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Nat Med. 2014 Apr;20(4):350-9. doi: 10.1038/nm.3490. Epub 2014 Mar 30.

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

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Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
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.
New York University, Langone School of Medicine, New York, New York, USA.
St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.


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.

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