Rsk-mediated phosphorylation and 14-3-3ε binding of Apaf-1 suppresses cytochrome c-induced apoptosis

Jiyeon Kim, Amanda B. Parrish, Manabu Kurokawa, Kenkyo Matsuura, Christopher D. Freel, Joshua L. Andersen, Carrie E. Johnson, Sally Kornbluth

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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 14-3-3ε 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 14-3-3ε 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 14-3-3ε, resulting in decreased cellular responsiveness to cytochrome c.

Original languageEnglish
Pages (from-to)1279-1292
Number of pages14
JournalEMBO Journal
Issue number5
StatePublished - Mar 7 2012


  • 14-3-3
  • Apaf-1
  • Rsk
  • apoptosis
  • cytochrome c


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