Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion
- Author(s)
- Thien, CBF; Blystad, FD; Zhan, YF; Lew, AM; Voigt, V; Andoniou, CE; Langdon, WY;
- Details
- Publication Year 2005-11-02,Volume 24,Issue #21,Page 3807-3819
- Journal Title
- EMBO JOURNAL
- Publication Type
- Journal Article
- Abstract
- Signaling from the T-cell receptor (TCR) in thymocytes is negatively regulated by the RING finger-type ubiquitin ligase c-Cbl. To further investigate this regulation, we generated mice with a loss-of-function mutation in the c-Cbl RING finger domain. These mice exhibit complete thymic deletion by young adulthood, which is not caused by a developmental block, lack of progenitors or peripheral T-cell activation. Rather, this phenotype correlates with greatly increased expression of the CD5 and CD69 activation markers and increased sensitivity to anti-CD3-induced cell death. Thymic loss contrasts the normal fate of the c-Cbl-/- thymus, even though thymocytes from both mutant mice show equivalent enhancement in proximal TCR signaling, Erk activation and calcium mobilization. Remarkably, only the RING finger mutant thymocytes show prominent TCR-directed activation of Akt. We show that the mutant c-Cbl protein itself is essential for activating this pathway by recruiting the p85 regulatory subunit of PI 3-kinase. This study provides a unique model for analyzing high-intensity TCR signals that cause thymocyte deletion and highlights multiple roles of c-Cbl in regulating this process.
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- PROTEIN-KINASE-B; IMMATURE CD4(+)CD8(+) THYMOCYTES; NEGATIVE SELECTION; T-CELLS; TYROSINE KINASES; IN-VIVO; PHOSPHORYLATION SITES; FAMILY PROTEINS; DOWN-REGULATION; ACTIVATION
- Publisher's Version
- https://doi.org/10.1038/sj.emboj.7600841
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2005-11-02 12:00:00