Constitutive endocytosis and degradation of the pre-T cell receptor.
The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56(lck), actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the gammadeltaTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR- but not gammadeltaTCR-expressing cells. A role of c-Cbl-mediated ubiquitination in pre-TCR degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl-deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function.[1]References
- Constitutive endocytosis and degradation of the pre-T cell receptor. Panigada, M., Porcellini, S., Barbier, E., Hoeflinger, S., Cazenave, P.A., Gu, H., Band, H., von Boehmer, H., Grassi, F. J. Exp. Med. (2002) [Pubmed]
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