SRC FAMILY TYROSINE KINASES ASSOCIATE WITH AND PHOSPHORYLATE CTLA-4 (CD152)

CTLA-4 (CD152) transduces inhibitory signals for T cell activation. Ph osphorylation and dephosphorylation of tyrosine residue (Y)-165 in the cytoplasmic region of CTLA-4 play an important role in the signal tra nsduction and in the cell surface. While signaling molecules such as S HP-2 and the p85 subunit of PI3 kinase associate with this tyrosine re sidue through SH2 domains upon phosphorylation, the adapter complex AP -2 interacts with the same tyrosine when dephosphorylated, leading to clathrin-mediated endocytosis of CTLA-4. We searched for the tyrosine kinase responsible for the phosphorylation of CTLA-4. Src family tyros ine kinases Fyn, Lyn, and Lck associate with CTLA-4 and phosphorylate both Y-165 and Y-182 that are mainly responsible for interaction with Fyn through its SH2 domain. SHP-2 associates with CTLA-4, in a Fyn-dep endent manner. Our observations show that src family tyrosine kinases associate with and phosphorylate CTLA-4 and thereby have an important role in the signal transduction and the endocytosis of CTLA-4. (C) 199 8 Academic Press.