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Greatwall promotes cell transformation by hyperactivating AKT in human malignancies

Jorge Vera1, Lydia Lartigue2, Suzanne Vigneron1

  • 1Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.

Elife
|November 28, 2015
PubMed

Insights

Greatwall (GWL) kinase overexpression drives cancer by activating the oncogenic AKT kinase. GWL promotes AKT hyperactivation through PHLPP phosphatase degradation, independent of endosulfines, and is found in colorectal tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Protein phosphatase 2 (PP2A) is a tumor suppressor frequently inactivated in cancer.
  • A novel pathway involving Greatwall (GWL) kinase and endosulfines regulates PP2A activity during mitosis.
  • GWL activation leads to endosulfine phosphorylation, inhibiting PP2A.

Purpose of the Study:

  • To investigate the role of GWL kinase overexpression in cancer development.
  • To elucidate the mechanism by which GWL influences cancer cell transformation and invasiveness.
  • To determine the clinical relevance of GWL expression in human malignancies.

Main Methods:

  • Analysis of GWL overexpression effects on cell transformation and invasion.
  • Investigation of AKT kinase phosphorylation status in response to GWL.
  • Examination of the interplay between GWL, endosulfines, GSK3, and PHLPP phosphatase.
  • Assessment of GWL expression in human colorectal tumor tissues.

Main Results:

  • GWL overexpression promotes cell transformation and enhances invasive capacities.
  • GWL induces AKT hyperphosphorylation, which is independent of endosulfines.
  • GWL triggers GSK3 kinase dephosphorylation, leading to SCF-dependent degradation of PHLPP phosphatase.
  • PHLPP phosphatase degradation results in sustained AKT dephosphorylation inhibition.
  • GWL is frequently overexpressed in human colorectal tumors.

Conclusions:

  • GWL acts as a human oncoprotein by promoting AKT hyperactivation.
  • GWL facilitates AKT hyperactivation via PHLPP phosphatase degradation, contributing to malignancies.
  • GWL overexpression is a significant factor in human cancer development and progression.
Keywords:
AktGreatwallPHLPPPP2Acell biologycell invasionhumanoncogene

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