title: ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.
abstract: E-cadherin controls a wide array of cellular behaviors, including cell-cell adhesion, differentiation, and tissue development. We show here that E-cadherin is cleaved specifically by ADAM (a disintegrin and metalloprotease) 10 in its ectodomain. Analysis of ADAM10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes. ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration. Furthermore, the shedding of E-cadherin by ADAM10 modulates the beta-catenin subcellular localization and downstream signaling. ADAM10 overexpression in epithelial cells increased the expression of the beta-catenin downstream gene cyclin D1 dose-dependently and enhanced cell proliferation. In ADAM10-deficient mouse embryos, the C-terminal E-cadherin fragment is not generated, and the full-length protein accumulates, highlighting the in vivo relevance for ADAM10 in E-cadherin shedding. Our data strongly suggest that this protease constitutes a major regulatory element for the multiple functions of E-cadherin under physiological as well as pathological conditions.
authors.affiliation: Biochemical Institute and Department of Dermatology, Christian-Albrechts-University Kiel, D-24098 Kiel, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maretzky
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.forename: Julian
authors.initials: J
authors.lastname: Buchholz
authors.forename: Felix
authors.initials: F
authors.lastname: Scholz
authors.forename: Erhardt
authors.initials: E
authors.lastname: Proksch
authors.forename: Bart
authors.initials: B
authors.lastname: de Strooper
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
mesh_terms: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014945:Wound Healing; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human