Src-like adaptor protein: A molecule that regulates TCR/CD3 expression by adapting the E3 ubiquitin ligasec-Cbl to the TCR/CD3 complex

Src-Like Adaptor Protein (SLAP) downregulates expression of the T cell receptor (TCR)/CD3 complex during a specific stage of thymocyte development when the TCR repertoire is selected. Consequently, SLAP -/- thymocytes display alterations in thymocyte development. Interestingly, mice deficient in either SLAP or c-Cb1 have very similar thymic phenotypes. We have studied the mechanism of TCR/CD3 downregulation by SLAP and c-Cb1. Using mice deficient for SLAP and/or c-Cb1 we demonstrate that thymocytes deficient in SLAP and/or c-Cb1 have increased TCRzeta chain expression due to a defect in TCRzeta degradation. Failure to degrade TCRzeta leads to an increased pool of fully assembled TCR/CD3 complexes that are capable of recycling back to the cell surface. SLAP functions in a pathway that requires the phosphorylated TCRzeta chain and the Src-family kinase Lck, but not ZAP-70 or Slp-76. In addition, TCR/CD3 downregulation requires multiple domains in SLAP as well as the ring finger of c-Cb1 Moreover, both SLAP and c-Cb1 are required to target the TCR chain for ubiquitination and degradation. Finally, we describe a previously uncharacterized dileucine-based motif present in the SH2 domain of SLAP that is required for TCR/CD3 downregulation and TCRzeta degradation by SLAP and c-Cb1 These studies reveal a unique mechanism by which SLAP and c-Cb1 contribute to the regulation of TCR expression during a distinct stage of thymocyte development.