ASSOCIATION OF PHOSPHATIDYLINOSITOL 3-KINASE WITH A SPECIFIC SEQUENCE OF THE T-CELL RECEPTOR XI-CHAIN IS DEPENDENT ON T-CELL ACTIVATION

The T cell antigen receptor (TCR) CDS complex contains several distinct but related signal transduction modules termed ''Reth motifs'': one each in the cytoplasmic domains of CD3-gamma, -delta, and -epsilon chains and three in the CD3-zeta polypeptide (zeta(A), zeta(B), and zeta(C)). Cross-linking of individual motifs expressed in chimeric molecules leads to early and late T cell activation events. Although the activated T cell receptor associates with nonreceptor tyrosine kinases, the sites of interaction with kinases and other potential effector molecules have not been fully mapped. Here we show that phosphatidylinositol 3-kinase (PI 3-kinase) preferentially associated with the zeta chain membrane proximal motif zeta(A). Maximal PI 3-kinase/zeta(A) association occurred following TCR.CD3 activation and was dependent upon phosphorylation of both tyrosine residues in zeta(A). The association of PI 3-kinase was specific for zeta(A) and could be ranked zeta(A) >> zeta(C) > zeta(B). Phosphorylation of the zeta(A) motif on tyrosine residues occurred in response to TCR.CD3 cross-linking in vivo. These results indicate that T cell activation leads to assembly of an intracellular signaling complex: recruitment of a tyrosine kinase, phosphorylation of zeta(A), and association of PI 3-kinase. These data also support a model in which different Reth motifs of the TCR.CD3 complex recruit distinct signal transduction molecules. Thus, the subdomains of the T cell antigen receptor zeta chain may serve different roles during T cell maturation and antigen-driven activation.