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

Publication ,  Journal Article
Kim, J; Parrish, AB; Kurokawa, M; Matsuura, K; Freel, CD; Andersen, JL; Johnson, CE; Kornbluth, S
Published in: The EMBO journal
March 2012

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.

Duke Scholars

Published In

The EMBO journal

DOI

EISSN

1460-2075

ISSN

0261-4189

Publication Date

March 2012

Volume

31

Issue

5

Start / End Page

1279 / 1292

Related Subject Headings

  • Ribosomal Protein S6 Kinases
  • Protein Binding
  • Phosphorylation
  • Molecular Sequence Data
  • Models, Biological
  • Humans
  • Developmental Biology
  • Cytochromes c
  • Chlorocebus aethiops
  • Cell Line
 

Citation

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Kim, J., Parrish, A. B., Kurokawa, M., Matsuura, K., Freel, C. D., Andersen, J. L., … Kornbluth, S. (2012). Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis. The EMBO Journal, 31(5), 1279–1292. https://doi.org/10.1038/emboj.2011.491
Kim, Jiyeon, Amanda B. Parrish, Manabu Kurokawa, Kenkyo Matsuura, Christopher D. Freel, Joshua L. Andersen, Carrie E. Johnson, and Sally Kornbluth. “Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis.The EMBO Journal 31, no. 5 (March 2012): 1279–92. https://doi.org/10.1038/emboj.2011.491.
Kim J, Parrish AB, Kurokawa M, Matsuura K, Freel CD, Andersen JL, et al. Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis. The EMBO journal. 2012 Mar;31(5):1279–92.
Kim, Jiyeon, et al. “Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis.The EMBO Journal, vol. 31, no. 5, Mar. 2012, pp. 1279–92. Epmc, doi:10.1038/emboj.2011.491.
Kim J, Parrish AB, Kurokawa M, Matsuura K, Freel CD, Andersen JL, Johnson CE, Kornbluth S. Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis. The EMBO journal. 2012 Mar;31(5):1279–1292.

Published In

The EMBO journal

DOI

EISSN

1460-2075

ISSN

0261-4189

Publication Date

March 2012

Volume

31

Issue

5

Start / End Page

1279 / 1292

Related Subject Headings

  • Ribosomal Protein S6 Kinases
  • Protein Binding
  • Phosphorylation
  • Molecular Sequence Data
  • Models, Biological
  • Humans
  • Developmental Biology
  • Cytochromes c
  • Chlorocebus aethiops
  • Cell Line