Cadherin controls nectin recruitment into adherens junctions by remodeling the actin cytoskeleton

Abstract

BSTRACTThe mechanism that coordinates activities of different adhesion receptors is poorly understood. We investigated this mechanism by focusing on the nectin-2 and E-cadherin adherens junction receptors. We found that, cadherin was not required for the basic process of nectin junction formation because nectin-2 formed junctions in cadherin-deficient A431D cells. Formation of nectin-2 junctions in these cells, however, became regulated by cadherin as soon as E-cadherin was re-expressed. E-cadherin recruited nectin-2 into adherens junctions, where both proteins formed distinct but tightly associated clusters. Live-cell imaging showed that the appearance of E-cadherin clusters often preceded that of nectin-2 clusters at sites of junction assembly. Inactivation of E-cadherin clustering by different strategies concomitantly suppressed the formation of nectin clusters. Furthermore, cadherin significantly increased the stability of nectin clusters, thereby making them resistant to the BC-12 antibody, which targets the nectin-2 adhesion interface. By testing different E-cadherin-a-catenin chimeras, we showed that the recruitment of nectin into chimera junctions is mediated by the actin-binding domain of a-catenin. Our data suggests that E-cadherin regulates assembly of nectin junctions through a-catenin-induced remodeling of the actin cytoskeleton around the cadherin clusters.

Integration of Cadherin Adhesion and Cytoskeleton atAdherensJunctions

“…The size of cadherin cluster may increase as cadherin ectodomains organize into a two-dimensional (2D) lattice arrangement (Harrison et al 2011). Increased local concentration of a-catenin through cadherin clustering and multiple a-catenins associating with the same actin filament may promote clustering of the a-catenin actin-binding domains (Chen et al 2015) and actin bundling (Rimm et al 1995), hence further associating multiple cadherin clusters intracellularly through the actin network to form a mature junction. Vinculin has not been considered in this representation, although it plays a major role, because the interface of its interaction with a-catenin is only very poorly resolved at the ultrastructural level and because its open/closed conformational switch at adherens junctions is not yet well established.…”

“…Coupling these clusters with F-actin through an a-catenin actin-binding domain dramatically extends cluster lifetime and alleviates the dependence of their formation on the presence of the cis-binding interface. In ad-dition, the a-catenin actin-binding domain has been shown to cooperatively bind to F-actin (Buckley et al 2014;Hansen et al 2013), form clusters on F-actin (Chen et al 2015) and facilitates actin bundling (Rimm et al 1995). Thus, the cadherin extracellular region produces intercellular adhesion clusters through trans and cis inter-cadherin bonds, although the intracellular region connects these clusters to the cytoskeleton and may promote further clustering through a-catenin (Fig.…”

Cellular recognition and patterning in sensory systems

“…Although both afadin and α-catenin are essential for the associations of nectins and cadherins, the underlying mechanism of how the nectin-afadin system is associated with the cadherincatenin system remains unknown [11,12]. Recent study reported that cadherins control nectin recruitment into AJs through actin clustering [17]. These observations suggest that both actin bundle formation and adhesion complex clustering mutually regulate cell-cell junction formation.…”

Regulation of Intracellular Structural Tension by Talin in the Axon Growth and Regeneration

“…E-cadherin is a transmembrane glycoprotein whose intracellular area can connect to microfilaments, intermediate filament proteins, and actin by catenins [20,21]. After forming a complex, E-cadherin is Banchored^to the cytoskeleton.…”

“…E-cadherin forms the key functional component of adherens junctions (AJs) between cells and is bound via a series of membrane proximal proteins to cytoskeletal actin [20]. AJs that connect cells can resist dissociating forces and transmit forces to adjacent cells, thereby making important contributions to the morphogenesis and homeostasis of tissues [13].…”