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Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT

Amrik Singh1, Min Ye, Octavian Bucur

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.

Molecular Biology of the Cell
|January 30, 2010
PubMed

Insights

Protein phosphatase 2A (PP2A) dephosphorylates FOXO3a, enabling its nuclear translocation and transcriptional activation. This study reveals PP2A

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Transcription Regulation

Background:

  • FOXO3a, a transcription factor regulating cell survival, is controlled by phosphorylation and localization.
  • Kinases affecting FOXO3a are known, but the role of protein phosphatases (PPs) remains unclear.
  • Understanding FOXO3a regulation is crucial for cell survival pathways.

Purpose of the Study:

  • To investigate the role of protein phosphatases, specifically PP2A, in controlling FOXO3a subcellular localization and function.
  • To elucidate the interplay between PP2A, AKT, and 14-3-3 in regulating FOXO3a activity.

Main Methods:

  • Investigated the interaction between FOXO3a and PP2A.
  • Assessed the impact of 14-3-3 on PP2A activity towards FOXO3a phosphorylation sites.
  • Disrupted PP2A function to observe effects on FOXO3a localization and activation following AKT inhibition.

Main Results:

  • A significant interaction between FOXO3a and PP2A was identified.
  • 14-3-3 protein restrains PP2A activity on AKT phosphorylation sites (T32/S253) of FOXO3a.
  • PP2A-mediated dephosphorylation of T32/S253 is essential for 14-3-3 dissociation, nuclear translocation, and transcriptional activation of FOXO3a after AKT inhibition.

Conclusions:

  • Protein phosphatase 2A (PP2A) plays a critical role in regulating FOXO3a subcellular localization and transcriptional activation.
  • PP2A acts in concert with AKT and 14-3-3 to control FOXO3a dynamics.
  • This study reveals PP2A's involvement in dephosphorylating conserved AKT motifs within the FOXO family.

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