Drebrin: crucial at cell–cell contacts

Cell–cell contacts are essential for the integrity of the vascular endothelium and ensure that the tissue is able to withstand the forces associated with vascular flow. However, the exact molecular events underlying the formation of endothelial cell–cell junctions are still unresolved, although it is known that one of the earliest steps is the recruitment of nectin to adherens junctions. Nectins are transmembrane proteins that form trans-dimers with nectins from adjacent cells and so establish the initial cell–cell connection. It has been proposed that afadin then interacts with and stabilises nectin. On page 3756, Stefan Linder and colleagues now demonstrate that drebrin, which binds to F-actin, has a crucial role in anchoring nectin to the cortical actin cytoskeleton. They show that knockdown of drebrin leads to reduced transendothelial resistance and to a rupture of endothelial monolayers under conditions that mimic vascular flow; this is accompanied by a loss of nectin at junctions and its subsequent degradation. Using different biochemical and imaging approaches, the authors decipher the molecular interactions underlying the stabilisation of nectin: the polyproline region of drebrin binds to the PR1-2 region of afadin, and afadin recruits nectin through its PDZ domain. Therefore, being able to bind to both F-actin and afadin, drebrin facilitates the stabilisation of nectin at the endothelial junction and helps to preserve its integrity under vascular flow.