The mechanotransduction machinery at work atadherensjunctions

Abstract

The shaping of a multicellular body, and the maintenance and repair of adult tissues require fine-tuning of cell adhesion responses and the transmission of mechanical load between the cell, its neighbors and the underlying extracellular matrix. A growing field of research is focused on how single cells sense mechanical properties of their micro-environment (extracellular matrix, other cells), and on how mechanotranduction pathways affect cell shape, migration, survival as well as differentiation. Within multicellular assemblies, the mechanical load imposed by the physical properties of the environment is transmitted to neighboring cells. Force imbalance at cell-cell contacts induces essential morphogenetic processes such as cell-cell junction remodeling, cell polarization and migration, cell extrusion and cell intercalation. However, how cells respond and adapt to the mechanical properties of neighboring cells, transmit forces, and transform mechanical signals into chemical signals remain open questions. A defining feature of compact tissues is adhesion between cells at the specialized Adherens Junction (AJ) involving the cadherin super-family of Ca2+-dependent cell-cell adhesion proteins (e.g., E-cadherin in epithelia). Cadherins bind to the cytoplasmic protein β-catenin, which in turn binds to the filamentous (F)-actin binding adaptor protein α-catenin, which can also recruit vinculin, making the mechanical connection between cell-cell adhesion proteins and the contractile actomyosin cytoskeleton. The cadherin-catenin adhesion complex is a key component of the AJ, and contributes to cell assembly stability and dynamic cell movements. It has also emerged as the main route of propagation of forces within epithelial and non-epithelial tissues. Here, we discuss recent molecular studies that point toward force-dependent conformational changes in α-catenin that regulate protein interactions in the cadherin-catenin adhesion complex, and show that α-catenin is the core mechanosensor that allows cells to locally sense, transduce and adapt to environmental mechanical constrain.

RhoA/ROCK Signaling Regulates TGFβ-Induced Epithelial-Mesenchymal Transition of Lens Epithelial Cells through MRTF-A

“…Based on the emerging role of E-cadherin-based adherens junctions as mechanosensors, it is possible that a RhoA/ROCK-mediated increase in cytoskeletal tension is sensed through cadherin-based contacts (64). A compromise in cell-cell adhesion integrity can then lead to dissociation of β-catenin, which is involved in regulating the transcription of EMT-related genes (65). Indeed, novel concurrent work in our lab downstream of RhoA (58).…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…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.…”

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

“…Although the role of cytoskeletal proteins in force transmission and mechanotransduction is quite well established [73,74], there is a paucity of knowledge regarding mechanosensitive gene regulatory networks.…”