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

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)alpha (cPLA(2)alpha) 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)alpha 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)alpha release from the Golgi apparatus. VE-cadherin depletion inhibits both recruitment of cPLA(2)alpha to the Golgi and formation of tubules by endothelial cells. Perturbing VE-cadherin and increasing the soluble cPLA(2)alpha fraction also stimulated arachidonic acid and prostaglandin production. Of importance, reverse genetics shows that alpha-catenin and delta-catenin, but not beta-catenin, regulates cPLA(2)alpha Golgi localization linked to cell confluence. Furthermore, cPLA(2)alpha Golgi localization also required partitioning defective protein 3 (PAR3) and annexin A1. Disruption of F-actin internalizes VE-cadherin and releases cPLA(2)alpha from the adhesion complex and Golgi apparatus. Finally, depletion of either PAR3 or alpha-catenin promotes cPLA(2)alpha-dependent endothelial tubule formation. Thus a VE-cadherin-PAR3-alpha-catenin adhesion complex regulates cPLA(2)alpha recruitment to the Golgi apparatus, with functional consequences for vascular physiology.