title: Actin-independent exclusion of CD95 by PI3K/AKT signalling: implications for apoptosis.
abstract: The immune system eliminates infected or transformed cells through the activation of the death receptor CD95. CD95 engagement drives the recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates and activates initiator caspases-8 and -10. The CD95-mediated apoptotic signal relies on the capacity to form the CD95/FADD/caspases complex termed the death-inducing signalling complex (DISC). Cells are classified according to the magnitude of DISC formation as either type I (efficient DISC formation) or type II (inefficient). CD95 localised to lipid rafts in type I cells, whereas the death receptor was excluded from these domains in type II cells. Here, we show that inhibition of both PI3K class IA and serine-threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts, DISC formation and the initiation of the apoptotic signal. Strikingly, these molecular events took place independently of CD95L and the actin cytoskeleton. Overall, these findings highlight that the oncogenic PI3K/Akt signalling pathway participates in maintaining cells in a type II phenotype by excluding CD95 from lipid rafts.
authors.affiliation: CNRS UMR 5164, Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Pizon
authors.forename: Hariniaina
authors.initials: H
authors.lastname: Rampanarivo
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tauzin
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chaigne-Delalande
authors.forename: Sophie
authors.initials: S
authors.lastname: Daburon
authors.forename: Michel
authors.initials: M
authors.lastname: Castroviejo
authors.forename: Patrick
authors.initials: P
authors.lastname: Moreau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.forename: Patrick
authors.initials: P
authors.lastname: Legembre
mesh_terms: D000199:Actins / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077191:Wortmannin; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000199:Actins; D000730:Androstadienes; D020169:Caspases; D002867:Chromones; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D009025:Morpholines; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one