ACTIVATION OF ZAP-70 KINASE-ACTIVITY BY PHOSPHORYLATION OF TYROSINE-493 IS REQUIRED FOR LYMPHOCYTE ANTIGEN RECEPTOR FUNCTION

ZAP-70 is a protein tyrosine kinase (PTK) required for T-cell developm ent and T-cell antigen receptor (TCR) function. ZAP-70 is associated w ith the phosphorylated antigen receptor and undergoes tyrosine phospho rylation following receptor activation. We demonstrate here that tyros ine phosphorylation of ZAP-70 results in an increase in its catalytic activity and that this activation is mediated by the phosphorylation o f tyrosine residue 493 by the src family of PTKs. The activity of bacu loviral expressed ZAP-70 was up-regulated 10-fold when ZAP-70 was co-i nfected and phosphorylated by the src family PTK, lck. Mutation of Y49 3 alone abrogated the ability of ZAP-70 to be activated by lck. Moreov er, we demonstrate that phosphorylation of Y493 and activation of ZAP- 70 is required for antigen receptor-mediated induction of interleukin- 2 (IL-2) secretion in lymphocytes.