title: Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis.
abstract: Many pro-apoptotic signals trigger mitochondrial cytochrome c release, leading to caspase activation and ultimate cellular breakdown. Cell survival pathways, including the mitogen-activated protein kinase (MAPK) cascade, promote cell viability by impeding mitochondrial cytochrome c release and by inhibiting subsequent caspase activation. Here, we describe a mechanism for the inhibition of cytochrome c-induced caspase activation by MAPK signalling, identifying a novel mode of apoptotic regulation exerted through Apaf-1 phosphorylation by the 90-kDa ribosomal S6 kinase (Rsk). Recruitment of 14-3-3ɛ to phosphorylated Ser268 impedes the ability of cytochrome c to nucleate apoptosome formation and activate downstream caspases. High endogenous levels of Rsk in PC3 prostate cancer cells or Rsk activation in other cell types promoted 14-3-3ɛ binding to Apaf-1 and rendered the cells insensitive to cytochrome c, suggesting a potential role for Rsk signalling in apoptotic resistance of prostate cancers and other cancers with elevated Rsk activity. Collectively, these results identify a novel locus of apoptosomal regulation wherein MAPK signalling promotes Rsk-catalysed Apaf-1 phosphorylation and consequent binding of 14-3-3ɛ, resulting in decreased cellular responsiveness to cytochrome c.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Parrish
authors.forename: Manabu
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Kenkyo
authors.initials: K
authors.lastname: Matsuura
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Freel
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Andersen
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Johnson
authors.forename: Sally
authors.initials: S
authors.lastname: Kornbluth
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; C482983:YWHAE protein, human; D045304:Cytochromes c; D019893:Ribosomal Protein S6 Kinases