First Author | Thien CB | Year | 2005 |
Journal | EMBO J | Volume | 24 |
Issue | 21 | Pages | 3807-19 |
PubMed ID | 16211006 | Mgi Jnum | J:103366 |
Mgi Id | MGI:3609288 | Doi | 10.1038/sj.emboj.7600841 |
Citation | Thien CB, et al. (2005) Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion. EMBO J 24(21):3807-19 |
abstractText | 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. |