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

Abstract

The YAP/TAZ family of transcriptional co-activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB-Hippo/MST-Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST-LATS or Src family kinase activity to modulate YAP/TAZ activity.

Keywords: Hippo pathway; TAZ; YAP; epithelial polarity; mechanosensing; mechanotransduction; wound healing.

Figure 1

Basal signals promote nuclear YAP localisation. A: In stratified squamous epithelia, YAP/TAZ is nuclear in the basal cell layer which contacts the basal lamina ECM via Integrins. Supra basal cells lose contact with the basal lamina and thus experience reduced Integrin signalling and relocalisation of YAP/TAZ to the cytoplasm. One exception are the extremely flattened terminally differentiated cells, where YAP/TAZ can once again become nuclear, possibly due to mechanical stretching. B: Integrin‐Src‐FAK signalling synergises with EGFR‐PI3K signalling to promote nuclear localisation of YAP. Src can directly tyrosine‐phosphorylate YAP, but may also act indirectly to inhibit Hippo signalling, which inhibits YAP via serine/threonine phosphorylation to promote cytoplasmic retention. PI3K induces PIP3 lipid formation, which may help stabilise Integrin adhesions as well as inducing PDK1 and Akt activation. F‐actin, Rho and ROCK also generate actomyosin contractility to help stabilise Integrin adhesions and thus may contribute to Src activation.

Figure 2

Apical signals inhibit nuclear YAP localisation. A: In columnar epithelia, YAP/TAZ is cytoplasmic in differentiated cells with an apical domain and nuclear in basal layer stem cells which lack an apical domain and contact the basal lamina ECM via Integrins. B: Crumbs‐Merlin‐Kibra‐Salvador‐MST‐LATS signalling (the canonical Hippo pathway) leads to phosphorylation of YAP/TAZ and retention in the cytoplasm (due to binding to 14‐3‐3 proteins) despite contact with the ECM. Thus, strong apical Hippo signalling is able to overcome basal Integrin signalling to maintain YAP/TAZ in the cytoplasm.

Figure 3

Regulation of YAP by Crumbs and Cadherin signalling. A: Crumbs and E‐cadherin distribute around the entire circumference of the epithelial cell's apical surface. In contrast, Fat and Dachsous cadherins planar polarise to opposite ends of the cell. B: Crumbs signals via canonical Merlin‐Ex‐Kibra‐Sav‐Hpo‐Warts/LATS signalling to inhibit YAP by direct ser/thr phosphorylation and cytoplasmic retention. E‐cadherin recruits Ajuba/Zyxin proteins, which may directly inhibit Warts/LATS kinases and Src family kinases, which tyrosine phosphorylate and activate YAP. Dachsous recruits the Dachs myosin, which increases junctional tension, as well as Riq and Mib, which may directly inhibit Warts/LATS kinases.

Figure 4

Models of mechano‐sensing that may control YAP localisation. A: Columnar epithelial cells exhibit cytoplasmic YAP at high density, but nuclear YAP at low density (which induces spreading out of cells). B: Model for inhibition of apical Crumbs‐Hippo signalling upon cellular stretching (due to de‐clustering of Crumbs complexes). C: Model for activation of Src at adherens junctions upon cellular stretching (due to induction of actomyosin contractility to resist stretching, clustering of adherens junctions, and recruitment of Ajuba/Zyxin family proteins as well as alpha‐actinin and Vinculin). D: Model for activation of basal Integrin‐Src signalling upon cellular stretching (due to formation of focal adhesions which cluster Integrins and recruit Ajuba/Zyxin, alpha‐actinin and Vinculin).