A Mechanoresponsive Cadherin-Keratin Complex Directs Polarized Protrusive Behavior and Collective Cell Migration

Abstract

Summary Collective cell migration requires maintenance of adhesive contacts between adjacent cells, coordination of polarized cell protrusions, and generation of propulsive traction forces. We demonstrate that mechanical force applied locally to C-cadherins on single Xenopus mesendoderm cells is sufficient to induce polarized cell protrusion and persistent migration typical of individual cells within a collectively migrating tissue. Local tension on cadherin adhesions induces reorganization of the keratin intermediate filament network toward these stressed sites. Plakoglobin, a member of the catenin family, is localized to cadherin adhesions under tension and is required for both mechanoresponsive cell behavior and assembly of the keratin cytoskeleton at the rear of these cells. Local tugging forces on cadherins occur in vivo through interactions with neighboring cells, and these forces result in coordinate changes in cell protrusive behavior. Thus, cadherin-dependent force-inducible regulation of cell polarity in single mesendoderm cells represents an emergent property of the intact tissue.

E-cadherin is under constitutive actomyosin-generated tension that is increased at cell–cell contacts upon externally applied stretch

“…Recent studies have reported that cadherins transmit actomyosingenerated forces to the extracellular environment (32,33). External forces applied to cells through cadherins reveal a mechanical coupling between the membrane and the cytoskeleton that requires the cadherin cytoplasmic domain (24) and may cause changes in cellular mechanical properties or protrusive activity (25,26). Conformational changes in α-catenin and/or the recruitment of cytoskeleton-binding proteins to sites of cadherin-mediated adhesion may be involved (17,18,(27)(28)(29).…”

“…It is possible that low levels of αE-catenin and actomyosin activity suffice to exert some tension on E-cadherin after drug treatment and/or protein depletion. In addition, E-cadherin may interact with intermediate filaments through desmosomal linker proteins (22,23,26,53). Intermediate filaments might constitutively exert tension on E-cadherin or compensate for reduced αE-catenin-mediated actomyosin tension following drug treatment or αE-catenin depletion.…”

“…In addition, mechanical stimulation of cells through the extracellular domain of cadherins results in vinculin-dependent cell stiffening (25), and membrane protrusion reorientation via a mechanism involving γ-catenin and intermediate filaments (26). Conversely, actomyosin activity is proposed to induce conformational changes in α-catenin and the recruitment of vinculin to cellcell contacts (27), which provides resistance to cell-cell contact disruption (28,29).…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…In turn, PG/JUP recruits KIF to these junctions to reorganize and reinforce the keratin cytoskeleton. Through this sequence of events, local forces from neighboring cells mediate keratin reorganization required for coordinated cell behavior (Weber et al 2012). …”

Changes in E-cadherin rigidity sensing regulate cell adhesion

“…E-cadherin is under constitutive tension at cell-cell junctions and dynamically responds to changes in tension (23). Cellular responses to exogenous tension applied directly to cadherins using functionalized beads have been studied extensively (22,24,25). However, few studies have investigated how cadherins sense and respond to changes in rigidity of cell-cell interactions.…”