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-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.
Lin
Fang-Yu
FY
Graduate Institute of Biochemical Sciences, National Taiwan University, Nankang, Taipei 115, Taiwan.
Chang
Ching-Wen
CW
Cheong
Mei-Leng
ML
Chen
Hsei-Chorn
HC
Lee
Der-Yen
DY
Chang
Geen-Dong
GD
Chen
Hungwen
H
D000107:Acetylation; D002459:Cell Fusion; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology; D054875:Ubiquitination
D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D012694:Serine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C497817:DUSP23 protein, human; D054637:Dual-Specificity Phosphatases