10779/crick.12668828.v1 A Elbediwy A Elbediwy ZI Vincent-Mistiaen ZI Vincent-Mistiaen B Spencer-Dene B Spencer-Dene RK Stone RK Stone S Boeing S Boeing SK Wculek SK Wculek J Cordero J Cordero EH Tan EH Tan R Ridgway R Ridgway VG Brunton VG Brunton E Sahai E Sahai H Gerhardt H Gerhardt A Behrens A Behrens I Malanchi I Malanchi OJ Sansom OJ Sansom BJ Thompson BJ Thompson Integrin signalling regulates YAP and TAZ to control skin homeostasis The Francis Crick Institute 2020 Hippo pathway Integrin Stratified squamous epithelium TAZ Yes-associated protein Adaptor Proteins, Signal Transducing Animals Cell Cycle Proteins Cell Differentiation Cell Line Cell Nucleus Dasatinib Epithelium ErbB Receptors Gene Expression Regulation Homeostasis Humans Integrins Intracellular Signaling Peptides and Proteins Keratinocytes Mice Neoplasms, Squamous Cell Phosphatidylinositol 3-Kinases Phosphoproteins Protein Stability Protein Transport Signal Transduction Skin Stem Cells Transcription Factors Wound Healing src-Family Kinases Thompson FC001180 Malanchi FC001112 Behrens FC001039 Sahai FC001144 HP CB 06 Biological Sciences 11 Medical and Health Sciences 2020-07-17 16:38:54 Journal contribution https://crick.figshare.com/articles/journal_contribution/Integrin_signalling_regulates_YAP_and_TAZ_to_control_skin_homeostasis/12668828 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.