c-Cbl promotes T cell receptor-induced thymocyte apoptosis by activating the phosphatidylinositol 3-kinase/Akt pathway.
J Biol Chem
; 285(14): 10969-81, 2010 Apr 02.
Article
en En
| MEDLINE
| ID: mdl-20133944
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Timo
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Receptores de Antígenos de Linfocitos T
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Apoptosis
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Fosfatidilinositol 3-Quinasas
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Proteínas Proto-Oncogénicas c-cbl
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Proteínas Proto-Oncogénicas c-akt
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2010
Tipo del documento:
Article