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

Authors
  • Ngok, Siu P1
  • Geyer, Rory
  • Liu, Miaoliang
  • Kourtidis, Antonis
  • Agrawal, Sudesh
  • Wu, Chuanshen
  • Seerapu, Himabindu Reddy
  • Lewis-Tuffin, Laura J
  • Moodie, Karen L
  • Huveldt, Deborah
  • Marx, Ruth
  • Baraban, Jay M
  • Storz, Peter
  • Horowitz, Arie
  • Anastasiadis, Panos Z
  • 1 Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA.
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Dec 24, 2012
Volume
199
Issue
7
Pages
1103–1115
Identifiers
DOI: 10.1083/jcb.201207009
PMID: 23253477
Source
Medline
License
Unknown

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 Ser(806), 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.

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