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Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization.

Adeline M Luperchio1, Daniel J Salamango1

  • 1Department of Microbiology, Immunology, and Molecular Genetics, UT Health Science Center, San Antonio, TX 78229, USA.

Cells
|March 12, 2025
PubMed
Summary

Protein Phosphatase 2A (PP2A) and AMP-activated protein kinase (AMPK) control forkhead box O (FoxO) protein nuclear entry. This process is crucial for cellular responses to metabolic changes and oxidative stress.

Keywords:
AKTFoxOPI3KPP2Asubcellular localizationtranscription factortumor suppressors

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Forkhead box O (FoxO) transcription factors are key regulators of glucose metabolism, stress resistance, DNA repair, and tumor suppression.
  • FoxO activity is modulated by signaling pathways and post-translational modifications, with phosphorylation promoting cytoplasmic retention.

Purpose of the Study:

  • To elucidate the mechanism of FoxO dephosphorylation and nuclear translocation.
  • To investigate the role of protein phosphatase 2A (PP2A) in regulating FoxO nuclear localization.

Main Methods:

  • Investigated the interplay between PP2A, AMP-activated protein kinase (AMPK), and FoxO family members.
  • Utilized chemical inhibitors, functional, genetic, and biochemical studies.
  • Analyzed FoxO-PP2A binding interfaces and mutations.

Main Results:

  • PP2A and AMPK cooperate to regulate nuclear translocation of multiple FoxO members under metabolic or oxidative stress.
  • Nuclear accumulation of FoxO proteins results from inhibited nuclear export, not enhanced import.
  • Identified specific PP2A complexes and binding motifs regulating FoxO nuclear translocation.
  • Altered PP2A binding affinity impacts FoxO nuclear translocation kinetics.

Conclusions:

  • PP2A and AMPK are critical regulators of FoxO nuclear translocation.
  • FoxO nuclear entry is primarily mediated by inhibition of nuclear export.
  • These findings provide mechanistic insights into FoxO regulation by metabolic and stress signals.