Nectin-3, a new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities

We have isolated a novel cell-cell adhesion system localized at cadherin-based adherens junctions (AJs), This system consists of at least nectin, a Ca2+ -independent immunoglobulin-like adhesion molecule, and afadin, an actin filament-binding protein, that connects nectin to the actin cytoskeleton, Nectin constitutes a family consisting of two members, nectin-1 and -2, We have isolated here a third member of the nectin family and named it nectin-3, Nectin-3 has three splicing variants, nectin-3 alpha (biggest), -3 beta (middle), and -3 gamma (smallest). Like nectin-1 and -2, nectin-3 alpha consists of three extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic region with the C-terminal consensus motif for binding to the PDZ domain. Nectin-3 alpha formed a cis-homo-dimer and showed Ca2+ -independent trans-homo-interaction to cause hemophilic cell-cell adhesion. Nectin-3 alpha furthermore showed trans-hetero-interaction with nectin-1 or -2 but did not form a cis-hetero-dimer with nectin-1 or -2, Nectin-1 did not show trans-heterointeraction with nectin-2. The affinity of trans-heterointeraction of nectin-3 alpha with nectin-1 or -2 was higher than that of trans homo-interaction of nectin-1, -2, or -3 alpha. Nectin-2 and -3 were ubiquitously expressed, whereas nectin-1 was abundantly expressed in brain. Nectin-3 alpha was colocalized with nectin-2 at cadherin-based AJs and interacted with afadin, These results indicate that the nectin family consists of at least three members, nectin-1, -2, and -3, all of which show hemophilic and heterophilic cell-cell adhesion activities and are localized at cadherin-based AJs.