Integrin signalling regulates YAP and TAZ to control skin homeostasis
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Ahmed Elbediwy ZI Vincent-Mistiaen B Spencer-Dene Richard Stone S Boeing SK Wculek J Cordero EH Tan R Ridgway VG Brunton Erik Sahai H Gerhardt Axel Behrens Ilaria Malanchi OJ Sansom BJ ThompsonAbstract
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.
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Journal Development
Volume 143
Issue number 10
Pages 1674-1687
Available online
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Publisher website (DOI) 10.1242/dev.133728
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Europe PubMed Central 26989177
Pubmed 26989177
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