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Kindlin-1 controls Wnt and TGF-beta availability to regulate cutaneous stem cell proliferation

Research output: Contribution to journalArticlepeer-review

Emanuel Rognoni, Moritz Widmaier, Madis Jakobson, Raphael Ruppert, Siegfried Ussar, Despoina Katsougkri, Ralph T Böttcher, Joey E Lai-Cheong, Daniel B Rifkin, John A McGrath, Reinhard Fässler

Original languageEnglish
Pages (from-to)350-359
Number of pages13
JournalNature Medicine
Issue number4
Early online date30 Mar 2014
E-pub ahead of print30 Mar 2014
PublishedApr 2014

King's Authors


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 αvβ6 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.

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