title: E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion.
abstract: Desmosomes provide strong intercellular cohesion essential for the integrity of cells and tissues exposed to continuous mechanical stress. For desmosome assembly, constitutively synthesized desmosomal cadherins translocate to the cell-cell border, cluster and mature in the presence of Ca(2+) to stable cell contacts. As adherens junctions precede the formation of desmosomes, we investigated in this study the relationship between the classical cadherin E-cadherin and the desmosomal cadherin Desmoglein 3 (Dsg3), the latter of which is indispensable for cell-cell adhesion in keratinocytes. By using autoantibodies from patients with the blistering skin disease pemphigus vulgaris (PV), we showed in loss of function studies that E-cadherin compensates for effects of desmosomal disassembly. Overexpression of E-cadherin reduced the loss of cell cohesion induced by PV autoantibodies and attenuated activation of p38 MAPK. Silencing of E-cadherin abolished the localization of Dsg3 at the membrane and resulted in a shift of Dsg3 from the cytoskeletal to the non-cytoskeletal protein pool which conforms to the notion that E-cadherin regulates desmosome assembly. Mechanistically, we identified a complex consisting of extradesmosomal Dsg3, E-cadherin, β-catenin and Src and that the stability of this complex is regulated by Src. Moreover, Dsg3 and E-cadherin are phosphorylated on tyrosine residues in a Src-dependent manner and Src activity is required for recruiting Dsg3 to the cytoskeletal pool as well as for desmosome maturation towards a Ca(2+)-insensitive state. Our data provide new insights into the role of E-cadherin and the contribution of Src signaling for formation and maintenance of desmosomal junctions.
authors.affiliation: Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Rötzer
authors.affiliation: Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hartlieb
authors.affiliation: Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Vielmuth
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gliem
authors.affiliation: Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany. volker.spindler@med.uni-muenchen.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Spindler
authors.affiliation: Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany. jens.waschke@med.uni-muenchen.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D051184:Desmoglein 3 / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D003896:Desmosomes / Q000378:metabolism / Q000502:physiology*; D020868:Gene Silencing; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008958:Models, Molecular; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D015820:Cadherins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D016392:Proto-Oncogene Proteins pp60(c-src)
keywords: Calcium switch assay; Desmoglein 3 (Dsg3); Desmosome; E-cadherin; Pemphigus; Src signaling