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

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Updated: May 25, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Jiyeon Kim1, Amanda B Parrish, Manabu Kurokawa

  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

The EMBO Journal
|January 17, 2012
PubMed

Insights

Mitogen-activated protein kinase (MAPK) signaling inhibits apoptosis by promoting Rsk-catalyzed Apaf-1 phosphorylation. This phosphorylation recruits 14-3-3ɛ, blocking cytochrome c-induced caspase activation and promoting cell survival.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Biochemistry

Background:

  • Pro-apoptotic signals initiate cell death via mitochondrial cytochrome c release and caspase activation.
  • Cell survival pathways, such as the mitogen-activated protein kinase (MAPK) cascade, counteract apoptosis by preventing cytochrome c release and caspase activation.

Purpose of the Study:

  • To elucidate the mechanism by which MAPK signaling inhibits cytochrome c-induced caspase activation.
  • To identify novel regulators of apoptosis and potential therapeutic targets in cancer.

Main Methods:

  • Investigated Apaf-1 phosphorylation by the 90-kDa ribosomal S6 kinase (Rsk).
  • Examined the role of 14-3-3ɛ binding to phosphorylated Apaf-1.
  • Assessed cellular sensitivity to cytochrome c in PC3 prostate cancer cells and other cell types with varying Rsk activity.

Main Results:

  • MAPK signaling inhibits apoptosis through Rsk-mediated phosphorylation of Apaf-1 at Ser268.
  • Phosphorylated Apaf-1 binds to 14-3-3ɛ, which prevents cytochrome c-induced apoptosome formation and caspase activation.
  • Elevated Rsk levels or activity confer resistance to cytochrome c-induced cell death, observed in PC3 cells.

Conclusions:

  • MAPK signaling provides a novel mechanism for regulating apoptosis by inhibiting the apoptosome.
  • Rsk-catalyzed Apaf-1 phosphorylation and subsequent 14-3-3ɛ binding represent a key step in this survival pathway.
  • This pathway's dysregulation may contribute to apoptotic resistance in cancers with high Rsk activity, offering potential therapeutic avenues.

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