The making and breaking of cell-cell junctions

Epithelial cells in an organism are kept together by protein structures called cell-cell junctions. These junctions allow for organized, multicellular structures, such as organs and blood vessels to be formed. Additionally, they provide a barrier between different compartments of the body, such as for example in the tight barrier of the gut, but also the dynamic barriers of microvasculature, where the passing of immune cells requires a delicate control over its transient opening and sealing. Epithelial tumor cells are also held together by cell-cell junctions. Nevertheless, tumor cells can detach from the primary tumor (thus, break their junctions) and form metastases indicating that adhesion control is malfunctioning. To accommodate the dynamic behaviors of tissues and barriers, cell-cell junctions are not static structures, but they are continuously remodeled. Besides responding to chemical signals, cell-cell junctions are also regulated by fluctuating mechanical forces, which occur during tissue remodeling and barrier opening. We have found that Adherens Junctions (AJs) are key during the formation of cell-cell junctions. We define two states of the AJ during this process: the Focal Adherens Junctions, which are punctate structures, connected to radial actin bundles and under tension, and the Linear Adherens Junctions, which are mature linear structures aligned by actin and not under tension. Cell-cell junctions go through these stages both when they are formed and when they are broken. At FAJs, the E-cadherin complex acts as a mechanosensor: junctions are reinforced in response to force. Perturbing this function resulted in malfunctioning of tissue barriers and increased metastatic activity of tumor cells. The molecular explanation for mechanosensing centers around the AJ protein α-catenin, which undergoes a conformational change when it is under tension. This allows the binding of vinculin, which probably stabilizes the open conformation of α-catenin and thereby the recruitment of a number of other proteins that help to reinforce the junction. Thus we have characterized the FAJ as a crucial mechanoresponsive element in the regulation of cell-cell adhesion.