Rianne M. Schoon, Tsveta S. van Krimpen-Malinova, Iris de Heer, Arie J. Hoogendijk, Floris P.J. Van Alphen, Annett de Haan, Anne-Marieke D. van Stalborch, Simon Tol, Jaap D. van Buul, Maartje van den Biggelaar, Stephan Huveneers
Blood vessel integrity is maintained by vascular endothelial-cadherin (VE-cadherin)-based adherens junctions, which form structural links between neighboring endothelial cells. In this study, we used mass spectrometry to identify the key proteins that interact with VE-cadherin. The proteomics identified a core group of proteins that bind to VE-cadherin, even when its intracellular domain is not tyrosine phosphorylated. The core VE-cadherin interactome includes known catenin proteins as well as ARVCF, ARHGAP23, KEAP1, and NGLY1. Co-immunoprecipitation and co-localization experiments verified that the VE-cadherin-binding protein ARVCF is a component of endothelial adherens junctions. During junction maturation, ARVCF selectively binds to a pool of VE-cadherin, which is unbound from p120-catenin, through a mechanism involving its C-terminal intrinsically disordered regions. Depletion of ARVCF results in unstable junctions, loss of endothelial barrier function, and impaired collective cell migration. Together, the results of this study demonstrate that ARVCF is an important stabilizer of VE-cadherin junctions to safeguard endothelial integrity.