Running with neighbors: coordinating cell migration and cell-cell adhesion

Abstract

Coordinated movement of large groups of cells is required for many biological processes, such as gastrulation and wound healing. During collective cell migration, cell-cell and cell-extracellular matrix (ECM) adhesions must be integrated so that cells maintain strong interactions with neighboring cells and the underlying substratum. Initiation and maintenance of cadherin adhesions at cell-cell junctions and integrin-based cell-ECM adhesions require integration of mechanical cues, dynamic regulation of the actin cytoskeleton, and input from specific signaling cascades, including Rho family GTPases. Here, we summarize recent advances made in understanding the interplay between these pathways at cadherin-based and integrin-based adhesions during collective cell migration and highlight outstanding questions that remain in the field.

Figure 1. Integration of forces at cell-cell and cell-ECM adhesions

In multicellular tissues, mechanical forces are balanced between cell-cell and cell-ECM adhesion, and tension on either structure reinforces the adhesion. At cell-cell junctions, mechanical force strengthens the interaction between the cadherin-catenin complex and the actin cytoskeleton. Similarly, force on cell-ECM adhesions, results in recruitment of actin binding proteins that reinforce association with actin filaments. Some key actin binding proteins, such as vinculin, are critical for force transduction at both adhesive structures, and the subcellular localization of such proteins must be regulated to fine-tune force balance at specific adhesions.

Figure 2. Coordination of cell-cell and cell-ECM adhesions in multicellular groups and collective cell migration

A) In individual migrating cells, GTPases at the leading edge of the lamellipodia drive actin polymerization and the formation of nascent focal contacts. RhoA activity promotes stress fiber formation, contractility and tail retraction. B) During formation of a naïve cell-cell contact, small cadherin adhesions form and begin recruiting regulators of GTPases and actin dynamics. Focal adhesions reorganize as force is transferred to the growing cell-cell adhesion. C) As cadherin adhesions grow in size and strength, we hypothesize that key signaling molecules (such as GAPs and GEFs) and regulators of actin dynamics are titrated to cell-cell adhesions. Cellular forces are balanced between cell-cell and cell-ECM adhesions to reach mechanical homeostasis. D) During collective cell migration of large groups of cells, cadherin adhesions enable local correlations in intercellular forces, and Rho GTPase activity is spatially regulated to facilitate coordinated movement of the monolayer.