FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours

Jae-Hong Kim, Yong-Hak Kim, Hong-Man Kim, Ho-Oak Park, Nam-Chul Ha, Tae Heon Kim, Mira Park, Kangseok Lee () and Jeehyeon Bae ()
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Jae-Hong Kim: College of Pharmacy, Chung-Ang University
Yong-Hak Kim: Catholic University of Daegu School of Medicine
Hong-Man Kim: College of Pharmacy, Chung-Ang University
Ho-Oak Park: College of Pharmacy, Chung-Ang University
Nam-Chul Ha: Pusan National University
Tae Heon Kim: CHA University
Mira Park: College of Pharmacy, Chung-Ang University
Kangseok Lee: Chung-Ang University
Jeehyeon Bae: College of Pharmacy, Chung-Ang University

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Approximately 97% of patients with ovarian granulosa cell tumours (GCTs) bear the C134W mutation in FOXL2; however, the pathophysiological mechanism of this mutation is unknown. Here we report how this mutation affects GCT development. Sequential posttranslational modifications of the C134W mutant occur where hyperphosphorylation at serine 33 (S33) by GSK3β induces MDM2-mediated ubiquitination and proteasomal degradation. In contrast, S33 of wild-type FOXL2 is underphosphorylated, leading to its SUMOylation and stabilization. This prominent hyperphosphorylation is also observed at S33 of FOXL2 in GCT patients bearing the C134W mutation. In xenograft mice, the S33 phosphorylation status correlates with the oncogenicity of FOXL2, and the inhibition of GSK3β efficiently represses GCT growth. These findings reveal a previously unidentified regulatory mechanism that determines the oncogenic attributes of the C134W mutation via differential posttranslational modifications of FOXL2 in GCT development.

Date: 2014
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DOI: 10.1038/ncomms3936

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