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Serine 58 of 14-3-3zeta is a molecular switch regulating ASK1 and oxidant stress-induced cell death

Jibin Zhou1, Zhili Shao, Risto Kerkela

  • 1Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut St., Philadelphia, PA 19107, USA.

Molecular and Cellular Biology
|May 20, 2009
PubMed

Insights

Oxidant stress triggers cell death by activating ASK1. This study reveals that phosphorylating 14-3-3zeta at S58 releases ASK1, with SOK-1 kinase regulating this critical pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Stress Signaling

Background:

  • Oxidant stress is a major cellular insult impacting diverse cell types.
  • Apoptosis Signal-regulating Kinase 1 (ASK1) mediates oxidant injury, but its activation mechanisms remain unclear.
  • Inhibition of ASK1 involves 14-3-3 proteins and thioredoxin, yet activation pathways are poorly understood.

Purpose of the Study:

  • To elucidate the obscure mechanisms regulating ASK1 activation.
  • To identify the signaling pathways controlling ASK1-mediated cell death.
  • To investigate the role of 14-3-3zeta phosphorylation in oxidant stress response.

Main Methods:

  • Investigated the dynamic regulation of 14-3-3zeta phosphorylation at serine 58 (S58).
  • Utilized cell-based assays to assess the impact of S58 phosphorylation on ASK1 release and activation.
  • Identified endogenous kinases regulating S58 phosphorylation using molecular biology techniques.

Main Results:

  • Phosphorylation of 14-3-3zeta at S58 dynamically regulates its interaction with ASK1.
  • S58 phosphorylation releases ASK1, leading to the activation of downstream stress-activated protein kinases and subsequent cell death.
  • Ste20/oxidant stress response kinase 1 (SOK-1) was identified as a key endogenous kinase phosphorylating S58 and regulating ASK1-mediated cell death.

Conclusions:

  • A novel pathway regulating ASK1 activation and oxidant stress-induced cell death has been identified.
  • 14-3-3zeta S58 phosphorylation is a critical switch controlling ASK1 activity in response to oxidant stress.
  • SOK-1 acts as a central regulator linking oxidant stress to ASK1 activation and cell death.

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