Nuclear Phospholipase D1 in Vascular Smooth Muscle

Abstract

See related article, pages 132–139 Activation of phospholipase D (PLD) is a major component of signal transduction cascades activated by G protein–coupled receptor (GPCR) agonists such as lysophosphatidic acid (LPA) and angiotensin II (Ang II), as well as growth factors such as PDGF and EGF that promote proliferation, migration, and inflammation of vascular smooth muscle cells (VSMCs). In mammalian cells, PLD catalyzes the hydrolysis of the principal membrane lipid phosphatidylcholine (PC), resulting in the formation of choline and bioactive lipid phosphatidic acid (PA). PA is subsequently metabolized to diacylglycerol by PA phosphohydrolase or to LPA by phospholipase A2. PLD been implicated in signal transduction, exocytosis and endocytosis, cell proliferation, cytoskeletal reorganization, and gene expression.1–3 There are two mammalian PLD genes, PLD1 and PLD2, and two splice variants of each isoform. PLD1 has a low basal activity and is activated by the small GTP-binding proteins (Rho, Ral, and ADP ribosylation factor [Arf]) and protein kinase C (PKC). In contrast, PLD2 has a high basal activity and its in vitro activity is not or less responsive to PKC, Rho, or Arf.1–3 Both PLD1 and PLD2 are activated by phosphatidylinositol 4,5- bis phosphate (PtdIns(4,5)P2), but PLD1 is inhibited whereas PLD2 is activated by oleic acid in vitro.1,4 PLD1 and PLD2 have been proposed to mediate isoform-specific functions, based on their selective abilities and variable patterns of subcellular localization.2 Numerous studies have used overexpression systems to show that PLD1 localizes to perinuclear vesicles,5–7 plasma membrane,8–10 including caveolin-enriched membrane,11 and that PLD2 localizes to the plasma membrane,5,12–14 and internalizes after agonist stimulation.5,15 In contrast, endogenous PLD2 detected by a specific antibody localizes to the rim of …