The Epithelial Circumferential Actin Belt Regulates YAP/TAZ through Nucleocytoplasmic Shuttling of Merlin

Abstract

Circumferential actin belts underlying the adherens junctions of columnar epithelial cell monolayers control intercellular surface tension and cell shape to maintain tissue integrity. Yes-associated protein (YAP) and its paralog TAZ are proliferation-activating transcriptional coactivators that shuttle between the nucleus and cytoplasm. Previous studies suggest the importance of stress fibers in the actin cytoskeleton for regulation of YAP nuclear localization; however, the role of the circumferential actin belt on YAP localization remains unclarified. By manipulating actin tension, we demonstrate that circumferential actin belt tension suppresses YAP/TAZ nuclear localization. This suppression requires Merlin, an F-actin binding protein associated with adherens junctions. Merlin physically interacts with YAP/TAZ, and nuclear export sequences of Merlin are required for suppression. Together, with the observation that the association between E-cadherin and Merlin was diminished by tension in circumferential actin belts, our results suggest that released Merlin undergoes nucleocytoplasmic shutting and mediates export of YAP/TAZ from the nucleus.

Mechanical Force-Driven Adherens Junction Remodeling and Epithelial Dynamics

“…In the nucleus, YAP/TAZ associates with several transcription factors, namely the TEAD family, to modulate the expression of genes controlling cell proliferation, cell death, and differentiation (reviewed in Yu et al, 2015). Recent work supports that mechanical forces acting at cell-cell contacts can also modulate the activity and transcriptional output of this mechanosensitive signaling pathway to mediate contact inhibition and regulate tissue tension (Benham-Pyle et al, 2015;Bosveld et al, 2016b;Fletcher et al, 2018;Furukawa et al, 2017;Hirata et al, 2017;Pan et al, 2016;Porazinski et al, 2015;Rauskolb et al, 2014).…”

“…Merlin/NF2, an F-actin-binding protein involved in collective cell migration (Das et al, 2015) ( Figures 4C and 4D), physically interacts with YAP/TAZ, and its nuclear export sequence is required to mediate YAP/TAZ nuclear export. Since E-cadherin-Merlin/ NF2 association at the AJs' actin belt is reduced under tension, it was proposed that Merlin/NF2 release from tense cell-cell contacts suppresses YAP/TAZ nuclear localization by promoting its nuclear export and cytoplasmic accumulation (Furukawa et al, 2017). Similarly, in keratinocytes, inhibiting actomyosin contractility induces YAP nuclear accumulation (Hirata et al, 2017).…”

Cell Adhesion Structures in Epithelial Cells Are Formed in Dynamic and Cooperative Ways

“…In this review, we briefly summarized recent findings on how AJ formation affects cellular architecture and enables TJ formation. In addition to topics that we cover in this review, AJ formation also affects gene expression and several signal transduction pathways, including Wnt signaling and Hippo signaling . It was long assumed that AJ assist the formation of TJ by bringing the plasma membranes of neighboring cells into close proximity, but now we know that the formation of AJ causes many changes required for TJ formation in epithelial cells.…”

The role of Hippo signaling pathway and mechanotransduction in tuning embryoid body formation and differentiation

“…Moreover, in most cases, direct genetic or the pharmacological inhibition of actomyosin contractility decreases YAP activity while increasing actomyosin contractility leads to an increase in YAP activity. However, actomyosin contractility is reported, in some contexts, to inhibit rather than promoting YAP activity possibly because of the role of actomyosin activity in stabilizing cell–cell junctions (Furukawa, Yamashita, Sakurai, & Ohno, 2017; Hirata, Samsonov, & Sokabe, 2017). Hippo signaling can also feedback onto tissue mechanics and F‐actin levels through YAP‐dependent and ‐independent mechanisms.…”