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mTORC2 Is the Major Second Layer Kinase Negatively Regulating FOXO3 Activity.

Lucia Jimenez1, Carlos Amenabar1, Victor Mayoral-Varo1

  • 1Institute of Biomedical Research Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.

Molecules (Basel, Switzerland)
|September 9, 2022
PubMed
Summary

Pharmacological targeting of kinases influences Forkhead box O (FOXO) protein activity. Inhibition of mTORC2, but not mTORC1, effectively promotes nuclear translocation of FOXO3, highlighting its role in regulating FOXO signaling.

Keywords:
FOXOagingcancerchemical biologyhigh content screeningkinasesmTOR

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Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Pharmacology

Background:

  • Forkhead box O (FOXO) proteins are crucial transcription factors implicated in cancer and aging.
  • FOXO activity is regulated by post-translational modifications, offering potential for pharmacological intervention.
  • Protein kinases play a significant role in modulating FOXO signaling pathways.

Purpose of the Study:

  • To investigate the effects of specific kinase inhibitors on FOXO3 activity and localization.
  • To identify key kinases regulating FOXO3 nuclear translocation and transcriptional activity.
  • To elucidate the role of mTORC1 and mTORC2 in FOXO regulation.

Main Methods:

  • Utilized specific inhibitors against PI3K, mTOR, MEK, ALK, and other receptor tyrosine kinases (RTKs).
  • Assessed FOXO3 nuclear translocation, phosphorylation status of AKT, FOXO3, and ERK.
  • Measured FOXO-dependent transcriptional activity and subcellular localization of other FOXO isoforms.

Main Results:

  • Inhibition of PI3K promoted FOXO3 nuclear entry; dual PI3K/mTOR inhibitors were more potent than PI3Kδ inhibitors.
  • Specific inhibition of mTOR (affecting both mTORC1 and mTORC2) potently induced FOXO3 nuclear translocation.
  • Rapamycin (mTORC1 specific) did not affect FOXO3 localization, while MAPK pathway inhibition had no effect.
  • Upstream RTK inhibition showed only weak induction of nuclear FOXO3.

Conclusions:

  • mTORC2 is identified as the primary kinase negatively regulating FOXO activity.
  • Targeting mTORC2 presents a promising therapeutic strategy for modulating FOXO signaling in cancer and aging.
  • Understanding kinase regulation of FOXO proteins is critical for developing novel treatments.