Integrity of the endothelial monolayer strongly depends on the actin cytoskeleton organisation at adherens junctions that are formed by vascular-endothelial (VE)-cadherin. The actin-network-organising GTPase Rac1 is involved in both junction maintenance and disassembly, but it is unclear how Rac1 is fine-tuned to perform these opposing activities. On page , Jaap van Buul and colleagues describe a new mechanism for regulation of endothelial junction stability, mediated by the GTP exchange factor (GEF) Trio. They found that Trio knockdown (KD) cells have unstable cell–cell junctions that undergo constant remodelling, resulting in lower integrity and increased permeability of the endothelial monolayer. Overexpression of the N-terminal Trio GEF1 domain that can activate Rac1 rescued the junction defects in a Rac1- and VE-cadherin-dependent manner. In addition, in a cell–cell junction disassembly assay, Trio KD interfered with the re-establishment of stable junctions. Furthermore, Trio was shown to interact with VE-cadherin through its spectrin repeats and, together with active Rac1, localised to cell junctions. Importantly, using a new Rac1 sensor, the authors found that homophilic VE-cadherin ligation activated Rac1 in a Trio-dependent manner during nascent cell–cell contacts. Taken together, these results provide new insights into endothelial cell biology by demonstrating that Trio activates Rac1 at endothelial junctions and so helps to stabilise nascent VE-cadherin junctions.
