A novel role for the cadherin/catenin complex in cell motility

beta-catenin functions as a component of the adherens junction where it creates a link between cadherins and the actin cytoskeleton through its interactions with alpha-catenin. beta-catenin also plays a role in Wnt signaling and contains a transcriptional activation domain in its C-terminal region. While the proteins that interact with the N-terminal and central regions have been characterized, little is known about the protein-protein interactions involving the C-terminus of beta-catenin. We found that NHERF-2 (Na +/H+ Exchanger Regulatory Factor 2) is a binding partner for the C-terminus of beta-catenin. NHERF-2 and its homolog NHERF-1 contain two N-terminal PSD-95/Dlg/ZO-1 (PDZ) domains. NHERFs are involved in the regulation of proteins at the surface of cell membranes including ion transporters and transmembrane receptors. In this study, we show that the PDZ II domain of NHERF-2 interacts with a PDZ binding motif at the C-terminus of beta-catenin. beta-catenin associates with both NHERF isoforms and this complex is present at the plasma membrane where beta-catenin is bound to cadherins.; N-cadherin expression has been shown to induce motility in multiple cell types. The PDZ I domain of NHERF is known to bind PDGF-Rbeta and lead to enhanced cell motility. We show that beta-catenin and N-cadherin are in a complex with NHERF and PDGF-Rbeta at lamellipodia in the fibrosarcoma cell line HT1080. Also, HT1080 cells with reduced N-cadherin or NHERF expression, expressing a mutant NHERF that is unable to associate with beta-catenin or cells treated with a PDGF-R inhibitor have increased stress fibers and impaired migration. HeLa cells expressing PDGF-Rbeta show PDGF-dependent cell migration is perturbed in cells with reduced N-cadherin or NHERF. When N-cadherin expression was reduced in the endothelial cell line HMEC-1, they were unable to form tubes in vitro and had decreased motility similar to cells treated with a PDGF-R inhibitor. We also demonstrated a PDGF dependent increase in the coimmunoprecipitation of PDGF-Rbeta and beta-catenin. These studies implicate N-cadherin and beta-catenin in cell migration and endothelial cell tube formation via PDGF-R mediated signaling through NHERF scaffolding molecules.