title: Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation.
abstract: Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Rognoni
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Widmaier
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Madis
authors.initials: M
authors.lastname: Jakobson
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Ruppert
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ussar
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Despoina
authors.initials: D
authors.lastname: Katsougkri
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Böttcher
authors.affiliation: 1] Department of Dermatology, King Edward VII Hospital, Windsor, UK. [2] St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.
authors.forename: Joey E
authors.initials: JE
authors.lastname: Lai-Cheong
authors.affiliation: New York University, Langone School of Medicine, New York, New York, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.affiliation: St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001768:Blister; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004820:Epidermolysis Bullosa; D018859:Hair Follicle / Q000473:pathology; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010510:Periodontal Diseases; D010787:Photosensitivity Disorders; D015398:Signal Transduction; D012867:Skin / Q000166:cytology* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D019012:Integrin beta1; D016023:Integrins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; C073878:integrin alphavbeta6; C534220:kindlin-1 protein, mouse