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The findings presented here demonstrate the role of α-catenin in cadherin-based adhesion and mechanotransduction in different mechanical contexts. Bead-twisting measurements in conjunction with imaging, and the use of different cell lines and α-catenin mutants reveal that the acute local mechanical manipulation of cadherin bonds triggers vinculin and actin recruitment to cadherin adhesions in an actin- and α-catenin-dependent manner. The modest effect of α-catenin on the two-dimensional binding affinities of cell surface cadherins further suggests that force-activated adhesion strengthening is due to enhanced cadherin-cytoskeletal interactions rather than to α-catenin-dependent affinity modulation. Complementary investigations of cadherin-based rigidity sensing also suggest that, although α-catenin alters traction force generation, it is not the sole regulator of cell contractility on compliant cadherin-coated substrata.

Cadherins are the principal adhesion proteins at intercellular junctions and function as the biochemical Velcro that binds cells together. Besides this mechanical function, cadherin complexes are also mechanotransducers that sense changes in tension and trigger adaptive reinforcement of intercellular junctions. The assembly and regulation of cadherin adhesions are central to their mechanical functions, and new evidence is presented for a comprehensive model of cadherin adhesion, which is surprisingly more complex than previously appreciated. Recent findings also shed new light on mechanisms that regulate cadherin junction assembly, adhesion, and mechanotransduction. We further describe recent evidence for cadherin-based mechanotransduction, and the rudiments of the molecular mechanism, which involves α-catenin and vinculin as key elements. Potential roles of a broader cast of possible force-sensitive partners are considered, as well as known and speculative biological consequences of adhesion and force transduction at cadherin-mediated junctions.

Endothelial cells lining blood vessels are in tight contact with each other, thereby maintaining vascular integrity. Compromising vascular integrity leads to an increase in vascular permeability, which is associated with chronic inflammation, edema, and tumor angiogenesis. Vascular endothelial (VE)-cadherin is an endothelium-specific cell-cell adhesion molecule involved in endothelial barrier functions. We previously reported that cyclic AMP-elevating agonists such as prostaglandins and adrenomedullin potentiate VE-cadherin-dependent cell adhesion by inducing activation of Rap1 small GTPase through Epac. We further investigated the mechanism whereby Rap1 potentiates VE-cadherin-dependent cell adhesion, and found that Rap1 induces the formation of circumferential actin bundles along the cell-cell junctions. Although it has been believed that α-/β-catenins anchor cadherin to the actin cytoskeleton to stabilize cadherin at cell-cell junctions (classical model), Nelson's and Weis' groups have recently suggested a new dynamic model in which α-/β-catenins do not stably connect actin to cadherin. However, our study clearly indicated that the circumferential actin bundles anchor VE-cadherin to the cell-cell junctions through α-/β-catenins. Thus Rap1 potentiates endothelial cell-cell junctions through the mechanism based on the static model.

alpha-Catenin is essential in cadherin-mediated epithelium development and maintenance of tissues and in cancer progression and metastasis. However, recent studies question the conventional wisdom that alpha-catenin directly bridges the cadherin adhesion complex to the actin cytoskeleton. Therefore, whether alpha-catenin plays a direct role in cadherin-dependent cell adhesion is unknown. Here, single-molecule force spectroscopy measurements in cells depleted of alpha-catenin or expressing the hereditary diffuse gastric cancer associated V832M E-cadherin germ-line missense mutation show that alpha-catenin plays a critical role in cadherin-mediated intercellular recognition and subsequent multibond formation within the first 300 ms of cell contact. At short contact times, alpha-catenin mediates a 30% stronger interaction between apposing E-cadherin molecules than when it cannot bind the E-cadherin-beta-catenin complex. As contact time between cells increases, alpha-catenin is essential for the strengthening of the first intercellular cadherin bond and for the ensuing formation of additional bonds between the cells, all without the intervention of actin. These results suggest that a critical decision to form an adhesion complex between 2 cells occurs within an extremely short time span and at a single-molecule level and identify a previously unappreciated role for alpha-catenin in these processes.