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Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear

Sung-Wuk Jang1, Seung-Ju Yang, Shanthi Srinivasan

  • 1Department of Pathology, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

The Journal of Biological Chemistry
|August 30, 2007
PubMed

Insights

The Akt kinase prevents apoptosis by phosphorylating MstI (a key apoptosis inducer). This phosphorylation blocks MstI activity, protecting cells from oxidative stress-induced cell death.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Oxidative stress triggers apoptosis via MstI activation, FOXO phosphorylation, and nuclear translocation.
  • MstI is crucial for stress-induced apoptosis, requiring autophosphorylation and caspase cleavage for activation.

Purpose of the Study:

  • To investigate the role of Akt in regulating MstI activity and its impact on apoptosis.
  • To elucidate the mechanism by which Akt influences MstI-mediated cell death pathways.

Main Methods:

  • Investigated MstI as a physiological substrate of Akt.
  • Utilized in vitro and in vivo models to assess Akt phosphorylation of MstI.
  • Examined the effect of Akt phosphorylation on MstI cleavage by caspases and its kinase activity on FOXO3.

Main Results:

  • Akt directly binds and phosphorylates MstI at the Thr(387) residue.
  • Akt phosphorylation inhibits MstI's kinase activity towards FOXO3 and prevents its cleavage by caspases.
  • A phosphorylation-mimetic MstI mutant (T387E) blocked H2O2-induced FOXO3 nuclear translocation and apoptosis.

Conclusions:

  • Akt acts as a negative regulator of MstI, inhibiting MstI-driven apoptosis.
  • Akt-mediated phosphorylation of MstI promotes cell survival by preventing MstI activation and downstream effects on FOXO3.

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