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

MPG-Autoren
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Rognoni,  Emanuel
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Widmaier,  Moritz
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Jakobson,  Madis
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Ruppert,  Raphael
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Ussar,  Siegfried
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Katsougkri,  Despoina
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Böttcher,  Ralph T.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Zitation

Rognoni, E., Widmaier, M., Jakobson, M., Ruppert, R., Ussar, S., Katsougkri, D., et al. (2014). Kindlin-1 controls Wnt and TGF-beta availability to regulate cutaneous stem cell proliferation. Nature Medicine, 20(4), 350-359. doi:10.1038/nm.3490.


Zitierlink: https://hdl.handle.net/11858/00-001M-0000-0019-8B93-8
Zusammenfassung
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 beta 1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting alpha(nu)beta(6) integrin-mediated transforming growth factor-beta (TGF-beta) activation and inhibiting Wnt-beta-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-beta-mediated growth-inhibitory signals and Wnt-beta-catenin-mediated growth-promoting signals.