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J. Cell Biol. 199 (7): 1103-1115

Copyright © 2012 by the Rockefeller University Press.

Article

VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx

Siu P. Ngok1, Rory Geyer1, Miaoliang Liu2, Antonis Kourtidis1, Sudesh Agrawal3, Chuanshen Wu3, Himabindu Reddy Seerapu3, Laura J. Lewis-Tuffin1, Karen L. Moodie2, Deborah Huveldt1, Ruth Marx4, Jay M. Baraban4, Peter Storz1, Arie Horowitz3,5, , and Panos Z. Anastasiadis1

1 Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224
2 Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756
3 Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH 44195
4 Solomon H. Snyder Department of Neuroscience, John Hopkins University, Baltimore, MD 21205
5 Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106

Correspondence to Panos Z. Anastasiadis: Anastasiadis.Panos{at}mayo.edu; or Arie Horowitz: horowia{at}ccf.org

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.

Abbreviations: AJ, adherens junction • Dia, Diaphanous • EC, endothelial cell • EDPVR, end-diastolic pressure–volume relation • GEF, guanine nucleotide exchange factor • HMVEC, human dermal microvascular EC • HUVEC, human umbilical vein EC • PBM, PDZ-binding motif • ROCK, Rho-associated protein kinase • TJ, tight junction

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