Document Type

Article

Publication Date

12-17-2012

Publication Title

The Journal of Cell Biology

Department

Geisel School of Medicine

Abstract

Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was caused by PKD1 (protein kinase D1)-mediated phosphorylation of Syx at Ser806, which reduced Syx association to its junctional anchors. In support of the pivotal role of Syx in regulating EC junctions, syx−/− mice had defective junctions, resulting in vascular leakiness, edema, and impaired heart function.

DOI

10.1083/jcb.201207009

Original Citation

Ngok SP, Geyer R, Liu M, Kourtidis A, Agrawal S, Wu C, Seerapu HR, Lewis-Tuffin LJ, Moodie KL, Huveldt D, Marx R, Baraban JM, Storz P, Horowitz A, Anastasiadis PZ. VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx. J Cell Biol. 2012 Dec 24;199(7):1103-15. doi: 10.1083/jcb.201207009. Epub 2012 Dec 17. PMID: 23253477; PMCID: PMC3529520.

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