The adaptor molecule SLAP and E3 ubiquitin ligase c-Cbl each regulate expression of T cell receptor (TCR)–CD3 on thymocytes. Here we provide genetic and biochemical evidence that both molecules function in the same pathway. TCR-CD3 expression was similar in the absence of SLAP and/or c-Cbl. SLAP and c-Cbl were found to interact, and their expression together downregulated CD3ε. This required multiple domains in SLAP and the ring finger of c-Cbl. Furthermore, expression of SLAP and c-Cbl together induced TCRζ ubiquitination and degradation, preventing the accumulation of fully assembled recycling TCR complexes. These studies indicate that SLAP links the E3 ligase activity of c-Cbl to the TCR, allowing for stage-specific regulation of TCR expression.
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We thank F. Brodsky, M. von Zastrow and members of the Weiss lab for comments and suggestions. Supported by the National Institutes of Health (CA72531 to A.W. and CA987986 to H.B.).
The authors declare no competing financial interests.
CD3ε internalization by DP thymocytes is normal in the absence of SLAP and/or c-Cbl. (PDF 184 kb)
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