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J. Biol. Chem., Vol. 282, Issue 49, 36048-36056, December 7, 2007

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p56^Lck Tyrosine Kinase Enhances the Assembly of Death-inducing Signaling Complex during Fas-mediated Apoptosis^*

Ehssan Sharif-Askari¹, Denis Gaucher^¶, Rabih Halwani^¶, Jennifer Ma, Kevin Jao, Ali Abdallah, Elias K. Haddad^¶||, and Rafick-Pierre Sékaly^¶||**2

From the Laboratoire d'Immunologie, Centre de Recherche CHUM Saint-Luc, Montréal H2X 1P1, Département de Médecine, Université de Montréal, Montréal H3T 3J7, ^¶Laboratoire d'Immunologie, Département de Microbiologie et d'Immunologie, Université de Montréal, Québec H3T 1J4, ^**INSERM U743, CR-CHUM, Université de Montréal, Montréal H2X 1P1, and ^||Département de Microbiologie et d'Immunologie, McGill University, Montréal, Québec H3A 2B4, Canada

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.

Received for publication, July 23, 2007 , and in revised form, September 17, 2007.

^* This work was supported in part by Canadian Institutes of Health Research Grant MOP 64428 (to R.-P. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A recipient of a postdoctoral fellowship from the Fonds de la Recherche en Santé du Québec.

² Holds the Canada Research Chair in Human Immunology. To whom correspondence should be addressed: Centre de Recherche, Campus St. Luc Pavillon Edouard-Asselin 264, Blvd. René Lévesque Est, Bureau 1307D Montréal, Québec, H2X 1P1, Canada. Tel.: 514-890-8000 (ext: 35289); Fax: 514-412-7415; E-mail: rafick-pierre.sekaly{at}umontreal.ca.

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