Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex

Margaret D Myers¹, Tomasz Sosinowski², Leonard L Dragone³, Carmen White³, Hamid Band⁴, Hua Gu⁵ & Arthur Weiss¹

¹  Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA.

²  Howard Hughes Medical Institute and National Jewish Medical and Research Center, Denver, Colorado 80206, USA.

³  Division of Pediatric Immunology/Rheumatology, Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA.

⁴  Division of Molecular Oncology, Department of Medicine, Evanston Northwestern Healthcare Research Institute, Feinberg School of Medicine; Department of Biochemistry, Molecular Biology & Cell Biology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois 60201, USA.

⁵  Microbiology Department, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.

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 CD3. This required multiple domains in SLAP and the ring finger of c-Cbl. Furthermore, expression of SLAP and c-Cbl together induced TCR 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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