E‐cadherin plays a major role in cell–cell adhesion and inactivating germline mutations in its encoding gene predispose to hereditary diffuse gastric cancer. Evidence indicates that aside from its recognized role in early tumourigenesis, E‐cadherin is also pivotal for tumour progression, including invasion and metastization. Herein, we discuss E‐cadherin alterations found in a cancer context, associated cellular effects and signalling pathways, and we raise new key questions that will impact in the management of GC patients and families.

α-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 α-catenin directly bridges the cadherin adhesion complex to the actin cytoskeleton. Therefore, whether α-catenin plays a direct role in cadherin-dependent cell adhesion is unknown. Here, single-molecule force spectroscopy measurements in cells depleted of α-catenin or expressing the hereditary diffuse gastric cancer associated V832M E-cadherin germ-line missense mutation show that α-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, α-catenin mediates a 30% stronger interaction between apposing E-cadherin molecules than when it cannot bind the E-cadherin–β-catenin complex. As contact time between cells increases, α-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 α-catenin in these processes.