title: Keratins Stabilize Hemidesmosomes through Regulation of β4-Integrin Turnover.
abstract: Epidermal integrity and wound healing depend on remodeling of cell-matrix contacts including hemidesmosomes. Mutations in β4-integrin and plectin lead to severe epidermolysis bullosa (EB). Whether mutations in keratins K5 or K14, which cause EB simplex, also compromise cell-matrix adhesion through altering hemidesmosomal components is not well investigated. In particular, the dependence of β4-integrin endocytosis and turnover on keratins remains incompletely understood. Here, we show that the absence of keratins causes loss of plectin-β4-integrin interaction and elevated β4-integrin phosphorylation at Ser1354 and Ser1362. This triggered a caveolin-dependent endocytosis of β4-integrin but not of other integrins through Rab5 and Rab11 compartments in keratinocytes. Expressing a phospho-deficient β4-integrin mutant reduces β4-integrin endocytosis and rescues plectin localization in keratin-free cells. β4-integrin phosphorylation in the absence of keratins resulted from elevated Erk1/2 activity downstream of increased EGFR and PKCα signaling. Further, increased Erk1/2 phosphorylation and altered plectin localization occur in keratin-deficient mouse epidermis in vivo. Strikingly, expression of the K14-R125P EBS mutant also resulted in plectin mislocalization and elevated β4-integrin turnover, suggesting disease relevance. Our data underscore a major role of keratins in controlling β4-integrin endocytosis involving a plectin-Erk1/2-dependent mechanism relevant for epidermal differentiation and pathogenesis.
authors: TRM Leipzig & Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, Leipzig, Germany.
authors: Kristin
authors: K
authors: Seltmann
authors: Department of Biosciences and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors: Fang
authors: F
authors: Cheng
authors: Department of Biochemistry and Cell Biology, Max F, Perutz Laboratories, University of Vienna, Vienna, Austria.
authors: Gerhard
authors: G
authors: Wiche
authors: Department of Biosciences and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors: John E
authors: JE
authors: Eriksson
authors: TRM Leipzig & Institute of Biology, Division of Cell and Developmental Biology, University of Leipzig, Leipzig, Germany. Electronic address: thomas.magin@trm.uni-leipzig.de.
authors: Thomas M
authors: TM
authors: Magin
mesh_terms: D000818:Animals; D022461:Caveolins / Q000378:metabolism; D002469:Cell Separation; D004705:Endocytosis; D004817:Epidermis / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D036681:Fluorescence Recovery After Photobleaching; D005786:Gene Expression Regulation; D005838:Genotype; D022002:Hemidesmosomes / Q000378:metabolism*; D039663:Integrin beta4 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D007633:Keratins / Q000378:metabolism*; D007834:Lasers; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D051190:Plectin / Q000378:metabolism; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D022461:Caveolins; D066246:ErbB Receptors; D039663:Integrin beta4; D007633:Keratins; D051190:Plectin; D051571:Protein Kinase C-alpha; D012694:Serine; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins