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

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.

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Nat Med . Author manuscript; available in PMC 2014 October 01
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 Creators:
Rognoni, Emanuel1, Author              
Widmaier, Moritz1, Author              
Jakobson, Madis1, Author              
Ruppert, Raphael1, Author              
Ussar, Siegfried1, Author              
Katsougkri, Despoina1, Author              
Böttcher, Ralph T.1, Author              
Lai-Cheong, Joey E.2, Author
Rifkin, Daniel B.2, Author
McGrath, John A.2, Author
Fässler, Reinhard1, Author              
Affiliations:
1Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
2external, ou_persistent22              

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Free keywords: HAIR FOLLICLE MORPHOGENESIS; ADULT-MOUSE EPIDERMIS; KINDLER-SYNDROME; FOCAL ADHESION; COMPREHENSIVE GUIDE; TUMOR-INDUCTION; SKIN; ACTIVATION; EXPRESSION; CATENIN
 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 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.

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Language(s): eng - English
 Dates: 2013-11-142014-02-032014-03-302014-04
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000334361500015
DOI: 10.1038/nm.3490
 Degree: -

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Project name : Integrin: signalling from the tail and the hub (SIGNAL2THEHUB) ERC-2012-ADG
Grant ID : 322652
Funding program : Funding Programme 7 (FP7)
Funding organization : European Commission (EC)

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Title: Nature Medicine
  Other : Nat. Med.
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Co.
Pages: - Volume / Issue: 20 (4) Sequence Number: - Start / End Page: 350 - 359 Identifier: ISSN: 1078-8956
CoNE: https://pure.mpg.de/cone/journals/resource/954925606824