Format

Send to

Choose Destination
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.

Author information

1
Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
2
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.
3
New York University, Langone School of Medicine, New York, New York, USA.
4
St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.

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.

Comment in

PMID:
24681597
PMCID:
PMC3982140
DOI:
10.1038/nm.3490
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center