The mechanical regulation of integrin-cadherin crosstalk organizes cells, signaling and forces

Abstract

Cadherins and integrins are intrinsically linked through the actin cytoskeleton and share common signaling molecules. Although mechanosensing by the integrin-actin axis has long been appreciated, a growing body of literature now demonstrates that cadherins also transduce and respond to mechanical forces. Mounting evidence shows that mechanically driven crosstalk between integrins and cadherins regulates the spatial distribution of these receptors, their signaling intermediates, the actin cytoskeleton and intracellular forces. This interplay between integrins and cadherins can control fibronectin matrix assembly and signaling, and a fine balance between traction forces at focal adhesions and intercellular tension at adherens junctions is crucial for directional collective cell migration. In this Commentary, we discuss two central ideas: (1) how the dynamic interplay between integrins and cadherins regulates the spatial organization of intracellular signals and the extracellular matrix, and (2) the emerging consensus that intracellular force is a central mechanism that dictates cell behavior, guides tissue development and ultimately drives physiology.

Keywords: Actin cytoskeleton; Adherens junction; Focal adhesion; Mechanotransduction.

Fig. 1.

Integrins and cadherins modulate the mechanical landscape of the cell. Integrin-based focal adhesions (A) and cadherin-dependent adherens junctions (B) relay mechanical signals through a contractile actin–myosin network (C) to actively modulate the mechanical landscape of the cell. Focal adhesions and adherens junctions form the linkages of the cell to the ECM and to neighboring cells, respectively. Integrins and cadherins are linked to the intracellular actin–myosin network and are thus intrinsically linked to each other. Forces are relayed between integrins and cadherins through the tensional changes in the actin–myosin network to shape the mechanical landscape of the cell.

Fig. 2.

Focal adhesions and adherens junctions signal through common molecular components. Focal adhesions and adherens junctions are each comprised of unique constituents (white), but they also share many common signaling components (yellow). For instance, several molecules typically associated with focal adhesions, such as FAK, vinculin, Rac, and DOCK and Elmo proteins, also localize to adherens junctions and regulate cadherin dynamics. Mechanical forces transduced across integrins and cadherins activate many of these signaling molecules. (Proteins are not drawn to scale and not all reported protein interactions are depicted.) pY1065, phosphorylation of Y1065 in vinculin.

Fig. 3.

Cross-regulatory pathways between focal adhesions and cadherins. Reciprocal regulation between focal adhesion proteins and cadherins occurs through different mechanochemical signals and is crucial to establish tensional homeostasis within cells. (A) A mechanosensory complex comprised of VE-cadherin, PECAM1 and VEGFR signals upstream of integrins to activate PI3K and Rac in response to shear flow. Conversely, actomyosin contractility drives integrin-dependent localization of VE-cadherin and p120-catenin to cell–cell junctions. Focal adhesion proteins linking integrins to F-actin are not shown. (B) Activation of the FAK–p130Cas–Rac signaling pathway at focal adhesions in response to substrate stiffness stimulates N-cadherin gene expression. Within adherens junctions, N-cadherin inhibits local PI3K and Rac activity. At adherens junctions, N-cadherin maintains α5 integrins in an inactive conformation to direct fibronectin matrix away from the junction. Focal adhesion proteins linking integrins to F-actin are not shown. (C) The coordinated effects described above in A and B regulate the spatial distribution of forces and signals to drive processes such as cell cycling, stem cell differentiation, fibronectin matrix assembly and collective cell migration.