Possible role of the exchange protein directly activated by cyclic AMP (Epac) in the cyclic AMP-dependent functional differentiation and syncytialization of human placental BeWo cells

Yoshie, Mikihiro; Kaneyama, Kei; Kusama, Kaoru; Higuma, Chinatsu; Nishi, Hirotaka; Isaka, Keiichi; Tamura, Kazuhiro

doi:10.1093/humrep/deq190

Cited by 34 publications

(35 citation statements)

References 37 publications

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“…Moreover, introduction of the RNAi-resistant phosphomimetic mutant GCM1(S47D) into GCM1-knockdown BeWo cells not only reversed cell fusion defect but further enhanced cell-cell fusion. A recent report published during the course of this study showed that activation of Epac proteins by 8-CPT-AM promotes cell-cell fusion of BeWo cells (37). Although Epac1 and Rap1 were implicated as downstream effectors of 8-CPT-AM in that report, the mechanism underlying Epac-stimulated cell fusion was not clear.…”

Section: Discussionmentioning

confidence: 73%

A Novel Cyclic AMP/Epac1/CaMKI Signaling Cascade Promotes GCM1 Desumoylation and Placental Cell Fusion

Chang

Chen

2011

Molecular and Cellular Biology

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Cyclic AMP (cAMP) signaling and the placental transcription factor glial cell missing 1 (GCM1) regulate expression of syncytin-1 and -2 fusogenic proteins, which are critical for syncytiotrophoblast formation by trophoblast fusion. We recently revealed a cAMP/protein kinase A (PKA)/CBP signaling pathway that activates GCM1 by coordinating GCM1 phosphorylation and acetylation. In contrast, GCM1 activity is downregulated by sumoylation of Lys156. How GCM1 sumoylation is regulated was unknown. Here, we identify a novel PKA-independent cAMP signaling pathway as the critical regulator of GCM1 sumoylation. We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. Using RNA interference (RNAi), we further demonstrate that 8-(4-chlorophenylthio)-2-O-Me-cAMP-AM (8-CPT-AM), an Epac activator, stimulates syncytin-1 and -2 gene expression and cell fusion of placental BeWo cells in a GCM1-dependent manner. Importantly, the cell fusion defect in GCM1-knockdown BeWo cells can be reversed and enhanced by the RNAi-resistant phosphomimetic GCM1(S47D) mutant. Our study has identified a novel cAMP/Epac1/CaMKI/GCM1 signaling cascade that stimulates trophoblast fusion through promoting GCM1 phosphorylation and desumoylation.The syncytiotrophoblast in human placental villus is a multinucleated cell layer that mediates gas and nutrient transport between mother and fetus. Differentiation of the syncytiotrophoblast involves cell fusion of subjacent mononucleated cytotrophoblast cells. As the syncytiotrophoblast layer undergoes apoptosis and sheds into circulation, replenishment with a new syncytiotrophoblast layer is required to maintain its structural and functional integrity. In this regard, cyclic AMP (cAMP) is a key player for syncytiotrophoblast differentiation by stimulating placental cell fusion and syncytin gene expression (4,19,24,33). Stimulation of placental cell fusion by cAMP is suppressed by the protein kinase A (PKA) inhibitor H89, indicating that PKA is a critical downstream effector of cAMP signaling in the regulation of placental cell fusion (19).The placental transcription factor GCM1 (also known as GCMa) controls trophoblast fusion via transcriptional activation of two membrane fusogenic proteins, syncytin-1 and -2 (22, 38). An RNA interference (RNAi) study by Baczyk et al.(2) has shown that GCM1 is required for the cAMP stimulant forskolin to promote placental BeWo cell fusion. Indeed, GCM1 activity can be regulated by multiple posttranslational modifications, which may be critical to fine-tune its activity in the regulation of trophoblast fusion and syncytiotrophoblast differentiation. GCM1 is a labile protein subject to ubiquitination via the F-box protein FBW2 when the Ser322 residue in GCM1 is phosphorylated by glycogen synthase kinase 3␤ (GSK-3␤) (7,31,36). Our recent studies have demonstrated that PKA enhances the interact...

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Section: Discussionmentioning

confidence: 73%

A Novel Cyclic AMP/Epac1/CaMKI Signaling Cascade Promotes GCM1 Desumoylation and Placental Cell Fusion

Chang

Chen

2011

Molecular and Cellular Biology

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“…cAMP stimulates human chorionic gonadotropin (HCG), P4/3␤HSD1, and 11␤HSD2 expression and synthesis in the human placenta through PKA, whereas cell syncytialization and differentiation are regulated through exchange protein activated by cAMP instead (14). This suggests that although intracytoplasmic cAMP may coordinate many important physiological aspects of the trophoblast, additional factors bring specificity to this common pathway.…”

Section: Discussionmentioning

confidence: 99%

The Protein Kinase A Pathway Regulates CYP17 Expression and Androgen Production in the Human Placenta

Escobar

Carr

2011

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…For example, Epac signaling pathway is associated with the cAMPmediated functional differentiation (hCG production) and syncytialization of human BeWo trophoblasts. 19 Further report reveals that cAMP/Epac1/Rap1 signaling cascade stimulates BeWo trophoblast fusion through promoting placental transcription factor glial cell missing 1 phosphorylation, which is PKAindependent. 20 The Epac/Rap1 signaling pathway involves in cAMP-mediated decidualization of human endometrial stromal cells.…”

Section: Placental Villous Mesenchymal Cells Trigger Trophoblast Invamentioning

confidence: 96%

Placental villous mesenchymal cells trigger trophoblast invasion

Chen¹

2014

Cell Adhesion & Migration

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Possible role of the exchange protein directly activated by cyclic AMP (Epac) in the cyclic AMP-dependent functional differentiation and syncytialization of human placental BeWo cells

Abstract: The Epac signaling pathway may be associated with the cAMP-mediated functional differentiation and syncytialization of human trophoblasts.

Cited by 34 publications

References 37 publications

A Novel Cyclic AMP/Epac1/CaMKI Signaling Cascade Promotes GCM1 Desumoylation and Placental Cell Fusion

A Novel Cyclic AMP/Epac1/CaMKI Signaling Cascade Promotes GCM1 Desumoylation and Placental Cell Fusion

The Protein Kinase A Pathway Regulates CYP17 Expression and Androgen Production in the Human Placenta

Placental villous mesenchymal cells trigger trophoblast invasion

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