E-cadherin-mediated force transduction signals regulate global cell mechanics

Abstract

This report elucidates an E-cadherin-based force-transduction pathway that triggers changes in cell mechanics through a mechanism requiring epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), and the downstream formation of new integrin adhesions. This mechanism operates in addition to local cytoskeletal remodeling triggered by conformational changes in the E-cadherin-associated protein α-catenin, at sites of mechanical perturbation. Studies using magnetic twisting cytometry (MTC), together with traction force microscopy (TFM) and confocal imaging identified force-activated E-cadherin-specific signals that integrate cadherin force transduction, integrin activation and cell contractility. EGFR is required for the downstream activation of PI3K and myosin-II-dependent cell stiffening. Our findings also demonstrated that α-catenin-dependent cytoskeletal remodeling at perturbed E-cadherin adhesions does not require cell stiffening. These results broaden the repertoire of E-cadherin-based force transduction mechanisms, and define the force-sensitive signaling network underlying the mechano-chemical integration of spatially segregated adhesion receptors.

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

“…The increased contractility in turn both increased traction force generation in single cells [26] and destabilized peripheral cell-cell junctions in endothelial monolayers, resulting in increased intercellular gap formation [21]. Here we investigated how substrate stiffness, which regulates the cell pre-stress—that is, the intrinsic cell contractility [43]—affects the force-activated, VE-cadherin-mediated stiffening of human pulmonary artery endothelial cells (HPAECs).…”

“…VE-cadherin and integrins are both involved in the mechanosensing in cells [46], and they are linked through common signaling pathways that regulate cell contractility and the distribution of tension between intercellular and cell-matrix adhesions [26,47–49]. Recent findings demonstrated that signals activated by force loading E-cadherin in epithelia and PECAM-1 in endothelia trigger the downstream formation of new integrin adhesions in single cells on relatively stiff hydrogels (34 kPa) or on glass [26,49].…”

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.…”

Pancreatic cancer: a mechanobiology approach

“…This setup is mounted on an inverted microscope, which allows the visualisation of the behaviours of cells and the attached beads ( figure 4(a)). A second channel in the microscope can be used to monitor the recruitment of fluorescent proteins after the application of mechanical forces [48][49][50][51].…”

“…See diagram below. Adhesion strength can be tested for cell-cell [49,50], or cell-ECM [47] interactions provided that the bead is coated with the cell adhesion molecule ligand or antibody, or with an ECM molecule, respectively. In this case, high static forces (1-5 nN) are applied, and the percentage of the beads that remained attached, or the time needed for detachment are quantified.…”