title: VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx.
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.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA.
authors.forename: Siu P
authors.initials: SP
authors.lastname: Ngok
authors.forename: Rory
authors.initials: R
authors.lastname: Geyer
authors.forename: Miaoliang
authors.initials: M
authors.lastname: Liu
authors.forename: Antonis
authors.initials: A
authors.lastname: Kourtidis
authors.forename: Sudesh
authors.initials: S
authors.lastname: Agrawal
authors.forename: Chuanshen
authors.initials: C
authors.lastname: Wu
authors.forename: Himabindu Reddy
authors.initials: HR
authors.lastname: Seerapu
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Lewis-Tuffin
authors.forename: Karen L
authors.initials: KL
authors.lastname: Moodie
authors.forename: Deborah
authors.initials: D
authors.lastname: Huveldt
authors.forename: Ruth
authors.initials: R
authors.lastname: Marx
authors.forename: Jay M
authors.initials: JM
authors.lastname: Baraban
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
authors.forename: Arie
authors.initials: A
authors.lastname: Horowitz
authors.forename: Panos Z
authors.initials: PZ
authors.lastname: Anastasiadis
mesh_terms: D042683:Angiopoietin-1 / Q000502:physiology*; D000818:Animals; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000378:metabolism; D004285:Dogs; D000080865:Formins; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D013318:Stroke Volume; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; C491750:Mpdz protein, mouse; C511269:Syx protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse