Mechanosensitive systems at the cadherin–F-actin interface

Abstract

SummaryCells integrate biochemical and mechanical information to function within multicellular tissue. Within developing and remodeling tissues, mechanical forces contain instructive information that governs important cellular processes that include stem cell maintenance, differentiation and growth. Although the principles of signal transduction (protein phosphorylation, allosteric regulation of enzymatic activity and binding sites) are the same for biochemical and mechanical-induced signaling, the first step of mechanosensing, in which protein complexes under tension transduce changes in physical force into cellular signaling, is very different, and the molecular mechanisms are only beginning to be elucidated. In this Commentary, we focus on mechanotransduction at cell-cell junctions, aiming to comprehend the molecular mechanisms involved. We describe how different junction structures are associated with the actomyosin cytoskeleton and how this relates to the magnitude and direction of forces at cell-cell junctions. We discuss which cell-cell adhesion receptors have been shown to take part in mechanotransduction. Then we outline the force-induced molecular events that might occur within a key mechanosensitive system at cell-cell junctions; the cadherin-F-actin interface, at which a-catenin and vinculin form a central module. Mechanotransduction at cell-cell junctions emerges as an important signaling mechanism, and we present examples of its potential relevance for tissue development and disease.

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

“…4 Although the cadherin-catenin complex is commonly described as the 'core' VE-cadherin complex, many other proteins can associate, such as scaffolding proteins and cytoskeletal regulators. 3,5 Some of these proteins, including vinculin, [6][7][8][9][10][11] epithelial protein lost in neoplasm (EPLIN) 12,13 a-actinin 14 and afadin, 15,16 have been found to bind to both a-catenin and actin and are therefore suggested to act as a link between the cadherin-catenin complex and actin. However, biochemical studies showed that a minimal cadherin-catenin complex consisting of E-cadherin, b-catenin and aE-catenin can directly bind to filamentous actin (F-actin).…”

“…To discriminate between the distinct junction morphologies, we will refer to these junctions as focal adherens junctions (FAJs). 3,11 Regulation of actin dynamics during endothelial cell-cell junction remodeling Many kinds of dynamic actin-based structures and organizations exist, depending on the proteins that bind to it. 28 Endothelial cells use distinct actin-based structures at different stages during the process of cell-cell junction formation, maintenance and remodeling, as was described in detail by Hoelzle and colleagues.…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…Sensing and transmitting forces depend to a large extent on tight interactions between cell adhesion complexes and the cytoskeleton. Mechanosensing and mechanotransduction can be defined as cellular processes that convert mechanical cues into intracellular signaling (Furuse et al 2002;Huveneers and de Rooij 2013;Janmey et al 2013). These processes are exemplified by epithelia that line organ and body surfaces to provide structural support and serve as barriers against diverse external stressors such as mechanical force, pathogens, toxins, and dehydration.…”

“…Recent data indicate that mechanosensor proteins can undergo force-induced conformational changes that, in turn, induce changes in their activity or affinity for binding partners (Yonemura et al 2010;Huveneers and de Rooij 2013). This can finally lead to the activation of chemical signaling cascades.…”

“…This can finally lead to the activation of chemical signaling cascades. As discussed in Yap (2017), AJs function as mechanosensors (Huveneers and de Rooij 2013;Yao et al 2014;Ladoux et al 2015;Muhamed et al 2016), whereas a role in force sensing has so far not been attributed to desmosomes. At the same time, desmosome-mediated intercellular adhesion is much stronger than AJmediated cohesion as shown by the epithelial sheet assay: Whereas depletion of the desmosomal plaque component plakophilin 1 (PKP1) in keratinocytes disrupts epithelial cohesion on application of mechanical stress, knockdown of the corresponding components from AJs, p120, or p0071/PKP4, has no immediate effect on intercellular cohesion (Fig.…”