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The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner

Belén Sanz-Castillo1, Begoña Hurtado1, Diana Vara-Ciruelos1

  • 1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

The EMBO Journal
|November 10, 2022
PubMed

Insights

The MASTL kinase regulates cell metabolism by controlling the AKT-mTOR pathway. Inhibiting MASTL boosts AKT activity and glucose uptake, impacting metabolic homeostasis.

Area of Science:

  • Cell Biology
  • Metabolism
  • Signal Transduction

Background:

  • The AKT-mTOR pathway is crucial for cell growth and metabolism.
  • A feedback loop normally restrains AKT activity during sustained mTOR signaling.
  • Mechanisms controlling this feedback loop remain incompletely understood.

Purpose of the Study:

  • To investigate the role of MASTL/Greatwall kinase in regulating the AKT-mTOR pathway.
  • To elucidate how MASTL controls feedback mechanisms limiting AKT activity.

Main Methods:

  • Genetic depletion of MASTL in cellular and mouse models.
  • Phosphorylation analysis of key pathway components (IRS1, GRB10).
  • Assessment of PI3K-AKT and mTORC1 signaling activity.
  • Measurement of glucose uptake and glucose tolerance.

Main Results:

  • MASTL sustains mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10, inhibiting PI3K-AKT.
  • Genetic MASTL depletion leads to inefficient feedback and AKT hyperactivity.
  • These effects were rescued by phosphomimetic ENSA/ARPP19 or PP2A/B55 inhibition.
  • MASTL is phosphorylated by mTORC1, linking it to the feedback loop.
  • MASTL downregulation increased glucose uptake and improved glucose tolerance in mice.

Conclusions:

  • MASTL acts as a critical regulator of the AKT-mTOR pathway feedback loop.
  • The MASTL-PP2A/B55 kinase-phosphatase module is vital for metabolic homeostasis.
  • Targeting MASTL may offer therapeutic potential for metabolic disorders.
Keywords:
AKTMASTLcell cycleglucose homeostasismTOR

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