RESTING LYMPHOCYTE KINASE (RLK TXK) PHOSPHORYLATES THE YVKM MOTIF ANDREGULATES PL 3-KINASE BINDING TO T-CELL ANTIGEN CTLA-4/

CTLA-4 and CD28 are differentially expressed on T-cells. They bind to a common ligand B71/2 (CD80/86), however with different avidities. Unl ike CD28 which augments the T-cell response, CTLA-4 operates predomina tely as a negative regulator of T-cell proliferation. The mechanism by which CTLA-4 can generate these intracellular signals is unclear. Lit tle is known regarding the identity of the protein-tyrosine kinase(s) responsible for CTLA-4 phosphorylation and thus creating conditions fo r the reported binding to PI 3-kinase and the protein tyrosine phospha tase SHP-2. In this study, we demonstrate that Rlk (resting lymphocyte kinase) is capable of phosphorylating CTLA-4 at the YVKM motif. Consi stent with this finding, Rlk is capable of providing conditions for th e binding of the SH2 domains of PI 3-kinase to the receptor. CTLA-4 is therefore the first known substrate for Rlk suggesting the possibilit y that this kinase may participate in CTLA-4 function. (C) 1998 Academ ic Press.