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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism
  • Blister*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology
  • Cell Proliferation*
  • Disease Models, Animal
  • Epidermolysis Bullosa*
  • Hair Follicle / pathology
  • Integrin beta1 / metabolism
  • Integrins / metabolism
  • Keratinocytes / metabolism*
  • Mice
  • Mice, Transgenic
  • Periodontal Diseases*
  • Photosensitivity Disorders*
  • Signal Transduction
  • Skin / cytology*
  • Skin / pathology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Stem Cells / physiology*
  • Transforming Growth Factor beta / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / physiology
  • beta Catenin / metabolism


  • Antigens, Neoplasm
  • Carrier Proteins
  • Integrin beta1
  • Integrins
  • Transforming Growth Factor beta
  • Wnt Proteins
  • beta Catenin
  • integrin alphavbeta6
  • kindlin-1 protein, mouse

Supplementary concepts

  • Poikiloderma of Kindler