Involvement of heterophilic trans‐interaction of Necl‐5/Tage4/PVR/CD155 with nectin‐3 in formation of nectin‐ and cadherin‐based adherens junctions

Nectins, Ca(2+)-independent immunoglobulin (Ig)-like cell-cell adhesion molecules and cadherins, Ca(2+)-dependent cell-cell adhesion molecules, are associated through their respective cytoplasmic tail-binding proteins, afadin and catenins and play roles in formation of adherens junctions (AJs) in epithelial cells and fibroblasts. Nectin-like molecule-5 (Necl-5) is a Ca(2+)-independent Ig-like molecule which does not homophilically trans-interact, but heterophilically trans-interacts with nectin-3, one member of the nectin family. Necl-5 does not directly bind afadin and therefore is not associated with cadherins. Necl-5 regulates cell motility and proliferation in cooperation with integrins and growth factor receptors, when it does not interact with nectin-3. We studied here a role of the heterophilic trans-interaction of Necl-5 with nectin-3 in cell-cell adhesion using L cells stably expressing Necl-5, nectin-3 and E-cadherin (Necl-5-nectin-3-EL cells). Afadin, E-cadherin and catenins were recruited to the nectin-3 side, but not to the Necl-5 side, of the contact sites formed by the heterophilic trans-interaction between Necl-5 and nectin-3. The anti-Necl-5 monoclonal antibody, which specifically inhibited the heterophilic trans-interaction of Necl-5 with nectin-3, inhibited the formation of the E-cadherin-based AJs in Necl-5-nectin-3-EL cells. These results indicate that Necl-5 plays roles not only in cell motility and proliferation but also in cell-cell adhesion in cooperation with nectin-3.