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AKT Regulates Mitotic Progression of Mammalian Cells by Phosphorylating MASTL, Leading to Protein Phosphatase 2A

Irfana Reshi1, Misbah Un Nisa2, Umer Farooq1

  • 1Department of Biotechnology, University of Kashmir, Srinagar, India.

Molecular and Cellular Biology
|March 4, 2020
PubMed

Insights

AKT phosphorylates MASTL at T299, enhancing its activity and promoting mitosis. This AKT-MASTL axis boosts cancer cell proliferation, offering new therapeutic targets for colorectal cancer.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Microtubule-associated serine/threonine kinase like (MASTL), or Greatwall (Gwl) kinase, regulates mitosis by inhibiting protein phosphatase 2A (PP2A) and activating cyclin-dependent kinase 1 (CDK1).
  • MASTL is implicated in various cancers and tumor recurrence, with its activation mechanism incompletely understood.
  • CDK1-mediated phosphorylation is known to activate MASTL, but other contributing factors remain elusive.

Purpose of the Study:

  • To elucidate the complete mechanism of MASTL activation during mitosis.
  • To investigate the role of AKT in MASTL activation and its downstream effects on mitotic progression.
  • To determine the interplay between AKT, MASTL, and cancer cell proliferation.

Main Methods:

  • Phosphorylation site mapping of MASTL.
  • In vitro kinase assays to assess AKT and CDK1 activity on MASTL.
  • Cellular assays in colorectal cancer lines to evaluate MASTL inhibition/silencing effects on AKT-mediated proliferation.
  • Western blotting and immunofluorescence to detect protein phosphorylation and localization.

Main Results:

  • AKT phosphorylates MASTL at threonine residue 299 (T299), a critical site for MASTL activation.
  • AKT enhances CDK1-mediated phosphorylation of MASTL, leading to increased MASTL activity.
  • Activated MASTL promotes mitotic progression via PP2A inhibition.
  • MASTL activation by AKT potentiates the oncogenic potential of AKT, driving proliferation in colorectal cancer cells.
  • Inhibition or silencing of MASTL attenuates AKT-driven proliferation in colorectal cancer cell lines.

Conclusions:

  • AKT plays a significant role in mammalian cell mitosis through the phosphorylation and activation of MASTL.
  • The AKT-MASTL signaling pathway is crucial for mitotic progression and contributes to cancer cell proliferation.
  • Targeting the AKT-MASTL axis presents a potential therapeutic strategy for cancers where this pathway is dysregulated.
Keywords:
AktGreatwall kinaseMASTLPP2Acancermitosis

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