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

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 in...

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Bibliographic Details
Published in:The EMBO journal 2012-03, Vol.31 (5), p.1279-1292
Main Authors: Kim, Jiyeon, Parrish, Amanda B, Kurokawa, Manabu, Matsuura, Kenkyo, Freel, Christopher D, Andersen, Joshua L, Johnson, Carrie E, Kornbluth, Sally
Format: Article
Language:English
Subjects:
14-3-3 Proteins - metabolism
Amino Acid Sequence
Animals
Apoptosis
Apoptotic Protease-Activating Factor 1 - metabolism
Cell Line
Cercopithecus aethiops
Cytochromes c - antagonists & inhibitors
Cytochromes c - metabolism
Humans
Models, Biological
Molecular Sequence Data
Phosphorylation
Protein Binding
Ribosomal Protein S6 Kinases - metabolism
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Summary: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.
ISSN:0261-4189
1460-2075
DOI:10.1038/emboj.2011.491