Rsk-mediated Phosphorylation and 14-3-3ɛ Binding of Apaf-1 Suppresses Cytochrome C-induced Apoptosis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2012 Jan 17

PMID 22246185

Citations 22

Authors

Jiyeon Kim

Amanda B Parrish

Manabu Kurokawa

Kenkyo Matsuura

Christopher D Freel

Joshua L Andersen

Carrie E Johnson

Sally Kornbluth

Affiliations

Soon will be listed here.

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.

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