title: Keratins control intercellular adhesion involving PKC-α-mediated desmoplakin phosphorylation.
abstract: Maintenance of epithelial cell adhesion is crucial for epidermal morphogenesis and homeostasis and relies predominantly on the interaction of keratins with desmosomes. Although the importance of desmosomes to epidermal coherence and keratin organization is well established, the significance of keratins in desmosome organization has not been fully resolved. Here, we report that keratinocytes lacking all keratins show elevated, PKC-α-mediated desmoplakin phosphorylation and subsequent destabilization of desmosomes. We find that PKC-α activity is regulated by Rack1-keratin interaction. Without keratins, desmosomes assemble but are endocytosed at accelerated rates, rendering epithelial sheets highly susceptible to mechanical stress. Re-expression of the keratin pair K5/14, inhibition of PKC-α activity, or blocking of endocytosis reconstituted both desmosome localization at the plasma membrane and epithelial adhesion. Our findings identify a hitherto unknown mechanism by which keratins control intercellular adhesion, with potential implications for tumor invasion and keratinopathies, settings in which diminished cell adhesion facilitates tissue fragility and neoplastic growth.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kröger
authors.forename: Fanny
authors.initials: F
authors.lastname: Loschke
authors.forename: Nicole
authors.initials: N
authors.lastname: Schwarz
authors.forename: Reinhard
authors.initials: R
authors.lastname: Windoffer
authors.forename: Rudolf E
authors.initials: RE
authors.lastname: Leube
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D051180:Desmoplakins / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism / Q000648:ultrastructure; D034281:Dynamins / Q000378:metabolism / Q000502:physiology; D004705:Endocytosis; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D007633:Keratins / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: D051180:Desmoplakins; D007633:Keratins; D051571:Protein Kinase C-alpha; D034281:Dynamins