p56Lck tyrosine kinase enhances the assembly of death-inducing signaling complex during Fas-mediated apoptosis |
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Authors: | Sharif-Askari Ehssan Gaucher Denis Halwani Rabih Ma Jennifer Jao Kevin Abdallah Ali Haddad Elias K Sékaly Rafick-Pierre |
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Institution: | Laboratoire d'Immunologie, Centre de Recherche CHUM Saint-Luc, Montréal H2X 1P1, Canada. |
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Abstract: | Although the death-inducing signaling complex (DISC) is rapidly assembled, several lines of evidence suggest that formation of this complex is not the first consequence of cell surface CD95 (Fas) stimulation but rather a later step in this process. Activation of Fas triggers a cascade of signaling events that culminate in cellular apoptosis. Tyrosine kinases are critical effectors in T cell activation. However, their functional involvement in death receptor-mediated apoptosis is unknown. Here, we used p56(Lck)-deficient cells to show that CD95-induced cell death is highly dependent on p56(Lck) activity and its localization within plasma membrane. We found that p56(Lck) acts upstream of the mitochondria; in the absence of p56(Lck), Bid cleavage and the release of cytochrome c were severely impaired. Moreover, p56(Lck)-deficient cells or cells expressing an inactive form of p56(Lck) displayed defective formation of the DISC post CD95 stimulation. In vivo reconstitution of thymocytes from p56(lck)-deficient mice, which are resistant to apoptosis, with p56(Lck) restored Fas-mediated cell death. Our results support a novel model whereby sensitivity to apoptosis is regulated through quantitative changes in the stoichiometry of DISC components triggered by p56(Lck) activation and localization. |
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