate in this process. In this report we demonstrate that Fc gamm a R ligation induced the tyrosine phosphorylation and increased the ca talytic activities of both syk family PTKs, ZAP-70, and syk. The phosp horylation of ZAP-70 and syk was enhanced markedly by overexpression o f wild-type lck but not by a kinase-inactive mutant, suggesting that e arly Fc gamma R-initiated activation of lck results in the subsequent regulation of syk family PTKs. The regulatory interplay between src an d syk family PTKs was emphasized further by the observation that lck o verexpression enhanced the association of ZAP-70 with the zeta chain o f the Fc gamma R complex. Additional analyses indicated that lck induc ed the subsequent tyrosine phosphorylation of phospholipase C (PLC)-ga mma 2. Interestingly, the regulatory effects of lck on ZAP-70, syk, an d PLC-gamma 2 could not be replaced by overexpression of either fyn or src, demonstrating a selective role for lck in effectively coupling F c gamma R stimulation to critical downstream signaling events. Taken t ogether, our results suggest not only that Fc gamma R stimulation on N K cells is coupled to the intracellular activation of both ZAP-70 and syk, but that the src family member, lck, can selectively regulate thi s tyrosine kinase cascade.