c-Cbl promotes T cell receptor-induced thymocyte apoptosis by activating the phosphatidylinositol 3-kinase/Akt pathway.

The Journal of Biological Chemistry
Christine B F ThienWallace Y Langdon

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.

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Citations

Sep 29, 2011·Calcified Tissue International·Tracy BrennanArchana Sanjay
Nov 10, 2010·Immunology and Cell Biology·G Jan WiegersAndreas Villunger
Sep 2, 2010·Proceedings of the National Academy of Sciences of the United States of America·Mayumi NaramuraHamid Band
Apr 8, 2015·Pharmacology & Therapeutics·Lixia WangWenyi Wei
Oct 19, 2010·Cancer Cell·Chozhavendan RathinamWallace Y Langdon
May 22, 2020·Proceedings of the National Academy of Sciences of the United States of America·Gaëtan BlaizeRenaud Lesourne
Jan 7, 2016·Frontiers in Immunology·Claire E O'LearyPaula M Oliver

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