SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling

Engagement of the T cell antigen receptor (TCR) leads to rapid activation o f protein tyrosine kinases, which in turn phosphorylate downstream enzymes and adapter proteins. Some adapter proteins, such as SLP-76, Vav, and LAT, positively regulate TCR-mediated signal transduction, whereas others, such as Cbl, play an inhibitory role. SLAP (Src-Like adapter protein), an adapte r protein containing a Src homology 3 and a Src homology 2 domain,,vas isol ated from a yeast interacting screen by using N-terminal Cbl as bait. N-ter minal Cbl interacts with SLAP in vivo and in vitro in a tyrosine phosphoryl ation-independent manner. We observed that SLAP is expressed in T cells, an d upon TCR activation, SLAP interacts with ZAP-70, Syk, LAT, and TCR zeta c hain in Jurkat T cells. In transiently transfected COS-7 cells, SLAP forms separate complexes with ZAP-70, Syk, and LAT through its Src homology 2 dom ain. Overexpression of a C-terminal-truncated SLAP mutant down-regulates nu clear factor of activated T cells-AP1 activity. We have evidence that SLAP forms homodimers through its C-terminal region. Serial truncations and muta tions in the C terminus of SLAP demonstrate that there is a correlation bet ween the loss of dimerization and the inhibition of nuclear factor of activ ated T cells-AP1 activity. The in vivo association of SLAP with key signali ng molecules and its inhibition of T cell activation suggests that SLAP pla ys an important role in TCR-mediated signal transduction.