Adherens junctions control fundamental aspects of metazoan development and tissue homeostasis; their dysfunction contributes to disease such as inflammation and cancer; and the field has learnt much about the many downstream molecular mechanisms that are affected by these junctions. Despite this, we still do not know what initiates the assembly of adherens junctions, to determine where and when they will form. What is the signal that cells sense that leads them to decide to assemble a new junction?
Our research answers this long-standing question. We report that cadherins are activated to assemble adherens junctions by the mechanical force of cortical flow. Importantly, the key to understanding how this works comes from conceptualizing the cadherin apparatus as a mechanically-sensitive clutch. We implement a clutch model as a new way to elucidate cadherin operation. Indeed, the model predicted unexpected features of the cadherin apparatus that were essential for junction assembly, which we confirmed experimentally.
Using a combination of specialised tissue culture techniques, high spatiotemporal-resolution microscopy and theoretical modelling, we step-by-step deciphered the pathway that leads to the initiation, expansion and stabilisation of adherens junctions. In short, we show that even before cells contact one another, their cadherins are coupled to the cortical cytoskeleton. So, the adhesion system is primed to be activated upon trans-ligation. E-cadherin trans-ligation couples together the cortical flows of contacting cells to exert tensile force that activates a-catenin within the cadherin-catenin complex. Furthermore, the system exploits a topological feature that is characteristic of contacts that make junctions: the antiparallel, oppositely-directed orientations of cortical flows that are found in these contacts was necessary to generate sufficient force to activate a-catenin. Finally, and surprisingly, “activated” a-catenin triggers junction assembly by a previously unknown mechanism: promoting the cis-clustering of cadherins by bundling cortical actin filaments. We therefore propose that the cadherin adhesion system can be understood as a tension-sensitive clutch, where the decision to assemble adherens junctions is triggered when the forces of antiparallel cortical flows are strong enough to activate a-catenin.