title: Transmembrane proteoglycans control stretch-activated channels to set cytosolic calcium levels.
abstract: Transmembrane heparan sulfate proteoglycans regulate multiple aspects of cell behavior, but the molecular basis of their signaling is unresolved. The major family of transmembrane proteoglycans is the syndecans, present in virtually all nucleated cells, but with mostly unknown functions. Here, we show that syndecans regulate transient receptor potential canonical (TRPCs) channels to control cytosolic calcium equilibria and consequent cell behavior. In fibroblasts, ligand interactions with heparan sulfate of syndecan-4 recruit cytoplasmic protein kinase C to target serine714 of TRPC7 with subsequent control of the cytoskeleton and the myofibroblast phenotype. In epidermal keratinocytes a syndecan-TRPC4 complex controls adhesion, adherens junction composition, and early differentiation in vivo and in vitro. In Caenorhabditis elegans, the TRPC orthologues TRP-1 and -2 genetically complement the loss of syndecan by suppressing neuronal guidance and locomotory defects related to increases in neuronal calcium levels. The widespread and conserved syndecan-TRPC axis therefore fine tunes cytoskeletal organization and cell behavior.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gopal
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Søgaard
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Hinke A B
authors.initials: HA
authors.lastname: Multhaupt
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Csilla
authors.initials: C
authors.lastname: Pataki
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Okina
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xian
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Pedersen
authors.affiliation: Department of Pharmacology, Center for Lung Biology, University of South Alabama, Mobile, AL 36688 Department of Medicine, Center for Lung Biology, University of South Alabama, Mobile, AL 36688.
authors.forename: Troy
authors.initials: T
authors.lastname: Stevens
authors.affiliation: Max Planck Institute of Neurobiology, 82152 Martinsried, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Griesbeck
authors.affiliation: Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115 Division of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Pyong Woo
authors.initials: PW
authors.lastname: Park
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Roger
authors.initials: R
authors.lastname: Pocock
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark john.couchman@bric.ku.dk.
authors.forename: John R
authors.initials: JR
authors.lastname: Couchman
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; C508304:SDC4 protein, human; C508306:Sdc4 protein, mouse; C508307:Sdc4 protein, rat; D053671:Syndecan-4; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D011493:Protein Kinase C; D002118:Calcium