Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex.
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 CD3epsilon. This required multiple domains in SLAP and the ring finger of c-Cbl. Furthermore, expression of SLAP and c-Cbl together induced TCRzeta 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.
Myers
Margaret D
MD
Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute, University of California San Francisco, 94143, USA.
Sosinowski
Tomasz
T
Dragone
Leonard L
LL
White
Carmen
C
Band
Hamid
H
Gu
Hua
H
Weiss
Arthur
A
D000818:Animals; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D051379:Mice; D008817:Mice, Mutant Strains; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; C095148:Sla protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D016392:Proto-Oncogene Proteins pp60(c-src); C493849:Cbl protein, mouse