title: The Cdc42 guanine nucleotide exchange factor FGD6 coordinates cell polarity and endosomal membrane recycling in osteoclasts.
abstract: The initial step of bone digestion is the adhesion of osteoclasts onto bone surfaces and the assembly of podosomal belts that segregate the bone-facing ruffled membrane from other membrane domains. During bone digestion, membrane components of the ruffled border also need to be recycled after macropinocytosis of digested bone materials. How osteoclast polarity and membrane recycling are coordinated remains unknown. Here, we show that the Cdc42-guanine nucleotide exchange factor FGD6 coordinates these events through its Src-dependent interaction with different actin-based protein networks. At the plasma membrane, FGD6 couples cell adhesion and actin dynamics by regulating podosome formation through the assembly of complexes comprising the Cdc42-interactor IQGAP1, the Rho GTPase-activating protein ARHGAP10, and the integrin interactors Talin-1/2 or Filamin A. On endosomes and transcytotic vesicles, FGD6 regulates retromer-dependent membrane recycling through its interaction with the actin nucleation-promoting factor WASH. These results provide a mechanism by which a single Cdc42-exchange factor controlling different actin-based processes coordinates cell adhesion, cell polarity, and membrane recycling during bone degradation.
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Steenblock
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Heckel
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Czupalla
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Espírito Santo
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Niehage
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sztacho
authors.affiliation: From the Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany bernard.hoflack@biotec.tu-dresden.de.
authors.forename: Bernard
authors.initials: B
authors.lastname: Hoflack
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D016764:Cell Polarity; D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C000592405:FGD6 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein
keywords: Actin; CDC42; FGD6; Membrane Recycling; Osteoclast; Podosome; Src