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.

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…YAP and TAZ also respond to the rigidity of the extracellular matrix, cell geometry, cell density, cell polarity, and the status of the actin cytoskeleton. Sensing of substrate stiffness by YAP/TAZ depends on the tension of the actin cytoskeleton (Zhang et al 2011;Elbediwy et al 2016). The AJ protein a-catenin limits YAP activity by modulating its interaction with 14-3-3 (Kanai et al 2000;Schlegelmilch et al 2011;Sambandam et al 2015).…”

YAP and TAZ in epithelial stem cells: A sensor for cell polarity, mechanical forces and tissue damage

“…The F-actin associated proteins Ajuba, Zyxin, and Src localise to adherens junctions and promote activation of Yorkie-target genes and tissue growth in the fly wing and eye [23,[42][43][44][45][46][47][48]. Since mammalian Src family kinases (Src, Fyn, Yes) are known to phosphorylate and activate mammalian homologues of Yorkie (YAP, or Yesassociated protein, and TAZ) [49,50], it is plausible that Ajuba and Zyxin act to promote Src activity at adherens junctions and thereby activate Yorkie to drive tissue growth. Alternatively, Ajuba and Zyxin may directly inhibit the Warts kinase, to reduce the inhibitory phosphorylation of Yorkie by this kinase [23].…”

“…The mammalian Yorkie homologs YAP and TAZ are clearly regulated by the presence or absence of an apical domain in mammalian epithelial cells [49]. In columnar epithelia, YAP and TAZ remain cytoplasmic, while in basal layer epithelial stem cells that lack an apical domain, YAP and TAZ localise to the nucleus [49].…”

“…The mammalian Yorkie homologs YAP and TAZ are clearly regulated by the presence or absence of an apical domain in mammalian epithelial cells [49]. In columnar epithelia, YAP and TAZ remain cytoplasmic, while in basal layer epithelial stem cells that lack an apical domain, YAP and TAZ localise to the nucleus [49]. The organisation of the bronchial epithelium is a good example of this phenomenon, and it has been shown that apical signalling requires CRB3, a Crumbs homolog [66] (Fig.…”

Producing tissue specific stem cells for regeneration: how YAP/TAZ may prove useful

“…They are key in regulating the switch between a proliferative and non-proliferative cell fate, but also regulate other cellular decisions and processes such as cell type determination, cytoskeletal dynamics, and cell-cell or cellmatrix interactions (2). While many progenitors express either YAP and/or TAZ, most mature cells lose expression of these proteins (3)(4)(5). Generally, dephosphorylated YAP/ TAZ is active and leads to tissue growth.…”