Integrin signalling regulates YAP and TAZ to control skin homeostasis

Development. 2016 May 15;143(10):1674-87. doi: 10.1242/dev.133728. Epub 2016 Mar 17.

Abstract

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

Keywords: Hippo pathway; Integrin; Stratified squamous epithelium; TAZ; Yes-associated protein.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Dasatinib / pharmacology
  • Epithelium / drug effects
  • Epithelium / metabolism
  • ErbB Receptors / metabolism
  • Gene Expression Regulation / drug effects
  • Homeostasis* / drug effects
  • Humans
  • Integrins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Mice
  • Neoplasms, Squamous Cell / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism*
  • Protein Stability / drug effects
  • Protein Transport / drug effects
  • Signal Transduction* / drug effects
  • Skin / drug effects
  • Skin / metabolism*
  • Skin / pathology
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Wound Healing / drug effects
  • YAP-Signaling Proteins
  • src-Family Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Integrins
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Yap1 protein, mouse
  • ErbB Receptors
  • src-Family Kinases
  • Dasatinib