Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation

Glial cells missing homolog 1 (GCM1) is a transcription factor essential for placental development. GCM1 promotes syncytiotrophoblast formation and placental vasculogenesis by activating fusogenic and proangiogenic gene expression in placenta. GCM1 activity is regulated by multiple post-translationa...

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Bibliographic Details
Published in:Nucleic acids research 2011-02, Vol.39 (3), p.848-861
Main Authors: Lin, Fang-Yu, Chang, Ching-Wen, Cheong, Mei-Leng, Chen, Hsei-Chorn, Lee, Der-Yen, Chang, Geen-Dong, Chen, Hungwen
Format: Article
Language:English
Subjects:
Acetylation
Cell Fusion
Cell Line
Cyclic AMP
Cyclic AMP - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Dephosphorylation
Dual-Specificity Phosphatases - metabolism
Gene expression
Gene Regulation, Chromatin and Epigenetics
Glial cells
Humans
Nuclear Proteins - chemistry
Nuclear Proteins - metabolism
Phosphorylation
Placenta
Post-translation
Serine - metabolism
Transcription factors
Transcription Factors - chemistry
Transcription Factors - metabolism
Trophoblasts - cytology
Trophoblasts - enzymology
Ubiquitination
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Summary:Glial cells missing homolog 1 (GCM1) is a transcription factor essential for placental development. GCM1 promotes syncytiotrophoblast formation and placental vasculogenesis by activating fusogenic and proangiogenic gene expression in placenta. GCM1 activity is regulated by multiple post-translational modifications. The cAMP/PKA-signaling pathway promotes CBP-mediated GCM1 acetylation and stabilizes GCM1, whereas hypoxia-induced GSK-3β-mediated phosphorylation of Ser322 causes GCM1 ubiquitination and degradation. How and whether complex modifications of GCM1 are coordinated is not known. Here we show that the interaction of GCM1 and dual-specificity phosphatase 23 (DUSP23) is enhanced by PKA-dependent phosphorylation of GCM1 on Ser269 and Ser275. The recruitment of DUSP23 reverses GSK-3β-mediated Ser322 phosphorylation, which in turn promotes GCM1 acetylation, stabilization and activation. Supporting a central role in coordinating GCM1 modifications, knockdown of DUSP23 suppressed GCM1 target gene expression and placental cell fusion. Our study identifies DUSP23 as a novel factor that promotes placental cell fusion and reveals a complex regulation of GCM1 activity by coordinated phosphorylation, dephosphorylation and acetylation.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkq838