Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions

Abstract

During normal development and in disease, cohesive tissues undergo rearrangements that require integration of signals from cell adhesions to neighboring cells and to the extracellular matrix (ECM). How a range of cell behaviors is coordinated by these different adhesion complexes is unknown. To analyze epithelial cell motile behavior in response to combinations of cell-ECM and cell-cell adhesion cues, we took a reductionist approach at the single-cell scale by using unique, functionalized micropatterned surfaces comprising alternating stripes of ECM (collagenIV) and adjustable amounts of E-cadherin-Fc (EcadFc). On these surfaces, individual cells spatially segregated integrin-and cadherin-based complexes between collagenIV and EcadFc surfaces, respectively. Cell migration required collagenIV and did not occur on surfaces functionalized with only EcadFc. However, E-cadherin adhesion dampened lamellipodia activity on both collagenIV and EcadFc surfaces and biased the direction of cell migration without affecting the migration rate, all in an EcadFc concentration-dependent manner. Traction force microscopy showed that spatial confinement of integrin-based adhesions to collagenIV stripes induced anisotropic cell traction on collagenIV and migration directional bias. Selective depletion of different pools of αE-catenin, an E-cadherin and actin binding protein, identified a membrane-associated pool required for E-cadherin-mediated adhesion and down-regulation of lamellipodia activity and a cytosolic pool that down-regulated the migration rate in an E-cadherin adhesion-independent manner. These results demonstrate that there is crosstalk between E-cadherin-and integrin-based adhesion complexes and that E-cadherin regulates lamellipodia activity and cell migration directionality, but not cell migration rate.D uring development, cohesive tissues exhibit extensive rearrangements that range from en masse migration, such as in wound healing (1), to complex local cell rearrangements, such as cell intercalation (2). In extreme cases in development (3) and in diseases such as metastatic cancers (4), tissue cohesion is lost and single-cell migration enabled, which results in cells populating distant sites. These morphogenetic processes reveal the importance of a fine coregulation, or crosstalk, between tissue cohesion (cadherin-based cell-cell adhesion) and cell migration [integrinbased extracellular matrix (ECM) adhesion] in the maintenance of tissue integrity and function.Interest in the crosstalk between cell-cell adhesion and cell migration dates back to the pioneering studies of Abercrombie and Heaysman in the 1950s (5, 6) and even earlier (7). Abercrombie coined the term "contact inhibition" to describe how cell-cell interactions between fibroblasts initially inhibited and then redirected their migration. Whether cell-cell contact inhibition of cell migration results from cell-cell contact-dependent spatial redistribution or down-regulation of the cell migration machinery, or both remains unknown.A major component of inte...

Changes in E-cadherin rigidity sensing regulate cell adhesion

“…Substrates immobilized with Ecad-Fc mimic cell-cell interactions, and cellular E-cadherin protein dynamics at the Ecad-Fc interface are similar to those found at endogenous cellcell junctions (27,28). Saturating amounts of Ecad-Fc were bound to substrates to ensure maximum engagement of E-cadherin in adhering cells (23).…”

Collective cell traction force analysis on aligned smooth muscle cell sheet between three-dimensional microwalls

“…Cadherins, major transmembrane proteins at the cell-cell adherent junctions, act as the intercellular bridge between the cytoskeleton of two adjacent cells [19,32]. For instance, E-cadherin, which is essential for collective directional migration [33], is connected to integrin-based focal adhesions [34] and conducts the loading forces exerted by the actomyosin cytoskeleton at the cell-cell adherent junctions in an epithelial cell sheet [35]. Interestingly, collective cells grown under two-dimensional geometrical constraints can form different modes of collective migration under cell-cell interactions [36].…”

‘Biogeneric’ developmental processes: drivers of major transitions in animal evolution

“…In contrast to a non-living liquid's molecules that translocate by randomly directed Brownian motion, cells in liquid tissues translocate by the analogous effect of uncorrelated cytoskeleton-driven fluctuations of their surfaces, which lead (in the absence of tissue gradients) to random locomotion [19]. The cell masses or layers from which body plans and organs develop thus behave formally like liquids [5,20].…”