ArticleMolecular and cellular biology2011
A novel cyclic AMP/Epac1/CaMKI signaling cascade promotes GCM1 desumoylation and placental cell fusion.
Article in Molecular and cellular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 53 citations in OpenAlex.
- The influence of cell-cell fusion on cancer heterogeneity and its promise for targeted treatments.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Trophoblast Fusion Deficiency in Placenta-Related Pregnancy Disorders.Advances in experimental medicine and biology · 2026Review
- Downregulation of SPARC Expression Enhances the Fusion of BeWo Choriocarcinoma Cells.Reproductive sciences (Thousand Oaks, Calif.) · 2024Article
- A comprehensive review of human trophoblast fusion models: recent developments and challenges.Cell death discovery · 2023Review
- Laminin switches terminal differentiation fate of human trophoblast stem cells under chemically defined culture conditions.The Journal of biological chemistry · 2023Article
- Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction.Frontiers in endocrinology · 2023Review
- How trophoblasts fuse: an in-depth look into placental syncytiotrophoblast formation.Cellular and molecular life sciences : CMLS · 2022Review
- Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation.Nature communications · 2022Article
- Omics Approaches to Study Formation and Function of Human Placental Syncytiotrophoblast.Frontiers in cell and developmental biology · 2021Review
- New insights into the regulation of placental growth factor gene expression by the transcription factors GCM1 and DLX3 in human placenta.The Journal of biological chemistry · 2018Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction.Cell death & disease · 2017Article
- Article
- Endogenous Retroviruses: With Us and against Us.Frontiers in chemistry · 2017Review
- A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation.Molecular and cellular biology · 2016Article
- ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion.Cell death and differentiation · 2015Article
- Spatiotemporal regulation of cAMP signaling controls the human trophoblast fusion.Frontiers in pharmacology · 2015Article
- Review
- Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses.The Journal of clinical investigation · 2014Article
- Transglutaminase 2-dependent deamidation of glyceraldehyde-3-phosphate dehydrogenase promotes trophoblastic cell fusion.The Journal of biological chemistry · 2014Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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