δ-Catenins couple cadherin adhesions to phospholipid-rich membrane domains

δ-Catenins interact with both classical and desmosomal cadherins and play essential, yet incompletely understood, role in adherens junctions (AJs) and desmosomes. According to the prevailing model, δ-catenins are recruited to these junctions exclusively through direct binding to the cadherin juxtamembrane domain (JMD). Here, we show that plakophilin 4 (Pkp4), one of the AJ-associated δ-catenins, is recruited into AJs through two distinct and independent mechanisms. The first is the conventional pathway based on direct interaction with the cadherin JMD. The second is a previously unrecognized mechanism that targets Pkp4 specifically to lateral AJs, submicron-sized, exceptionally stable junctions located along the mid-lateral region of epithelial cell-cell contacts. This targeting occurs independently of the cadherin JMD but requires an interaction with phospholipid-rich plasma membrane domains. We identify the conserved insert between ARM repeats 5 and 6 as the phospholipid-binding module of Pkp4. Because both membrane-binding determinants within this insert, a palmitoylated cysteine residue and a polybasic motif, are highly conserved throughout the δ-catenin family, our findings suggest that recognition of specialized plasma membrane domains is a general property of δ-catenins. We propose that the interplay between cadherin- and phospholipid-dependent targeting mechanisms enables individual δ-catenins to selectively stabilize distinct cadherin-based cell-cell junctions, thereby contributing to the overall architecture of the cell-cell adhesion system.