VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin.
How vascular endothelial growth factor (VEGF) induces vascular permeability, its first described function, remains poorly understood. Here, we provide evidence of a novel signalling pathway by which VEGF stimulation promotes the rapid endocytosis of a key endothelial cell adhesion molecule, VE-cadherin, thereby disrupting the endothelial barrier function. This process is initiated by the activation of the small GTPase Rac by VEGFR-2 through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor. Rac activation, in turn, promotes the p21-activated kinase (PAK)-mediated phosphorylation of a highly conserved motif within the intracellular tail of VE-cadherin. Surprisingly, this results in the recruitment of beta-arrestin2 to serine-phosphorylated VE-cadherin, thereby promoting its internalization into clathrin-coated vesicles and the consequent disassembly of intercellular junctions. Ultimately, this novel biochemical route by which VEGF promotes endothelial permeability through the beta-arrestin2-dependent endocytosis of VE-cadherin may help identify new therapeutic targets for the treatment of many human diseases that are characterized by vascular leakage.
Gavard
Julie
J
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda, MD 20892-4340, USA.
Gutkind
J Silvio
JS
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D019390:Arrestins / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects*; D017124:Conserved Sequence / Q000235:genetics; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D000071557:beta-Arrestins; D054462:p21-Activated Kinases; D000099152:Cadherin 5
D015703:Antigens, CD; D019390:Arrestins; D015820:Cadherins; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D051567:Proto-Oncogene Proteins c-vav; D016392:Proto-Oncogene Proteins pp60(c-src); D034741:RNA, Small Interfering; D012694:Serine; D042461:Vascular Endothelial Growth Factor A; D000071557:beta-Arrestins; D054462:p21-Activated Kinases; D000099152:Cadherin 5; C093651:VAV2 protein, human; C515907:PAK2 protein, human