title: A VE-cadherin-PAR3-α-catenin complex regulates the Golgi localization and activity of cytosolic phospholipase A(2)α in endothelial cells.
abstract: Phospholipase A(2) enzymes hydrolyze phospholipids to liberate arachidonic acid for the biosynthesis of prostaglandins and leukotrienes. In the vascular endothelium, group IV phospholipase A(2)α (cPLA(2)α) enzyme activity is regulated by reversible association with the Golgi apparatus. Here we provide evidence for a plasma membrane cell adhesion complex that regulates endothelial cell confluence and simultaneously controls cPLA(2)α localization and enzymatic activity. Confluent endothelial cells display pronounced accumulation of vascular endothelial cadherin (VE-cadherin) at cell-cell junctions, and mechanical wounding of the monolayer stimulates VE-cadherin complex disassembly and cPLA(2)α release from the Golgi apparatus. VE-cadherin depletion inhibits both recruitment of cPLA(2)α to the Golgi and formation of tubules by endothelial cells. Perturbing VE-cadherin and increasing the soluble cPLA(2)α fraction also stimulated arachidonic acid and prostaglandin production. Of importance, reverse genetics shows that α-catenin and δ-catenin, but not β-catenin, regulates cPLA(2)α Golgi localization linked to cell confluence. Furthermore, cPLA(2)α Golgi localization also required partitioning defective protein 3 (PAR3) and annexin A1. Disruption of F-actin internalizes VE-cadherin and releases cPLA(2)α from the adhesion complex and Golgi apparatus. Finally, depletion of either PAR3 or α-catenin promotes cPLA(2)α-dependent endothelial tubule formation. Thus a VE-cadherin-PAR3-α-catenin adhesion complex regulates cPLA(2)α recruitment to the Golgi apparatus, with functional consequences for vascular physiology.
authors.affiliation: Endothelial Cell Biology Unit, Institute for Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. a.f.odell@leeds.ac.uk
authors.forename: Adam F
authors.initials: AF
authors.lastname: Odell
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
authors.forename: Sreenivasan
authors.initials: S
authors.lastname: Ponnambalam
authors.forename: John H
authors.initials: JH
authors.lastname: Walker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D006056:Golgi Apparatus / Q000201:enzymology*; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D059386:Reverse Genetics; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015820:Cadherins; D018797:Cell Cycle Proteins; D054513:Group IV Phospholipases A2; D008565:Membrane Proteins; D051178:alpha Catenin; D000099152:Cadherin 5; C509689:PARD3 protein, human