1. A PKA-ezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion
- Author
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Jim Dompierre, Therese Solstad, Kjetil Taskén, Danièle Evain-Brion, Guillaume Pidoux, Pascale Gerbaud, Birgitte Lygren, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo (UiO)-Oslo University Hospital [Oslo], Plate Forme Microscopie & Biologie Cellulaire, Imagif IFR87, FRC3115, Centre National de la Recherche Scientifique (CNRS), Jebsen Inflammation Research Centre, University of Oslo (UiO), Jebsen Centre for Cancer Immunotherapy, Oslo University Hospital [Oslo], Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Pidoux, Guillaume
- Subjects
medicine.medical_specialty ,endocrine system ,Immunoprecipitation ,Gap junction ,[SDV]Life Sciences [q-bio] ,Connexin ,Cell Communication ,Ezrin ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Internal medicine ,cAMP ,medicine ,Humans ,Protein kinase A ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Cell fusion ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology ,reproductive and urinary physiology ,030304 developmental biology ,0303 health sciences ,Syncytium ,Gap Junctions ,Membrane Proteins ,Cell Differentiation ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,Cell biology ,Trophoblasts ,[SDV] Life Sciences [q-bio] ,Cytoskeletal Proteins ,Endocrinology ,030220 oncology & carcinogenesis ,Connexin 43 ,Phosphorylation ,Female ,Cytotrophoblasts ,Signal Transduction - Abstract
International audience; Cell fusion occurs as part of the differentiation of some cell types, including myotubes in muscle and osteoclasts in remodeling bone. In the human placenta, mononuclear cytotrophoblasts in a human chorionic gonadotropin (hCG)-driven process fuse to form multinucleated syncytia that allow the exchange of nutrients and gases between the maternal and fetal circulation. Experiments in which protein kinase A (PKA) is displaced from A-kinase anchoring proteins (AKAPs), or in which specific AKAPs are depleted by siRNA-mediated knockdown, point to ezrin as a scaffold required for hCG-, cAMP-and PKA-mediated regulation of the fusion process. By a variety of immunoprecipitation and immunolocalization experiments, we show that ezrin directs PKA to a molecular complex of connexin 43 (Cx43, also known as GJA1) and zona occludens-1 (ZO-1, also known as TJP1). A combination of knockdown experiments and reconstitution with ezrin or Cx43 with or without the ability to bind to its interaction partner or to PKA demonstrate that ezrin-mediated coordination of the localization of PKA and Cx43 is necessary for discrete control of Cx43 phosphorylation and hCG-stimulated gap junction communication that triggers cell fusion in cytotrophoblasts.
- Published
- 2014
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