title: A PKA-ezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion.
abstract: 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.
authors: INSERM, U767, Paris, F-75006 France Université Paris Descartes, Paris F-75006, France PremUp, Paris, F-75006 France Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo N-0318, Norway Biotechnology Centre, University of Oslo, Oslo N-0317, Norway.
authors: Guillaume
authors: G
authors: Pidoux
authors: INSERM, U767, Paris, F-75006 France Université Paris Descartes, Paris F-75006, France.
authors: Pascale
authors: P
authors: Gerbaud
authors: CNRS, FRC3115, Centre de Recherche de Gif, IMAGIF, Plateforme de Microscopie Photonique, Gif-sur-Yvette, F-91198, France.
authors: Jim
authors: J
authors: Dompierre
authors: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo N-0318, Norway Biotechnology Centre, University of Oslo, Oslo N-0317, Norway.
authors: Birgitte
authors: B
authors: Lygren
authors: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo N-0318, Norway Biotechnology Centre, University of Oslo, Oslo N-0317, Norway.
authors: Therese
authors: T
authors: Solstad
authors: INSERM, U767, Paris, F-75006 France Université Paris Descartes, Paris F-75006, France PremUp, Paris, F-75006 France.
authors: Danièle
authors: D
authors: Evain-Brion
authors: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo N-0318, Norway Biotechnology Centre, University of Oslo, Oslo N-0317, Norway K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo N-0317, Norway K.G. Jebsen Centre for Cancer Immunotherapy, University of Oslo, Oslo N-0317, Norway Department of Infectious Diseases, Oslo University Hospital, N-0407 Oslo, Norway kjetil.tasken@ncmm.uio.no.
authors: Kjetil
authors: K
authors: Taskén
mesh_terms: D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation; D002459:Cell Fusion; D018031:Connexin 43 / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D018031:Connexin 43; D017868:Cyclic AMP-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D000099149:Ezrin
keywords: Cell fusion; Connexin 43; Ezrin; Gap junction; cAMP