Integrin signalling regulates YAP/TAZ to control skin homeostasis

• Published in: Development (Cambridge) Vol. 143; no. 10; pp. 1674 - 1687
• Main Authors: Elbediwy, A., Vincent-Mistiaen, Z. I., Spencer-Dene, B., Stone, R. K., Boeing, S., Wculek, S. K., Cordero, J., Tan, E. H., Ridgway, R., Brunton, V. G., Sahai, E., Gerhardt, H., Behrens, A., Malanchi, I., Sansom, O. J., Thompson, B. J.
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.05.2016
• Subjects: 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; src-Family Kinases - metabolism; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells and Regeneration; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Wound Healing - drug effects; YAP-Signaling Proteins; Yes-associated protein; Hippo pathway; Integrin; Stratified squamous epithelium; TAZ
• ISSN: 0950-1991; 1477-9129; 1477-9129
• DOI: 10.1242/dev.133728

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 YAP and TAZ are nuclear localised 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 YAP/TAZ nuclear localisation 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. In contrast, columnar epithelia differentiate an apical domain that recruits CRB3, MERLIN, KIBRA and SAV 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.