Integrin signalling regulates YAP/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.

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

“…9a,b). Consistent with YAP/TAZ being upregulated during epidermal development and wound healing, rather than in steady-state adult epidermis304142, we observed reduced IFE proliferation in neonatal (P5) but not adult WBP2 knockout mice (Fig. 4a,b and Supplementary Fig.…”

“…It is well documented that YAP and TAZ are required for normal epidermal development and hair growth in the mouse304142, and YAP and TAZ drive pro-tumorigenic signals in mouse and human cSCC3043. Nevertheless, there is ambiguity about YAP/TAZ function: YAP and TAZ are largely dispensible for homoeostasis of the IFE in adult mouse skin3042, and in cSCC both growth-promoting and growth-inhibiting functions have been documented4344.…”

“…Nevertheless, there is ambiguity about YAP/TAZ function: YAP and TAZ are largely dispensible for homoeostasis of the IFE in adult mouse skin3042, and in cSCC both growth-promoting and growth-inhibiting functions have been documented4344. This led us to hypothesize that nuclear YAP/WBP2 abundance (and thus YAP/WBP2/TEAD-mediated transcriptional activity) might differ in different subpopulations of NHKs, according to their proliferative potential.…”

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

“…Notably, activation of ILK, which links F-actin to focal adhesions and is required for integrin-mediated force generation, sustains nuclear YAP accumulation in pulmonary arterial vascular smooth muscle cells to promote cell proliferation in pulmonary arterial hypertension, a disease characterized by increased deposition of extracellular matrix and vascular stiffness (Kudryashova et al, 2016). Consistent with this notion, regulation of Hippo activation by ILK (Serrano et al, 2013), Src-FAK (Kim and Gumbiner, 2015; Li et al, 2016), and beta1 integrins (Martin et al, 2016) has been observed in the context of epithelial-mesenchyme transition, cancer, as well as tissue homeostasis in the skin (Elbediwy et al, 2016). Although the physiological relevance of Hippo pathway regulation by integrins and their effectors needs to be confirmed in the context of fibrosis there is accumulating evidence supporting such a role.…”

Tension in Cancer

“…Recently, the transcription factors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) have been suggested as key mediators in integrin-mediated mechano-transduction [37]. The nuclear localization of both factors seems to be regulated by contractile F-actin structures and maybe, by so far unidentified molecular effectors, depending on the cell type [37,38]. However, the detailed mechanisms and signalling hierarchy by which cytoskeletal tension regulates the translocation of YAP/TAZ await further evaluation.…”