Journal of Biological Chemistry
Volume 274, Issue 33, 13 August 1999, Pages 23463-23467
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CELL BIOLOGY AND METABOLISM
Vascular Endothelial Growth Factor Induces Rapid Phosphorylation of Tight Junction Proteins Occludin and Zonula Occluden 1: A POTENTIAL MECHANISM FOR VASCULAR PERMEABILITY IN DIABETIC RETINOPATHY AND TUMORS*

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Vascular endothelial growth factor (VEGF) may have a physiologic role in regulating vessel permeability and contributes to the pathophysiology of diabetic retinopathy as well as tumor development. We set out to ascertain the mechanism by which VEGF regulates paracellular permeability in rats. Intra-ocular injection of VEGF caused a post-translational modification of occludin as determined by a gel shift from 60 to 62 kDa. This event began by 15 min post-injection and was maximal by 45 min. Alkaline phosphatase treatment revealed this modification was caused by a change in occludin phosphorylation. In addition, the quantity of extracted occludin increased 2-fold in the same time frame. The phosphorylation and increased extraction of occludin was recapitulated in retinal endothelial cells in culture after VEGF stimulation. The data presented herein are the first demonstration of a change in the phosphorylation of this transmembrane protein under conditions of increased endothelial permeability. In addition, intra-ocular injection of VEGF also caused tyrosine phosphorylation of ZO-1 as early as 15 min and increased phosphorylation 4-fold after 90 min. In conclusion, VEGF rapidly increases occludin phosphorylation as well as the tyrosine phosphorylation of ZO-1. Phosphorylation of occludin and ZO-1 likely contribute to regulated endothelial paracellular permeability.

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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This research was supported by National Institutes of Health RO1 Grant EY/DK12021 (to T. W. G.), Juvenile Diabetes Foundation Career Development Award 298212 to (D. A. A.), and a Pennsylvania Lions grant (to D. A. A.), as well as by Research to Prevent Blindness and the financial assistance of Mr. and Mrs. Jack Turner of Athens, GA.