Cell-cell adhesion-mediated tyrosine phosphorylation of nectin-2 delta, animmunoglobulin-like cell adhesion molecule at adherens junctions

We have recently found a novel functional unit of cell-cell adhesion at cad herin-based adherens junctions, consisting of at least nectin, an immunoglo bulin-like cell adhesion molecule, and afadin, an actin filament-binding pr otein which connects nectin to the actin cytoskeleton. Among the members of the nectin family, we have found here that nectin-2 delta is tyrosine-phos phorylated in response to cell-cell adhesion. Expression of E-cadherin indu ced tyrosine phosphorylation of nectin-2 delta, while disruption of cell-ce ll adhesion by an anti-E-cadherin antibody reduced the tyrosine phosphoryla tion of nectin-2 delta. An inhibitor specific for Src family kinase or expr ession of Csk reduced tyrosine phosphorylation of nectin-2 delta. In additi on, Src kinase tyrosine phosphorylates the recombinant cytoplasmic region o f nectin-2 delta in vitro. The major tyrosine phosphorylation site of necti n-2 delta was Tyr(505) in the cytoplasmic region, because the mutant nectin -2 delta, of which Tyr(505) was replaced by Phe, showed a loss of tyrosine phosphorylation in vivo and in vitro. These results, together with our rece nt observations, indicate that the cadherin-catenin system and the nectin-a fadin system are closely connected to each other. The cadherin-mediated cel l-cell adhesion system may link to the activation of a Src family kinase, t hat is, at least in part, responsible for the tyrosine phosphorylation of t he cytoplasmic region of nectin-2 delta.