A VE-cadherin–PAR3–α-catenin complex regulates the Golgi localization and activity of cytosolic phospholipase A2α in endothelial cells

Abstract

Phospholipase A2enzymes hydrolyze phospholipids to liberate arachidonic acid for the biosynthesis of prostaglandins and leukotrienes. In the vascular endothelium, group IV phospholipase A2α (cPLA2α) 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 cPLA2α 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 cPLA2α release from the Golgi apparatus. VE-cadherin depletion inhibits both recruitment of cPLA2α to the Golgi and formation of tubules by endothelial cells. Perturbing VE-cadherin and increasing the soluble cPLA2α fraction also stimulated arachidonic acid and prostaglandin production. Of importance, reverse genetics shows that α-catenin and δ-catenin, but not β-catenin, regulates cPLA2α Golgi localization linked to cell confluence. Furthermore, cPLA2α Golgi localization also required partitioning defective protein 3 (PAR3) and annexin A1. Disruption of F-actin internalizes VE-cadherin and releases cPLA2α from the adhesion complex and Golgi apparatus. Finally, depletion of either PAR3 or α-catenin promotes cPLA2α-dependent endothelial tubule formation. Thus a VE-cadherin–PAR3–α-catenin adhesion complex regulates cPLA2α recruitment to the Golgi apparatus, with functional consequences for vascular physiology.