c-Cbl Promotes T Cell Receptor-induced Thymocyte Apoptosis by Activating the Phosphatidylinositol 3-Kinase/Akt Pathway
Details
Publication Year 2010-04-02,Volume 285,Issue #14,Page 10969-10981
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type
Journal Article
Abstract
The ability of thymocytes to assess T cell receptor (TCR) signaling strength and initiate the appropriate downstream response is crucial for determining their fate. We have previously shown that a c-Cbl RING finger mutant knock-in mouse, in which the E3 ubiquitin ligase activity of c-Cbl is inactivated, is highly sensitive to TCR-induced death signals that cause thymic deletion. This high intensity signal involves the enhanced tyrosine phosphorylation of the mutant c-Cbl protein promoting a marked increase in the activation of Akt. Here we show that this high intensity signal in c-Cbl RING finger mutant thymocytes also promotes the enhanced induction of two mediators of TCR-directed thymocyte apoptosis, Nur77 and the pro-apoptotic Bcl-2 family member, Bim. In contrast, a knock-in mouse harboring a mutation at Tyr-737, the site in c-Cbl that activates phosphatidylinositol 3-kinase, shows reduced TCR-mediated responses including suppression of Akt activation, a reduced induction of Nur77 and Bim, and greater resistance to thymocyte death. These findings identify tyrosine-phosphorylated c-Cbl as a critical sensor of TCR signal strength that regulates the engagement of death-promoting signals.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords
FAMILY-MEMBER BIM; NEGATIVE SELECTION; TYROSINE PHOSPHORYLATION; AUTOREACTIVE THYMOCYTES; OF-FUNCTION; KINASE; DOMAIN; INHIBITORS; ZAP-70; LIGASE
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Creation Date: 2010-04-02 12:00:00
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