title: Integrin signalling regulates YAP and TAZ to control skin homeostasis.
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.
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elbediwy
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Zoé I
authors.initials: ZI
authors.lastname: Vincent-Mistiaen
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Stone
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boeing
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Wculek
authors.affiliation: The Beatson Institute, Switchback Rd, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Cordero
authors.affiliation: The Beatson Institute, Switchback Rd, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Ee H
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ridgway
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Val G
authors.initials: VG
authors.lastname: Brunton
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Malanchi
authors.affiliation: The Beatson Institute, Switchback Rd, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK barry.thompson@crick.ac.uk.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Thompson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018307:Neoplasms, Squamous Cell / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D014945:Wound Healing / Q000187:drug effects; D000091102:YAP-Signaling Proteins; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D000069439:Dasatinib; D066246:ErbB Receptors; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; D019061:src-Family Kinases; C551991:WWTR1 protein, human; C517794:Wwtr1 protein, mouse; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse
keywords: Hippo pathway; Integrin; Stratified squamous epithelium; TAZ; Yes-associated protein