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JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3

Jun Sunayama1, Fuminori Tsuruta, Norihisa Masuyama

  • 1Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.

The Journal of Cell Biology
|July 13, 2005
PubMed

Insights

Cellular stress triggers c-Jun NH2-terminal kinase (JNK) to phosphorylate 14-3-3 proteins. This phosphorylation releases pro-apoptotic proteins, promoting cell death and antagonizing survival signals.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Signaling

Background:

  • Mammalian cells integrate diverse apoptotic and survival signals for life-or-death decisions.
  • A common integration mechanism for these signals is hypothesized.
  • 14-3-3 proteins are proposed as key integration points, binding pro-apoptotic proteins phosphorylated by survival kinases like Akt.

Purpose of the Study:

  • To investigate the role of 14-3-3 proteins as signal integrators in apoptosis.
  • To elucidate the mechanism by which c-Jun NH2-terminal kinase (JNK) mediated phosphorylation of 14-3-3 impacts apoptotic pathways.
  • To determine how JNK-mediated 14-3-3 phosphorylation affects the binding and activity of pro-apoptotic proteins like Bad and FOXO3a.

Main Methods:

  • Investigated the phosphorylation of 14-3-3zeta at Ser184 by JNK.
  • Analyzed the release of pro-apoptotic proteins (Bad, FOXO3a) from 14-3-3 upon JNK-mediated phosphorylation.
  • Examined the consequences of protein dissociation, including dephosphorylation and mitochondrial translocation of Bad.

Main Results:

  • Cellular stresses induce JNK-mediated phosphorylation of 14-3-3zeta at Ser184.
  • Phosphorylation of 14-3-3 by JNK leads to the release of pro-apoptotic proteins Bad and FOXO3a.
  • This release antagonizes Akt signaling, causing Bad dephosphorylation and mitochondrial translocation, promoting apoptosis.

Conclusions:

  • JNK-mediated phosphorylation of 14-3-3 acts as a critical regulatory switch in apoptosis.
  • This mechanism releases multiple pro-apoptotic proteins, coordinating their activity and increasing cellular susceptibility to death signals.
  • 14-3-3 proteins serve as crucial integration hubs for apoptotic and survival signaling pathways.

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