Two δ-catenins, plakophilin 4 and p120, promote formation of distinct types of adherens junctions.

Classical cadherins are instrumental for connecting cells into tissues by forming adherens junctions (AJs), a structurally diverse class of cell-cell adhesions tailored to specific membrane domains, cell types, and particular functions. The mechanisms that underlie the AJ diversification remain unknown. Here, we show that two δ-catenin family members, p120 and plakophilin 4 (pkp4), which bind the intracellular region of classical cadherins, promote distinct modes of cadherin clustering, thereby contributing to AJ specialization. The mode promoted by p120 is driven by interactions between cadherin-associated protein, α-catenin, and actin filaments. This "canonical" clustering mechanism generates apical and basal AJs that play a major role in overall cell-cell adhesion. The mode promoted by pkp4 is driven by an α-catenin-independent mechanism. It generates lateral AJs, which apparently function in processes other than cell-cell adhesion. Collectively, our findings show that δ-catenins regulate the balance between different AJ assembly pathways, thereby contributing to AJ diversification.