Ngok et al. describe how two growth factors control the localization of a guanine nucleotide exchange factor (GEF) to exert opposing effects on vascular permeability.
Vascular endothelial growth factor (VEGF) increases blood vessel leakiness by disrupting the junctions between endothelial cells, whereas Angiopoietin-1 (Ang1) stabilizes intercellular adhesions to decrease vascular permeability. Intercellular junctions are regulated by Rho family GTPases and by polarity proteins like the Crumbs complex. Ngok et al. discovered that a GEF called Syx localizes to endothelial cell junctions by binding to the Crumbs complex member Mupp1. Syx stabilized intercellular adhesions by locally activating RhoA and its downstream effector, the formin Dia.
VEGF disrupted endothelial cell contacts by displacing Syx from intercellular junctions. The growth factor inhibited Syx’s association with Mupp1 by stimulating its phosphorylation by protein kinase D1 (PKD1). A non-phosphorylatable Syx mutant remained bound to Mupp1 at cell junctions and prevented VEGF from destabilizing cell–cell contacts. Ang1 also prevented VEGF from displacing Syx and disrupting intercellular adhesions, but Ang1 was unable to stabilize junctions in the absence of Syx.
Mice lacking Syx had leaky blood vessels, resulting in edemas and reduced heart function. Increased vascular permeability is associated with many human diseases, including strokes and tumor metastasis. The authors now want to investigate whether promoting Syx’s localization to endothelial cell junctions, by inhibiting PKD1 for example, could be used to prevent vascular leakiness.
Text by Ben Short