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Updated: May 4, 2026

Genetic Manipulation of Cerebellar Granule Neurons In Vitro and In Vivo to Study Neuronal Morphology and Migration
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FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours

Jae-Hong Kim1, Yong-Hak Kim2, Hong-Man Kim3

  • 11] College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Korea [2].

Nature Communications
|January 7, 2014
PubMed

Insights

The C134W mutation in FOXL2 drives ovarian granulosa cell tumor (GCT) development by promoting hyperphosphorylation, leading to protein degradation. Inhibiting GSK3β kinase represses GCT growth.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Ovarian granulosa cell tumors (GCTs) are frequently associated with the FOXL2 C134W mutation.
  • The precise mechanism by which this mutation contributes to GCT pathogenesis remains largely unknown.

Purpose of the Study:

  • To elucidate the pathophysiological role of the FOXL2 C134W mutation in GCT development.
  • To investigate the posttranslational modifications affecting FOXL2 stability and oncogenicity.

Main Methods:

  • Analysis of FOXL2 posttranslational modifications (phosphorylation, ubiquitination, SUMOylation).
  • Utilizing GSK3β and MDM2 inhibitors in cellular and xenograft models.
  • Correlating S33 phosphorylation status with FOXL2 oncogenicity in vivo.

Main Results:

  • The C134W mutation induces hyperphosphorylation of FOXL2 at serine 33 (S33) via GSK3β.
  • Hyperphosphorylated FOXL2 undergoes MDM2-mediated ubiquitination and proteasomal degradation.
  • Wild-type FOXL2, in contrast, is SUMOylated and stabilized due to underphosphorylation at S33.
  • Elevated S33 phosphorylation of FOXL2 is observed in GCT patients with the C134W mutation.
  • GSK3β inhibition significantly reduces GCT xenograft growth.

Conclusions:

  • Differential posttranslational modifications of FOXL2, specifically S33 phosphorylation, are critical in GCT development.
  • The FOXL2 C134W mutation promotes oncogenicity through GSK3β-mediated degradation.
  • Targeting GSK3β represents a potential therapeutic strategy for GCTs.

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