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cJun N-terminal kinase (JNK) phosphorylation of serine 36 is critical for p66Shc activation

Sana Khalid1, Astrid Drasche1, Marco Thurner1

  • 1Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.

Scientific Reports
|February 13, 2016
PubMed

Insights

Inhibiting c-Jun N-terminal kinases (JNKs) reduces p66Shc phosphorylation and reactive oxygen species (ROS) production, offering a potential therapy for oxidative stress and organ damage.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biology

Background:

  • p66Shc-dependent reactive oxygen species (ROS) production is implicated in various pathologies, including ischemia/reperfusion injury (IRI).
  • Targeting p66Shc activation presents a novel therapeutic strategy, as traditional antioxidants are often ineffective in vivo.
  • Mitochondrial import, dependent on serine 36 (S36) phosphorylation, is crucial for p66Shc's pro-oxidant and pro-apoptotic functions.

Purpose of the Study:

  • To investigate the role of JNKs and PKCß in phosphorylating p66Shc at S36.
  • To determine the impact of JNK1/2-mediated p66Shc phosphorylation on ROS production and cell damage.
  • To explore the therapeutic potential of inhibiting JNK1/2 in preventing oxidative damage.

Main Methods:

  • Simulated ischemia/reperfusion (IR) using H2O2 or hypoxia/reoxygenation (HR) in mouse embryonic fibroblasts (MEFs) and HL-1 cardiomyocytes.
  • Utilized specific kinase inhibitors and JNK1/2 deficient MEFs.
  • Employed recombinant p66Shc phosphorylation assays and a phosphomimetic S36E mutant.

Main Results:

  • Hypoxia/reoxygenation and H2O2 treatment increased JNK and p38 activity, p66ShcS36 phosphorylation, ROS production, and cell damage.
  • JNK1/2 inhibitors significantly reduced p66ShcS36 phosphorylation.
  • JNK1, but not PKCß, phosphorylated recombinant p66Shc at S36.
  • JNK1/2 deficiency prevented ROS production and cell death, which was reversed by the S36E mutant.

Conclusions:

  • JNK1/2 directly regulates p66Shc phosphorylation at S36, leading to increased ROS production and cell damage.
  • Inhibiting JNK1/2-dependent p66Shc activation offers a promising therapeutic avenue for preventing oxidative damage in conditions like IRI.

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