title: A molecular switch for the orientation of epithelial cell polarization.
abstract: The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a β1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKCβII phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization.
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Bryant
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Roignot
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Arend W
authors.initials: AW
authors.lastname: Overeem
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Eastburn
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ewald
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158-2140, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158-2140, USA. Electronic address: keith.mostov@ucsf.edu.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000502:physiology*; D004848:Epithelium / Q000254:growth & development*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D009024:Morphogenesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D051417:Focal Adhesion Kinase 1; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; D010750:Phosphoproteins; D064546:Protein Kinase C beta; D054648:Protein Phosphatase 2; D034741:RNA, Small Interfering; D012795:Sialoglycoproteins; D017923:Sodium-Hydrogen Exchangers; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099149:Ezrin; C001643:podocalyxin; C093376:sodium-hydrogen exchanger regulatory factor